Sulfite-Induced N-Alkylation and Thioketonization of Azoles Enable Access to Diverse Azole Thiones

Article abstract of DOI:10.1002/adsc.201801166

The direct modification of azole skeletons enables access to drug-like molecules. The development of a highly compatible reaction platform for this pursuit still remains challenging. Herein, we report the use of sulfite as the single electron transfer (SET) reducing agent for the activation of functionalized bromoalkanes, elemental sulfur, and imidazoliniums for the transition metal-free and base-free N-alkylation and thioketonization of azoles. Excellent functional group tolerance and high synthetic efficiency proved particularly advantageous for the rapid assembly of a large array of pharmaceutically-oriented azole thiones, many of which contain synthetically and biologically useful functional groups. The direct transformation of drug molecules (such as Ketoconazole, Econazole, and Fluconazole) into their corresponding azole thiones has also been successfully achieved. Reactions with selenium also proceeded smoothly under the optimized conditions. Successful gram-scale reactions demonstrate the good applicability of this methodology. (Figure presented.).

Full text of DOI:10.1002/adsc.201801166

Title: Sulfite-Induced N-Alkylation and Thioketonization of Azoles
Enable Access to Diverse Azole Thiones
Authors: Jian-Chao Deng, Jia-Hao Chen, Jun-Rong Zhang, Ting-Ting
Lu, and Ri-Yuan Tang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801166
Link to VoR: http://dx.doi.org/10.1002/adsc.201801166

10.1002/adsc.201801166
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Sulfite-Induced N-Alkylation and Thioketonization of Azoles
Enable Access to Diverse Azole Thiones
Jian-Chao Deng,a Jia-Hao Chen,a Jun-Rong Zhang,a Ting-Ting Lu,a and Ri-Yuan
Tang*abc
a
Department of Applied Chemistry, College of Materials and Energy, South China Agricultural University, Guangzhou
510642, China
E-mail: rytang@scau.edu.cn
b
Key Laboratory of Natural Pesticide & Chemical Biology, Ministry of Education, South China Agricultural University,
Guangzhou 510642, China.
Key Lab of Functional Molecular Engineering of Guangdong Province, Guangzhou, 510642, P. R. China.
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The direct modification of azole skeletons enables
access to drug-like molecules. The development of a highly
compatible reaction platform for this pursuit still remains
challenging. Herein, we report the use of sulfite as the single
electron transfer (SET) reducing agent for the activation of
functionalized bromoalkanes, elemental sulfur, and
imidazoliniums for the transition metal-free and base-free N-
alkylation and thioketonization of azoles. Excellent
functional group tolerance and high synthetic efficiency
proved particularly advantageous for the rapid assembly of a
large array of pharmaceutically-oriented azole thiones, many
of which contain synthetically and biologically useful
functional groups. The direct transformation of drug
molecules (such as Ketoconazole, Econazole, and
Fluconazole) into their corresponding azole thiones has also
been successfully achieved. Reactions with selenium also
proceeded smoothly under the optimized conditions.
Successful gram-scale reactions demonstrate the good
applicability of this methodology.
Keywords: azoles; sulfite; single electron transfer; nitrogen
heterocycles; sulfur
compounds,[5] as well as be able as fluorescence
probes for the efficient imaging of hypochlorite in
cells and tissue.[6] In addition to these highly valuable
Introduction
From an industrial perspective,
a
practicable functionalities,
the
metal
complexes
of
methodology possesses a good level of tolerance to a imidazothiones have shown excellent photothermal
diverse array of functional groups and nitrogen- and photoswitchable properties.[7, 8]
containing heterocycles found in biologically active The versatility of azole thiones has received
molecules.[1] The development of versatile reaction considerable attention from the synthetic community.
platforms for the diverse modification of privileged In 1889, Marckwald reported the first synthesis of 1-
scaffolds enables access to a vast set of biologically substituted imidazole-2-thiones via the reaction of
useful molecules. Azoles, including benzimidazoles, isothiocyanates with an amino acetal.[10] Since this
imidazoles, and triazoles, are a robust class of initial discovery, significant effort has been devoted
privileged scaffolds for drug discovery.[2] Azole drugs to the synthesis of such compounds. The cyclization
(such as Ganciclovir, Ketoconazole, Econazole, of linear thioureas or isothiocyanates is an effective
Miconazole, and Fluconazole etc.) exhibit a large pathway for the preparation of imidazole thiones.[11]
range of biological activities and have important However, the starting materials, particularly those
clinical applications (Scheme 1A).[2b,c] The possessing rich functional groups, are not easily
transformation of these azoles into their accessible, which has limited the use of this strategy.
corresponding azole thiones allows for the preparation The reaction of a 1,3-disubstituted alkylimidazolium
of a diverse array of new functional molecules that with elemental sulfur offers an alternative pathway
can be applied in medicine,[3-5] material science[6-8] towards the synthesis of imidazole thiones.[12]
and synthetic chemistry (Scheme 1B).[9] For example, However, this methodology possesses several
Thibenzazoline and Carbimazole serve as antithyroid disadvantages, there being: The need for a strong base;
drugs,[3] and the pesticide Prothioconazole is a broad a non-trivial post-treatment of imidazolium and
spectrum antimicrobial used in the agriculture narrow substrate scope, with the inert alkyl groups
industry.[4] Imidazole thiones can also be applied to being tolerated under the reaction conditions. These
the chemical detoxification of organomercury methods are insufficient for the preparation of
1
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10.1002/adsc.201801166
Advanced Synthesis & Catalysis
pharmaceutically useful azole thiones. A large in the absence of sulfite, suggesting that sulfite is
number of halo alkanes possessing rich functionalities essential for this transformation (entry 6). The
are commercially available for the purpose of reaction efficiency may be affected by the reducibility
diversity-oriented synthesis. For the preparation of of sulfites. In terms of the valence of sulfur, Na2S2O4
drug molecules, the metal generation of metal and Na2S2O3 may have stronger reducibility than
pollutants still remains a challenge that must be Na2SO3 and HOCH2SO2Na, which could account for
overcome. Thus, the development of a direct and their higher reaction efficiency. Although the sulfur in
diverse alkylation and thioketonization strategy of NaHSO3 is +4 valence, the acidity of NaHSO3 may
azoles towards drug-like azole thiones under metal- enhance the reducibility, leading to a high yield (entry
free and neutral conditions is highly desired (Scheme 2).
1C). It has been reported that inorganic sulfite is an
Table 1. Screening of optimal conditions [a]
.
effective agent for dehalogenation in the addition
reaction of perfluoroalkyl iodides to activated
alkenes.[13] The sulfonate-promoted dehalogenation
function of sulfite was first reported by Huang and his
co-workers in 1981.[13b] We envisioned that sulfite
could serve as a SET reducing agent for the N-
alkylation of azoles with common halo alkanes; for
the activation of S-S bonds in S8; and for the in situ
formation of imidazole carbenes for thioketonization.
Based on these assumptions, we applied sulfites to the
transformation of azoles into azole-thiones. Herein,
we disclose a new sulfite-induced diverse N-
alkylation and thioketonization of azoles toward azole
thiones via a SET process (Scheme 1C).
Entry
1
Sulfite
Na2S2O4
Yield (%)
92
91
92
75
58
26
NaHSO3
Na2S2O3
Na2SO3
2
3
4
5
6
HOCH2SO2Na
―
[a]
Reaction conditions: N-methylbenzimidazole 1a (0.4
mmol), S (0.8 mmol, 2 equiv), 2a (1 mmol, 2.5 equiv),
sulfite (0.8 mmol, 2 equiv) in DCE (2 mL) at 80 oC,
reaction for 24h.
We next focused on the reaction scope of the
substituted benzimidazole substrates (table 2). A
variety of important functional groups, such as
methoxy, amino, halogens (Br, Cl, and F), ester, and
nitro groups were well tolerated, affording their
corresponding products 3-15 in good to high yields.
Interestingly, a substrate bearing a free amino group
still selectively underwent N-alkylation to afford
product 6 in 78% yield. The scope of N-substituents
on the benzimidazoles was also investigated.
Numerous functional groups, including butyl,
terminal alkenes, alkynes, cyano, tetrahydrofunan,
acetal, ether, acetoxy, ester, benzyl, and
Scheme 1. Azole and azole thiones drugs.
Results and Discussion
pentafluorobenzyl,
all
exhibited
excellent
Our study began with the reaction of N-
methylbenzimidazole 1a and ethyl 2-bromo-2-
fluoroacetate 2a in the presence of elemental sulfur.
Ethyl 2-bromo-2-fluoroacetate, which bears a fluorine
atom and an ester group,[14] is of great interest
because incorporation of this structural motif into the
azole ring system enables access to a class of
interesting amino acid derivatives. After extensive
screening (for detailed information, see the ESI),
Na2S2O4 was found to be effective for the tandem
alkylation and thioketonization of benzimidazole 1a
in DCE at 80 oC over 24 h, affording
benzimidazothione 3 in 92% yield (table 1, entry 1).
Carrying out the reaction with NaHSO3 or Na2S2O3
gave an almost comparable yield to that of Na2S2O4
(entries 2 and 3); whereas Na2SO3 and HOCH2SO2Na
gave the desired product in only moderate yields
(entries 4 and 5). Product 3 was obtained in only 26%
compatibility with the reaction conditions, providing
their corresponding products in high yields (products
16-28). All of these functional groups are
synthetically and biologically useful (table 2A). To
our satisfaction, the pharmaceutically privileged
scaffolds,
imidazo[4,5-b]pyridine,
imidazo[4,5-
c]quinolone, and purine derivatives, are suitable for
this chemical transformation giving the corresponding
products in moderate yields (products 29-31). Such
compounds are undoubtedly very promising for the
use in medicinal chemistry (table 2A).
Subsequently, we investigated the reaction scope of
the imidazoles (table 2B). N-substituents, including
methyl, ester, and amide groups, were compatible
with the reaction conditions, affording their
corresponding products 32-34 in moderate to high
yields.
2
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10.1002/adsc.201801166
Advanced Synthesis & Catalysis
Table 2 The reaction scope of azoles and bromo alkanes[a].
could also be used as suitable substrates to give
products 38 and 39 in moderate yields. The broad-
spectrum antifungal agent, Fluconazole, was also
tolerated under the reaction conditions, giving product
40 in 48% yield; the presence of an active hydroxyl
group may hinder the reaction.
A number of other bromoalkanes were also subjected
to the reaction conditions (table 2C). A diverse array
of functional groups, including terminal alkene,
alkyne, cyano, benzyls, acetoxy, esters, and multiple-
substituted fluoro alkenes, were well tolerated to
afford the corresponding products in moderate to high
yields (products 41-48). The versatility of these
functional groups is of great interest in medicinal
chemistry and organic synthesis. However, both
benzo[d]oxazole and benzo[d]thiazole are not suitable
substrates for such transformation.
Gram-scale reactions were conducted with 10 mmol
of starting materials. Three examples (products 3, 27
and 39) are shown in Scheme 2A. Both N-
methylbenzimidazole and N-benzylbenzimidazole
underwent reaction smoothly to give 2.04 g and 2.58
g of the corresponding products 3 and 27, respectively.
To our delight, Econazole was also tolerated at 100 oC
giving the desired product 39 in 59% yield (3.93 g).
Scheme 2. Gram-scale reactions.
We speculated that replacement of sulfur with
selenium may be feasible. N-Methylbenzoimidazole,
Econazole, and N-methyltriazole were subjected to
the reaction conditions in the presence of selenium
and ethyl 2-bromo-2-fluoroacetate (Scheme 3). The
results show that selenium was effective for these
substrates, affording the corresponding products 49-
51 in moderate yields.
[a] Reaction conditions: azole 1 (0.4 mmol), S (0.8 mmol, 2
equiv), bromo alkane 2 (1 mmol, 2.5 equiv), Na2S2O4 (0.8
o
mmol, 2 equiv) in DCE (2 mL) at 80 C (100 oC, 110 oC or
120 oC), reaction for 24h.
Scheme 3. Synthesis of azole selenones.
An N-aryl substituted imidazole bearing a fluorine
atom and an acetyl group was also amenable to the
reaction conditions, giving product 35 in 72% yield.
4-Phenyl substituted imidazole also gave its
corresponding product 36 in 81% yield. N-methyl
triazole also underwent reaction smoothly to afford
the product 37 in 79% yield. Significantly, well-
known drugs, such as Ketoconazole and Econazole,
In order to demonstrate the versatility of the azole
thione products, the hydrolysis of compound 3 was
carried out (scheme 4). The imidazothione-containing
amino acid derivative 52 was obtained in 96% yield.
In the presence of EDCl (N-(3-dimethylaminopropyl)-
N'-ethylcarbodiimide hydrochloride) and DMAP (4-
3
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10.1002/adsc.201801166
Advanced Synthesis & Catalysis
Dimethylaminopyridine), compound 52 successfully 5, eqn 5). The addition of a radical-trapping agent
underwent condensation with 2-aminothiazole to such as TEMPO (2,2,6,6-tetramethylpiperidin-1-
provide the corresponding amide 53 in 85% yield oxide) or BHT (2,6-di-tert-butyl-4-methylphenol)
(Scheme 4).
would suppress the reaction, affording product 3 in
62% and 65% yields, respectively, suggesting that the
reaction may involve certain radical species (Scheme
5, eqn 6). In order to prove that Na2S2O4 did not serve
as a base but only a reducing agent, the pH value of
Na2S2O4 in water or DCE was measured, respectively
(for detailed information, see the ESI). The results
demonstrated that Na2S2O4 is an acidic substance (pH
= 3.19 in aqueous solution; pH = 2.37 in DCE
solution).
Scheme 4. Modification of a benzimidazole thione.
To gain a better understanding of the reaction
mechanism, control experiments were carried out
(Scheme 5). The results show that Na2S2O4 is
essential for the highly efficient chemical
transformation (Scheme 5, eqns 1 and 2). The reaction
of benzimidazole with elemental sulfur did not occur,
suggesting that the N-alkylation occurred prior to
thioketonization (Scheme 5, eqn 3). In this reaction, a
1,2,3,4-tetrathiane was observed in the presence of
Na2S2O4, suggesting that the S-S bond in S8 is
activated by Na2S2O4 to produce certain active species
for the thioketonization (Figure S1, see the ESI).
Na2S2O4 accelerated the thioketonization of 3-allyl-1-
methyl-1H-benzo[d]imidazol-3-ium bromide in the
presence of elemental sulfur, giving product 41 in
80% yield, whereas the desired product was obtained
in only 16% yield in the absence of Na2S2O4 (Scheme
5, eqn 4).
On the basis of the results of the control experiments,
plausible reaction mechanisms are depicted in scheme
∙−
6. First, Na2S2O4 releases SO2 (species A), which
react with 2a to produce an intermediate C.[13]
Elemental sulfur may also be activated by species A
to afford an intermediate B. The N-alkylation reaction
may proceed via one or two pathways: direct
nucleophilic substitution of 1a with 2a to afford a
benzimidazolium D; or a radical addition of 1a with
intermediate C to afford an intermediate E.[15] The
sulfur anion in B may play as a base to remove the
hydrogen atom of intermediate D to generate a
carbene F,[16] which undergoes a thioketonization
with sulfur to produce product 3. Intermediate E may
also couple with the sulfur species B to form an
intermediate G. The sulfur anion in G may be basic
enough to facilitate the removal of the hydrogen atom
on the imidazole ring, leading to the formation of
product 3.
Scheme 6. Plausible reaction mechanisms.
Conclusion
In summary, sulfite was found to be effective for the
N-alkylation and thioketonization of azoles. Our work
represents to our knowledge the first example of the
sulfite-induced base-free transformation of azoles into
their corresponding azole thiones or azole selenones
via a SET reductive process. A variety of
benzimidazoles, imidazoles, and triazoles performed
well to afford a vast set of new azole thiones in good
to high yields. Numerous synthetically and
biologically useful functional groups were all well
tolerated. Important privileged scaffolds, such as
imidazo[4,5-b]pyridine, imidazo[4,5-c]quinolone, and
Scheme 5. Control experiments.
The addition of electron-trapping agents, such as
Mn(OAc)2, Co(OAc)2, DDQ (4,5-dichloro-3,6-
dioxocyclohexa-1,4-diene-1,2-dicarbonitrile), AgNO3,
and 1,4-dinitrobenzene, remarkably inhibited the
reaction. These results suggest that sulfite serves as a
SET reducing agent for the thioketonization (Scheme
4
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10.1002/adsc.201801166
Advanced Synthesis & Catalysis
The released SO2 was introduced into aqueous NaOH by
air flow. The crude reaction mixture was then diluted with
EtOAc (5 ml) and filtered through a short pad of Celite.
The sealed tube and Celite pad were washed with an
additional 20 ml of EtOAc. The filtrate was concentrated in
vacuo, and the resulting residue was purified by flash
column chromatography using hexanes and EtOAc as the
eluent (CAUTION! All operations should be carried out in
a fume hood to avoid inhalation of SO2, which can be
generated during these reactions).
purine derivatives have also been successfully
modified.
Importantly,
Ketoconazole-thione,
Econazole-thione, and Fluconazole-thione have all
been successfully prepared using this methodology.
We believe that all of these synthesized azole thiones
are of great interest to the medicinal and agricultural
community. This practicable reaction methodology is
high yielding, scalable, and uses inexpensive reagents
such as sulfite and stable, odorless, and non-toxic
elemental sulfur.[17,18] Further studies concerning the
mechanism and utility of this reaction are underway
in our laboratory.
General experimental procedure for the gram-scale
reactions: A 150-ml sealed tube (with a Teflon cap)
equipped with a magnetic stir bar was charged with azole
(10.0 mmol), Na2S2O4 (20.0 mmol, 2 equiv) and S (20.0
mmol, 2.0 equiv.). DCE (15.0 ml) was added to the mixture,
followed by bromoalkane (25.0 mmol, 2.5 equiv) and,
finally, another portion of DCE (15.0 ml). The tube was
then capped and submerged into an oil bath pre-heated to
Experimental Section
o
80 C. The reaction was stirred for 24 hours and cooled to
room temperature. The branch of reaction tube was
connected to an absorption device of sulfur dioxide. The
released SO2 was introduced into aqueous NaOH by air
flow. The crude reaction mixture was diluted with EtOAc
(30.0 ml) and filtered through a short pad of Celite. The
sealed tube and Celite pad were washed with an additional
20 ml of EtOAc. The filtrate was concentrated in vacuo,
and the resulting residue was purified by flash column
chromatography using hexanes and EtOAc as the eluent
(CAUTION! All operations should be carried out in a fume
hood to avoid inhalation of SO2, which can be generated
during these reactions).
General remarks
1H and 13C NMR spectra were measured on a Bruker
Avance-Ⅲ 600 instrument (600MHz for H, 151 MHz for
1
13C NMR spectroscopy) using CDCl3 or DMSO-d6 as the
solvent. Chemical shifts for 1H and 13C NMR were referred
to internal Me4Si (0 ppm) as the standard. The following
abbreviations (or combinations thereof) were used to
explain chemical shift (δ ppm), multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), integration,
and coupling constants (J) in hertz (Hz). IR spectra were
measured on a Nicolet IS10. Mass spectra were measured
on an Agilent GC-MS-5975C Plus spectrometer (EI).
LCMS (ESI) analysis was measured on an AB Sciex
API3200. HRMS (ESI) analysis was measured on a
Thermo Scientific LTQ Orbitrap XL.
Ethyl
2-fluoro-2-(3-methyl-2-thioxo-2,3-dihydro-1H-
benzo[d]imidazol-1-yl)acetate (3). Light yellow solid. Mp.
1
82.4 – 84.0 C. 92% yield (98.7 mg). H NMR (600 MHz,
CDCl3) δ 7.55 (d, J = 45.5 Hz, 1H), 7.33 – 7.28 (m, 1H),
7.28 – 7.23 (m, 2H), 7.23 – 7.20 (m, 1H), 4.37 – 4.28 (m,
2H), 3.82 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (151
MHz, CDCl3) δ 171.7, 164.6 (d, JC-F = 34.7 Hz, 1C), 132.6,
129.3 (d, JC-F = 2.1 Hz, 1C), 124.3, 123.9, 110.3, 109.3,
87.8 (d, JC-F = 212.9 Hz, 1C), 63.2, 31.7, 14.0. IR (KBr,
cm-1): 2943, 1765, 1488, 1444, 1387, 1333, 1292, 1217,
1178, 1051, 751. LRMS (EI, 70 eV) m/z (%): 268 (94), 196
(100), 175 (23), 163 (15). HRMS (ESI) for C12H14FN2O2S+
(M+H)+: calcd 269.0755, found 269.0759.
General procedure for the synthesis of 1-((1,3-dioxolan-
2-yl)methyl)-1H-benzo[d]imidazole:
To an oven-dried 100 mL round flask, equipped with a
magnetic stirrer was charged with benzimidazole (5.0
mmol, 0.59 g), 2-bromomethyl-1,3-dioxolane (6.0 mmol,
0.63 mL) and K2CO3 (10.0 mmol,1.38 g). The reaction
mixture was stirred at 80 °C under reflux conditions in
acetonitrile for 8 hours. After the reaction finished, the
reaction mixture was cooled down to room temperature.
Acetonitrile was removed under vacuo, and the residue was
dissolved in dichloromethane and filtered to remove
inorganic salts. The filtrate was concentrated in vacuo, and
the resulting residue was purified by flash column
chromatography using petroleum and EtOAc as the eluent.
1-((1,3-dioxolan-2-yl)methyl)-1H-benzo[d]imidazole:
Yellow oil. 87% yield (0.89 g). 1H NMR (600 MHz,
CDCl3) δ 7.87 (s, 1H), 7.78 – 7.70 (m, 1H), 7.45 – 7.38 (m,
1H), 7.25 – 7.19 (m, 2H), 5.15 (t, J = 2.9 Hz, 1H), 4.23 (d,
J = 2.9 Hz, 2H), 3.74 – 3.66 (m, 2H), 3.60 – 3.52 (m, 2H).
13C NMR (151 MHz, CDCl3) δ 144.1, 143.3, 134.5, 122.9,
122.0, 120.0, 110.2, 101.5, 65.4, 47.2. IR (KBr, cm-1): 2947,
2887, 1611, 1495, 1457, 1383, 1263, 1198, 1146, 1040,
1003, 747. LRMS (EI, 70 eV) m/z (%): 204 (80), 131 (56),
104 (10), 73 (100). HRMS (ESI) for C11H13N2O2+ (M+H)+:
calcd 205.0972, found 205.0971.
Ethyl 2-fluoro-2-(3,5,6-trimethyl-2-thioxo-2,3-dihydro-
1H-benzo[d]imidazol-1-yl)acetate (4). White solid. Mp.
1
158.3 – 159.3 C. 92% yield (109.1mg). H NMR (600
MHz, CDCl3) δ 7.53 (d, J = 45.7 Hz, 1H), 7.01 (d, J = 34.0
Hz, 2H), 4.38 – 4.28 (m, 2H), 3.77 (s, 3H), 2.34 (s, 3H),
2.31 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz,
CDCl3) δ 170.8, 164.7 (d, JC-F = 34.7 Hz, 1C), 133.2, 132.8,
130.9, 127.5 (d, JC-F = 1.5 Hz, 1C), 110.9, 110.1, 87.8 (d,
JC-F = 212.9 Hz, 1C), 63.1, 31.6, 20.2, 20.1, 14.0. IR (KBr,
cm-1): 2980, 2943, 2919, 2845, 1764, 1467, 1392, 1318,
1225, 1049, 1007, 743. LRMS (EI, 70 eV) m/z (%): 296
(100), 224 (99), 223 (60), 208 (15), 203 (20), 191 (27).
HRMS (ESI) for C14H18FN2O2S+ (M+H)+: calcd 297.1068,
found 297.1071.
Ethyl
2-fluoro-2-(6-methoxy-3-methyl-2-thioxo-2,3-
dihydro-1H-benzo[d]imidazol-1-yl)acetate (5). White
1
solid. Mp. 140.1 – 140.7 C. 89% yield (106.2 mg). H
NMR (600 MHz, CDCl3) δ 7.54 (d, J = 45.5 Hz, 1H), 7.07
(d, J = 8.7 Hz, 1H), 6.86 (dd, J = 8.7, 2.2 Hz, 1H), 6.81 (d,
J = 2.1 Hz, 1H), 4.39 – 4.24 (m, 2H), 3.80 (s, 3H), 3.76 (s,
3H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3)
δ 171.0, 164.6 (d, JC-F = 34.7 Hz, 1C), 157.3, 130.0 (d, JC-F
General experimental procedure for the synthesis of
azole-thiones or azole-selenones: A 15-ml sealed tube
(with a Teflon cap) equipped with a magnetic stir bar was
charged with azole (0.40 mmol), Na2S2O4 (0.80 mmol, 2
equiv) and S (0.80 mmol, 2.0 equiv.). DCE (1.0 ml) was
added to the mixture, followed by bromoalkane (1.0 mmol,
2.5 equiv) and, finally, another portion of DCE (1.0 ml).
The tube was then capped and submerged into an oil bath
= 1.8 Hz, 1C), 126.7, 111.2, 109.8, 95.9, 87.8 (d, JC-F
=
212.9 Hz, 1C), 63.2, 56.0, 31.7, 14.0. IR (KBr, cm-1): 2966,
2924, 2841, 1764, 1625, 1504, 1439, 1392, 1323, 1244,
1054, 789. LRMS (EI, 70 eV) m/z (%): 298 (100), 226 (76),
211 (48), 205 (12), 195 (17). HRMS (ESI) for
C13H16FN2O3S+ (M+H)+: calcd 299.0860, found 299.0864.
o
pre-heated to 80 C. The reaction was stirred for 24 h and
cooled to room temperature. The branch of reaction tube
was connected to an absorption device of sulfur dioxide.
5
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10.1002/adsc.201801166
Advanced Synthesis & Catalysis
Ethyl
2-(6-amino-3-methyl-2-thioxo-2,3-dihydro-1H- 4.41 – 4.28 (m, 2H), 3.76 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).
benzo[d]imidazol-1-yl)-2-fluoroacetate (6). Yellow solid. 13C NMR (151 MHz, CDCl3) δ 172.6, 164.1 (d, JC-F = 34.7
Mp. 136.8 – 137.6 C. 78% yield (88.4 mg). 1H NMR (600 Hz, 1C), 148.9 (dd, JC-F = 92.1, 15.1 Hz, 1C), 147.2 (dd, JC-
MHz, CDCl3) δ 7.52 (d, J = 45.5 Hz, 1H), 6.96 (d, J = 8.4 F = 92.1, 15.1 Hz, 1C), 128.3 (dd, JC-F = 10.6, 1.5 Hz, 1C),
Hz, 1H), 6.65 – 6.62 (m, 2H), 4.38 – 4.27 (m, 2H), 3.74 (s, 124.5 (d, JC-F = 10.6 Hz, 1C), 100.1 (d, JC-F = 24.2 Hz, 1C),
3H), 3.45 (s, 2H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (151 98.6 (d, JC-F = 22.7 Hz, 1C), 87.9 (d, JC-F = 214.4 Hz, 1C),
MHz, CDCl3) δ 170.2, 164.7 (d, JC-F = 34.7 Hz, 1C), 143.5, 63.4, 31.9, 14.0. IR (KBr, cm-1): 3054, 2919, 2845, 1745,
130.3 (d, JC-F = 2.3 Hz, 1C), 125.7, 112.1, 110.0, 96.9, 87.8 1634, 1504, 1374, 1341, 1258, 1026, 859, 650, 589. LRMS
(d, JC-F = 211.4 Hz, 1C), 63.1, 31.7, 14.0. IR (KBr, cm-1): (EI, 70 eV) m/z (%): 304 (100), 232 (99), 231 (55), 216
3430, 3356, 2933, 2855, 1754, 1629, 1504, 1346, 1225, (16), 211 (24), 199 (23), 196 (18), 172 (12), 167 (12).
1058, 1040, 794. LRMS (EI, 70 eV) m/z (%): 283 (100), HRMS (ESI) for C12H12F3N2O2S+ (M+H)+: calcd 305.0566,
211 (49), 195 (23), 178 (19), 175 (11). HRMS (ESI) for found 305.0567.
C12H15FN3O2S+ (M+H)+: calcd 284.0864, found 284.0866.
Methyl
3-(2-ethoxy-1-fluoro-2-oxoethyl)-1-methyl-2-
Ethyl
2-(5-bromo-3-methyl-2-thioxo-2,3-dihydro-1H- thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate
benzo[d]imidazol-1-yl)-2-fluoroacetate (7). White solid. (12). White solid. Mp. 143.1 – 145.3 C. 65% yield (84.8
1
1
Mp. 130.2 – 130.5 C. 91% yield (126.4 mg). H NMR mg). H NMR (600 MHz, CDCl3) δ 8.03 – 7.95 (m, 1H),
(600 MHz, CDCl3) δ 7.49 (d, J = 45.3 Hz, 1H), 7.37 – 7.32 7.89 (s, 1H), 7.49 (d, J = 45.5 Hz, 1H), 7.20 (d, J = 8.4 Hz,
(m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 4.38 – 4.26 (m, 2H), 3.77 1H), 4.41 – 4.29 (m, 2H), 3.91 (s, 3H), 3.79 (s, 3H), 1.28 (t,
(s, 3H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 173.2,
CDCl3) δ 172.2, 164.2 (d, JC-F = 34.7 Hz, 1C), 133.8, 128.3 166.1, 164.2 (d, JC-F = 34.7 Hz, 1C), 135.8, 129.1 (d, JC-F
(d, JC-F = 2.4 Hz, 1C), 126.6, 117.4, 112.4, 111.3, 87.8 (d, 2.1 Hz, 1C), 126.4, 125.8, 111.4, 108.8, 87.9 (d, JC-F
=
=
JC-F = 212.9 Hz, 1C), 63.3, 31.8, 14.0. IR (KBr, cm-1): 3101, 215.9 Hz, 1C), 63.4, 52.4, 31.8, 14.0. IR (KBr, cm-1): 2980,
2989, 2933, 1764, 1481, 1430, 1392, 1314, 1226, 1068, 2951, 2919, 2850, 1745, 1727, 1434, 1392, 1300, 1249,
849, 764. LRMS (EI, 70 eV) m/z (%): 346 (96), 348 (95), 1044, 757. LRMS (EI, 70 eV) m/z (%): 326 (89), 295 (11),
274 (100), 276 (100), 258 (10), 260 (10), 253 (19), 255 254 (100), 253 (50), 233 (10), 223 (23), 207 (20). HRMS
(20), 195 (14), 94 (17). HRMS (ESI) for C12H13BrFN2O2S+ (ESI) for C14H16FN2O4S+ (M+H)+: calcd 327.0809, found
(M+H)+: calcd 346.9860, found 346.9862.
327.0812.
Ethyl
2-(6-bromo-3-methyl-2-thioxo-2,3-dihydro-1H- Ethyl
3-(2-ethoxy-1-fluoro-2-oxoethyl)-1-methyl-2-
benzo[d]imidazol-1-yl)-2-fluoroacetate (8). White solid. thioxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate
1
Mp. 132.0 – 132.6 C. 92% yield (127.8 mg). H NMR (13). White solid. Mp. 115.7 – 116.4 C. 58% yield (79.0
1
(600 MHz, CDCl3) δ 7.49 (d, J = 45.3 Hz, 1H), 7.43 – 7.37 mg). H NMR (600 MHz, CDCl3) δ 7.83 (d, J = 44.7 Hz,
(m, 2H), 7.06 (d, J = 8.9 Hz, 1H), 4.41 – 4.30 (m, 2H), 3.76 1H), 7.78 (dd, J = 7.5, 1.6 Hz, 1H), 7.39 – 7.31 (m, 2H),
(s, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, 4.45 – 4.38 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H),
CDCl3) δ 172.0, 164.1 (d, JC-F = 34.7 Hz, 1C), 131.7, 130.2 1.41 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H). 13C NMR
(d, JC-F = 2.3 Hz, 1C), 127.3, 116.8, 113.3, 110.3, 87.8 (d, (151 MHz, CDCl3) δ 172.9, 165.5, 164.6 (d, JC-F = 28.7 Hz,
JC-F = 214.4 Hz, 1C), 63.4, 31.8, 14.0. IR (KBr, cm-1): 3101, 1C), 134.1, 129.0 (d, JC-F = 2.2 Hz, 1C), 125.9, 123.5,
2989, 2933, 1768, 1481, 1430, 1392, 1314, 1216, 1068, 116.8, 112.8, 89.8 (d, JC-F = 220.5 Hz, 1C), 62.7, 62.1, 31.9,
849, 798. LRMS (EI, 70 eV) m/z (%): 346 (94), 348 (96), 14.1, 14.0. IR (KBr, cm-1): 2982, 2919, 2896, 1745, 1722,
274 (100), 276 (100), 258 (14), 260 (14), 253 (14), 255 1443, 1341, 1263, 1142, 1072, 752. LRMS (EI, 70 eV) m/z
(15), 194 (13), 94 (9). HRMS (ESI) for C12H13BrFN2O2S+ (%): 340 (69), 268 (29), 191 (100), 163 (22). HRMS (ESI)
(M+H)+: calcd 346.9860, found 346.9859.
for C15H18FN2O4S+ (M+H)+: calcd 341.0966, found
341.0969.
Ethyl 2-(5-chloro-3-methyl-2-thioxo-2,3-dihydro-1H-
benzo[d]imidazol-1-yl)-2-fluoroacetate (9). White solid. Ethyl
2-fluoro-2-(3-methyl-5-nitro-2-thioxo-2,3-
1
Mp. 134.9 – 135.4 C. 90% yield (109.0 mg). H NMR dihydro-1H-benzo[d]imidazol-1-yl)acetate (14). Yellow
1
(600 MHz, CDCl3) δ 7.50 (d, J = 45.3 Hz, 1H), 7.22 – 7.15 solid. Mp. 151.7 – 152.4 C. 72% yield (90.2 mg). H
(m, 3H), 4.38 – 4.27 (m, 2H), 3.77 (s, 3H), 1.25 (t, J = 7.1 NMR (600 MHz, CDCl3) δ 8.20 (dd, J = 8.8, 2.0 Hz, 1H),
Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 172.4, 164.3 (d, 8.11 (d, J = 2.1 Hz, 1H), 7.52 (d, J = 44.9 Hz, 1H), 7.36 (d,
JC-F = 34.7 Hz, 1C), 133.5, 130.3, 127.9 (d, JC-F = 2.1 Hz, J = 8.8 Hz, 1H), 4.43 – 4.30 (m, 2H), 3.88 (s, 3H), 1.29 (t,
1C), 123.8, 110.9, 109.6, 87.8 (d, JC-F = 212.9 Hz, 1C), J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 173.9,
63.3, 31.8, 14.0. IR (KBr, cm-1): 3082, 2929, 2855, 1764, 163.9 (d, JC-F = 33.2 Hz, 1C), 144.7, 133.6 (d, JC-F = 2.4 Hz,
1610, 1485, 1374, 1341, 1220, 1063, 817. LRMS (EI, 70 1C), 132.9, 120.0, 109.9, 105.0, 87.9 (d, JC-F = 214.4 Hz,
eV) m/z (%): 302 (88), 232 (38), 230 (100), 229 (53), 209 1C), 63.6, 32.0, 14.0. IR (KBr, cm-1): 3082, 2989, 2938,
(25), 197 (19), 165 (10). HRMS (ESI) for 2850, 1764, 1536, 1337, 1225, 1077, 873, 798, 729. LRMS
C12H13ClFN2O2S+ (M+H)+: calcd 303.0365, found (EI, 70 eV) m/z (%): 313 (80), 241 (100), 240 (41), 195
303.0368.
(44), 194 (34), 94 (15). HRMS (ESI) for C12H13FN3O4S+
(M+H)+: calcd 314.0605, found 314.0611.
Ethyl
2-(6-chloro-3-methyl-2-thioxo-2,3-dihydro-1H-
benzo[d]imidazol-1-yl)-2-fluoroacetate (10). White solid. Ethyl
2-fluoro-2-(3-methyl-6-nitro-2-thioxo-2,3-
1
Mp. 136.5 – 137.2 C. 91% yield (110.2 mg). H NMR dihydro-1H-benzo[d]imidazol-1-yl)acetate (15). Yellow
1
(600 MHz, CDCl3) δ 7.51 (d, J = 45.3 Hz, 1H), 7.30 – 7.25 solid. Mp. 118.3 – 119.4 C. 63% yield (79.0 mg). H
(m, 2H), 7.11 (d, J = 9.0 Hz, 1H), 4.42 – 4.31 (m, 2H), 3.78 NMR (600 MHz, CDCl3) δ 8.27 (dd, J = 8.8, 2.1 Hz, 1H),
(s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, 8.14 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 45.1 Hz, 1H), 7.29 (d,
CDCl3) δ 172.1, 164.2 (d, JC-F = 34.7 Hz, 1C), 131.3, 129.9 J = 8.8 Hz, 1H), 4.46 – 4.34 (m, 2H), 3.85 (s, 3H), 1.34 (t,
(d, JC-F = 2.1 Hz, 1C), 129.8, 124.5, 110.6, 109.9, 87.8 (d, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 174.2,
JC-F = 214.4 Hz, 1C), 63.4, 31.8, 14.0. IR (KBr, cm-1): 3082, 163.8 (d, JC-F = 31.7 Hz, 1C), 144.1, 137.0, 129.1 (d, JC-F
=
2929, 2855, 1754, 1610, 1485, 1374, 1341, 1225, 1063, 2.2 Hz, 1C), 120.7, 108.7, 106.2, 88.0 (d, JC-F = 215.9 Hz,
817. LRMS (EI, 70 eV) m/z (%): 302 (85), 232 (100), 209 1C), 63.7, 32.0, 14.0. IR (KBr, cm-1): 3085, 2989, 2938,
(19), 194 (19), 136 (9). HRMS (ESI) for C12H13ClFN2O2S+ 2850, 1764, 1536, 1337, 1225, 1077, 873, 798, 743. LRMS
(M+H)+: calcd 303.0365, found 303.0367.
(EI, 70 eV) m/z (%): 313 (81), 241 (100), 240 (41), 195
(44), 94 (15), 77 (12). HRMS (ESI) for C12H13FN3O4S+
(M+H)+: calcd 314.0605, found 314.0607.
Ethyl
2-(5,6-difluoro-3-methyl-2-thioxo-2,3-dihydro-
1H-benzo[d]imidazol-1-yl)-2-fluoroacetate (11). White
1
solid. Mp. 103.7 – 104.6 C. 85% yield (103.5 mg). H Ethyl
2-(3-butyl-2-thioxo-2,3-dihydro-1H-
NMR (600 MHz, CDCl3) δ 7.48 (d, J = 45.1 Hz, 1H), 7.16 benzo[d]imidazol-1-yl)-2-fluoroacetate (16). Colorless oil.
1
(dd, J = 9.3, 6.6 Hz, 1H), 7.05 (dd, J = 9.2, 6.5 Hz, 1H), 93% yield (115.5 mg). H NMR (600 MHz, CDCl3) δ 7.56
6
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10.1002/adsc.201801166
Advanced Synthesis & Catalysis
(d, J = 45.6 Hz, 1H), 7.30 – 7.19 (m, 4H), 4.36 – 4.25 (m, Ethyl
2-(3-(2-cyanoethyl)-2-thioxo-2,3-dihydro-1H-
4H), 1.86 – 1.79 (m, 2H), 1.48 – 1.41 (m, 2H), 1.22 (t, J = benzo[d]imidazol-1-yl)-2-fluoroacetate (21). White solid.
7.1 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, Mp. 104.0 – 104.5 C. 85% yield (104.5 mg). H NMR
1
CDCl3) δ 171.1, 164.6 (d, JC-F = 34.7 Hz, 1C), 132.1, 129.4, (600 MHz, CDCl3) δ 7.48 (d, J = 45.4 Hz, 1H), 7.38 – 7.33
124.2, 123.6, 110.2, 109.5, 87.8 (d, JC-F = 212.9 Hz, 1C), (m, 2H), 7.32 – 7.26 (m, 2H), 4.59 (hept, J = 7.0 Hz, 2H),
63.1, 45.2, 29.6, 20.1, 14.0, 13.8. IR (KBr, cm-1): 2952, 4.40 – 4.29 (m, 2H), 3.08 – 2.99 (m, 2H), 1.26 (t, J = 7.1
2929, 2868, 1764, 1485, 1411, 1332, 1225, 1063, 743. Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 171.2, 164.2 (d,
LRMS (EI, 70 eV) m/z (%): 310 (78), 277 (100), 249 (28), JC-F = 34.7 Hz, 1C), 131.5, 129.3 (d, JC-F = 2.4 Hz, 1C),
205 (17), 196 (37), 182 (51), 161 (74), 134 (17). HRMS 124.7, 124.4, 117.1, 110.6, 109.3, 87.7 (d, JC-F = 214.4 Hz,
(ESI) for C15H20FN2O2S+ (M+H)+: calcd 311.1224, found 1C), 63.3, 41.0, 16.1, 14.0. IR (KBr, cm-1): 3063, 2980,
311.1227.
2924, 2246, 1764, 1485, 1448, 1406, 1327, 1225, 1068,
743. LRMS (EI, 70 eV) m/z (%): 307 (100), 234 (34), 182
(84), 161 (63), 134 (15), 102 (11). HRMS (ESI) for
C14H15FN3O2S+ (M+H)+: calcd 308.0864, found 308.0866.
Ethyl
2-(3-allyl-2-thioxo-2,3-dihydro-1H-
benzo[d]imidazol-1-yl)-2-fluoroacetate (17). Colorless oil.
1
92% yield (108.3 mg). H NMR (600 MHz, CDCl3) δ 7.55
(d, J = 45.5 Hz, 1H), 7.27 – 7.17 (m, 4H), 5.94 (ddt, J = Ethyl 2-fluoro-2-(3-((tetrahydrofuran-2-yl)methyl)-2-
17.2, 10.6, 5.5 Hz, 1H), 5.28 – 5.26 (m, 1H), 5.23 – 5.19 thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate
(m, 1H), 5.03 – 4.92 (m, 2H), 4.35 – 4.28 (m, 2H), 1.22 (t, (22). A mixture of diastereomers; Colorless oil. 91% yield
J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 171.4, (123.2 mg). H NMR (600 MHz, CDCl3) δ 7.55 (d, J =
1
164.5 (d, JC-F = 34.7 Hz, 1C), 131.9, 130.2, 129.4 (d, JC-F
=
45.8 Hz 1H), 7.43 – 7.38 (m, 1H), 7.28 – 7.18 (m, 3H),
2.4 Hz, 1C), 124.3, 123.9, 118.6, 110.2, 110.0, 88.0 (d, JC-F 4.63 – 4.53 (m, 1H), 4.44 – 4.38 (m, 1H), 4.37 – 4.23 (m,
= 212.9 Hz, 1C), 63.2, 47.6, 14.0. IR (KBr, cm-1): 2980, 3H), 3.87 – 3.81 (m, 1H), 3.76 – 3.69 (m, 1H), 2.13 – 2.06
2915, 2841, 1754, 1476, 1406, 1327, 1249, 1220, 1044, (m, 1H), 1.92 – 1.85 (m, 2H), 1.84 – 1.77 (m, 1H), 1.24 (t,
738. LRMS (EI, 70 eV) m/z (%): 294 (92), 279 (100), 251 J = 7.2 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 171.6,
(49), 221 (17), 207 (38), 189 (18), 161 (28), 134 (17), 102 164.5 (d, JC-F = 34.7 Hz, 1C), 132.9, 129.2, 124.2 (d, JC-F
=
(11). HRMS (ESI) for C14H16FN2O2S+ (M+H)+: calcd 2.5 Hz, 1C), 123.7, 111.0, 109.9, 87.9 (d, JC-F = 212.9 Hz,
295.0911, found 295.0914.
1C), 77.1, 68.2, 63.1, 49.6, 29.1, 25.6, 14.0. IR (KBr, cm-1):
2971, 2933, 2868, 1764, 1481, 1411, 1332, 1258, 1225,
1072, 742. LRMS (EI, 70 eV) m/z (%): 338 (36), 254 (82),
182 (100), 160 (59), 85 (23). HRMS (ESI) for
C16H20FN2O3S+ (M+H)+: calcd 339.1173, found 339.1175.
Ethyl
2-(3-(but-3-en-1-yl)-2-thioxo-2,3-dihydro-1H-
benzo[d]imidazol-1-yl)-2-fluoroacetate (18). Colorless oil.
1
91% yield (112.2 mg). H NMR (600 MHz, CDCl3) δ 7.55
(d, J = 45.5 Hz, 1H), 7.30 – 7.18 (m, 4H), 5.89 – 5.82 (m,
1H), 5.15 – 5.04 (m, 2H), 4.44 – 4.27 (m, 4H), 2.67 – 2.57 Ethyl
2-(3-((1,3-dioxolan-2-yl)methyl)-2-thioxo-2,3-
(m, 2H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, dihydro-1H-benzo[d]imidazol-1-yl)-2-fluoroacetate (23).
1
CDCl3) δ 171.1, 164.5 (d, JC-F = 33.2 Hz, 1C), 133.8, 132.0, Colorless oil. 92% yield (125.3 mg). H NMR (600 MHz,
129.3 (d, JC-F = 2.3 Hz, 1C), 124.2, 123.7, 118.0, 110.2, CDCl3) δ 7.55 (d, J = 45.5 Hz, 1H), 7.41 – 7.36 (m, 1H),
109.6, 87.8 (d, JC-F = 212.9 Hz, 1C), 63.1, 44.7, 31.7, 14.0. 7.31 – 7.19 (m, 3H), 5.32 (t, J = 4.3 Hz, 1H), 4.59 – 4.47
IR (KBr, cm-1): 3063, 2980, 2919, 2845, 1759, 1481, 1411, (m, 2H), 4.38 – 4.27 (m, 2H), 4.04 – 3.96 (m, 2H), 3.93 –
1332, 1225, 1053, 743. LRMS (EI, 70 eV) m/z (%): 308 3.85 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz,
(70), 279 (98), 275 (47), 262 (39), 261 (40), 251 (14), 182 CDCl3) δ 172.2, 164.5 (d, JC-F = 36.2 Hz, 1C), 132.6, 129.2
(89), 161 (100), 149 (11), 134 (22), 118 (11). HRMS (ESI) (d, JC-F = 2.1 Hz, 1C), 124.2, 123.8, 110.7, 110.0, 101.1,
for C15H18FN2O2S+ (M+H)+: calcd 309.1068, found 87.9 (d, JC-F = 212.9 Hz, 1C), 65.3, 65.2, 63.2, 48.1, 14.0.
309.1069.
IR (KBr, cm-1): 2980, 2915, 2850, 1764, 1481, 1411, 1332,
1137, 1049, 738. LRMS (EI, 70 eV) m/z (%): 340 (56), 267
(13), 254 (57), 196 (16), 182 (99), 161 (57), 149 (10), 131
(14), 118 (14), 87 (100), 86 (70), 73 (38). HRMS (ESI) for
C15H18FN2O4S+ (M+H)+: calcd 341.0966, found 341.0967.
Ethyl
2-fluoro-2-(3-(2-methylallyl)-2-thioxo-2,3-
dihydro-1H-benzo[d]imidazol-1-yl)acetate (19). White
solid. Mp. 69.8 – 70.5 C. 92% yield (113.5 mg). 1H NMR
(600 MHz, CDCl3) δ 7.57 (d, J = 45.4 Hz, 1H), 7.31 – 7.16
(m, 4H), 5.02 – 4.90 (m, 3H), 4.77 (d, J = 1.9 Hz, 1H), 4.36 Ethyl
2-(3-(2-(2-ethoxyethoxy)ethyl)-2-thioxo-2,3-
– 4.28 (m, 2H), 1.78 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). 13C dihydro-1H-benzo[d]imidazol-1-yl)-2-fluoroacetate (24).
1
NMR (151 MHz, CDCl3) δ 171.9, 164.5 (d, JC-F = 34.7 Hz, Colorless oil. 93% yield (137.8 mg). H NMR (600 MHz,
1C), 138.3, 132.1, 129.3 (d, JC-F = 2.4 Hz, 1C), 124.2, CDCl3) δ 7.53 (d, J = 45.5 Hz, 1H), 7.39 (d, J = 8.0 Hz,
123.8, 113.3, 110.2, 110.1, 88.1 (d, JC-F = 212.9 Hz, 1C), 1H), 7.26 – 7.16 (m, 3H), 4.57 – 4.50 (m, 1H), 4.49 –4.44
63.1, 50.9, 20.0, 14.0. IR (KBr, cm-1): 3087, 2980, 2915, (m, 1H), 4.35 – 4.24 (m, 2H), 3.92 – 3.85 (m, 2H), 3.59 –
1745, 1485, 1443, 1411, 1332, 1249, 1058, 1021, 742. 3.53 (m, 2H), 3.45 (t, J = 4.6 Hz, 2H), 3.40 (q, J = 7.0 Hz,
LRMS (EI, 70 eV) m/z (%): 308 (86), 293 (100), 275 (19), 2H), 1.21 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H). 13C
265 (30), 247 (17), 221 (18), 215 (21), 203 (20), 161 (19), NMR (151 MHz, CDCl3) δ 171.2, 164.5 (d, JC-F = 34.7 Hz,
134 (13), 55 (19). HRMS (ESI) for C15H18FN2O2S+ 1C), 132.9, 129.1 (d, JC-F = 2.3 Hz, 1C), 124.0, 123.6,
(M+H)+: calcd 309.1068, found 309.1069.
110.8, 109.9, 87.7 (d, JC-F = 214.4 Hz, 1C), 70.8, 69.7, 68.3,
66.6, 63.1, 45.7, 15.1, 14.0. IR (KBr, cm-1): 2971, 2915,
2850, 1759, 1481, 1411, 1323, 1225, 1109, 1054, 742.
LRMS (EI, 70 eV) m/z (%): 370 (3), 298 (83), 291 (24),
280 (12), 254 (62), 182 (100), 161 (55). HRMS (ESI) for
C17H24FN2O4S + (M+H)+: calcd 371.1435, found 371.1439.
Ethyl
2-fluoro-2-(3-(prop-2-yn-1-yl)-2-thioxo-2,3-
dihydro-1H-benzo[d]imidazol-1-yl)acetate (20). White
1
solid. Mp. 131.4 – 132.3 C. 85% yield (99.4 mg). H
NMR (600 MHz, CDCl3) δ 7.52 (d, J = 45.5 Hz, 1H), 7.42
(d, J = 8.0 Hz, 1H), 7.35 – 7.31 (m, 1H), 7.31 – 7.24 (m,
2H), 5.20 (qd, J = 17.7, 2.5 Hz, 2H), 4.43 – 4.25 (m, 2H), Ethyl
2-(3-(2-acetoxyethyl)-2-thioxo-2,3-dihydro-1H-
2.39 (t, J = 2.5 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR benzo[d]imidazol-1-yl)-2-fluoroacetate (25). Colorless oil.
1
(151 MHz, CDCl3) δ 171.3, 164.4 (d, JC-F = 34.7 Hz, 1C), 93% yield (126.6 mg). H NMR (600 MHz, CDCl3) δ 7.53
131.2, 129.4 (d, JC-F = 1.8 Hz, 1C), 124.4, 124.2, 110.4, (d, J = 45.5 Hz, 1H), 7.32 – 7.21 (m, 4H), 4.64 – 4.54 (m,
110.1, 88.0 (d, JC-F = 214.4 Hz, 1C), 75.7, 74.0, 63.2, 34.9, 2H), 4.50 (t, J = 5.2 Hz, 2H), 4.37 – 4.28 (m, 2H), 1.97 (s,
14.0. IR (KBr, cm-1): 3274, 2971, 2929, 2850, 2121, 1759, 3H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3)
1481, 1434, 1406, 1225, 1072, 1044, 743. LRMS (EI, 70 δ 171.5, 170.6, 164.4 (d, JC-F = 34.7 Hz, 1C), 132.5, 129.3,
eV) m/z (%): 292 (99), 264 (36), 219 (15),199 (12), 187 124.3, 123.9, 110.3, 109.6, 87.8 (d, JC-F = 214.4 Hz, 1C),
(100), 180 (16), 160 (21), 136 (12), 129 (15), 102 (13). 63.2, 61.1, 44.1, 20.8, 14.0. IR (KBr, cm-1): 2919, 2845,
HRMS (ESI) for C14H14FN2O2S+ (M+H)+: calcd 293.0755, 1741, 1481, 1406, 1332, 1220, 1049, 747. LRMS (EI, 70
found 293.0757.
eV) m/z (%): 340 (100), 280 (60), 254 (20), 207 (24), 182
(93), 161 (66), 149 (10), 134 (12), 118 (10), 87 (18).
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801166
Advanced Synthesis & Catalysis
HRMS (ESI) for C15H18FN2O4S+ (M+H)+: calcd 341.0966, 115.3, 88.7 (d, JC-F = 214.4 Hz, 1C), 63.6, 53.9, 28.7, 19.9,
found 341.0969.
19.9, 14.0. IR (KBr, cm-1): 2957, 2929, 2845, 1764, 1420,
1392, 1267, 1225, 1072, 984, 761. LRMS (EI, 70 eV) m/z
(%): 361 (77), 305 (88), 233 (100), 212 (79), 185 (21).
HRMS (ESI) for C18H21FN3O2S+ (M+H)+: calcd 362.1333,
found 362.1336.
Methyl 3-(3-(2-ethoxy-1-fluoro-2-oxoethyl)-2-thioxo-2,3-
dihydro-1H-benzo[d]imidazol-1-yl)propanoate
(26).
White solid. Mp. 98.5 – 100.1 C. 92% yield (125.3 mg).
1H NMR (600 MHz, CDCl3) δ 7.51 (d, J = 45.5 Hz, 1H),
7.36 (d, J = 8.0 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.26 – 7.19 Ethyl
2-(6-(benzylamino)-7-methyl-8-thioxo-7,8-
(m, 2H), 4.57 (hept, J = 7.1 Hz, 2H), 4.36 – 4.27 (m, 2H), dihydro-9H-purin-9-yl)-2-fluoroacetate (31). White solid.
1
3.65 (d, J = 2.1 Hz, 3H), 2.95 (t, J = 7.1 Hz, 2H), 1.23 (t, J Mp. 93.1 – 94.0 C. 55% yield (82.6 mg). H NMR (600
= 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 171.4, 171.2, MHz, CDCl3) δ 8.40 (s, 1H), 7.79 (d, J = 43.8 Hz, 1H),
164.4 (d, JC-F = 34.7 Hz, 1C), 131.8, 129.3 (d, JC-F = 2.2 Hz, 7.43 – 7.28 (m, 5H), 6.21 (d, J = 6.1 Hz, 1H), 4.87 – 4.73
1C), 124.3, 123.8, 110.2, 109.8, 87.6 (d, JC-F = 212.9 Hz, (m, 2H), 4.28 – 4.16 (m, 2H), 3.78 (s, 3H), 1.19 (t, J = 7.1
1C), 63.2, 52.0, 41.0, 31.7, 14.0. IR (KBr, cm-1): 2915, Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 170.7, 165.3 (d,
2845, 1731, 1634, 1481, 1411, 1327, 1225, 1170, 1049, JC-F = 34.7 Hz, 1C), 154.0, 150.3, 146.9, 138.0, 128.7,
1012, 742. LRMS (EI, 70 eV) m/z (%): 340 (100), 309 (14), 127.6, 127.5, 106.7, 88.6 (d, JC-F = 209.9 Hz, 1C), 63.9,
267 (13), 254 (21), 235 (12), 207 (19), 182 (89), 161 (47), 45.1, 30.7, 13.8. IR (KBr, cm-1): 3445, 3356, 2929, 2855,
+
134 (13), 87 (13). HRMS (ESI) for C15H18FN2O4S
1754, 1629, 1504, 1346, 1225, 1058, 1040, 784. LRMS (EI,
70 eV) m/z (%): 375 (100), 302 (16), 282 (20), 270 (80),
180 (28), 106 (34), 91 (81), 65 (10). HRMS (ESI) for
C17H19FN5O2S+ (M+H)+: calcd 376.1238, found 376.1236.
(M+H)+: calcd 341.0966, found 341.0968.
Ethyl
2-(3-benzyl-2-thioxo-2,3-dihydro-1H-
benzo[d]imidazol-1-yl)-2-fluoroacetate (27). White solid.
1
Mp. 140.2 – 141.2 C. 91% yield (125.4 mg). H NMR Ethyl
2-fluoro-2-(3-methyl-2-thioxo-2,3-dihydro-1H-
(600 MHz, CDCl3) δ 7.63 (d, J = 45.5 Hz, 1H), 7.40 – 7.26 imidazol-1-yl)acetate (32). Light yellow oil. 92% yield
(m, 6H), 7.25 – 7.16 (m, 2H), 7.11 – 7.09 (m, 1H), 5.67 – (80.3 mg). 1H NMR (600 MHz, CDCl3) δ 7.13 (d, J = 47.1
5.52 (m, 2H), 4.39 – 4.30 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). Hz, 1H), 6.88 (d, J = 2.5 Hz, 1H), 6.72 (d, J = 2.5 Hz, 1H),
13C NMR (151 MHz, CDCl3) δ 172.2, 164.5 (d, JC-F = 34.7 4.39 – 4.26 (m, 2H), 3.60 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H).
Hz, 1C), 134.8, 132.0, 129.5 (d, JC-F = 1.7 Hz, 1C), 128.9, 13C NMR (151 MHz, CDCl3) δ 166.2, 164.3 (d, JC-F = 33.2
128.1, 127.5, 124.3, 123.9, 110.3, 110.1, 88.2 (d, JC-F
=
Hz, 1C), 119.3, 114.0, 88.0 (d, JC-F = 212.9 Hz, 1C), 63.1,
214.4 Hz, 1C), 63.2, 48.9, 14.0. IR (KBr, cm-1): 3063, 3026, 35.2, 14.0. IR (KBr, cm-1): 3103, 2917, 2849, 2335, 1761,
2929, 2845, 1768, 1480, 1411, 1332, 1249, 1225, 1068, 1456, 1397, 1231, 1141, 1066, 764. LRMS (EI, 70 eV) m/z
1044, 742. LRMS (EI, 70 eV) m/z (%): 344 (80), 311 (18), (%): 218 (95), 146 (100), 125 (21), 113 (22), 72 (15).
239 (21), 163 (20), 91 (100), 65(11). HRMS (ESI) for HRMS (ESI) for C8H12FN2O2S+ (M+H)+: calcd 219.0598,
C18H18FN2O2S+ (M+H)+: calcd 345.1068, found 345.1071.
found 219.0597.
Ethyl 2-fluoro-2-(3-((perfluorophenyl)methyl)-2-thioxo- Ethyl 2-(3-(2-ethoxy-2-oxoethyl)-2-thioxo-2,3-dihydro-
2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate
(28). 1H-imidazol-1-yl)-2-fluoroacetate (33). Yellow oil. 75%
1
Colorless oil. 83% yield (144.2 mg). H NMR (600 MHz, yield (87.1 mg). 1H NMR (600 MHz, CDCl3) δ 7.10 (d, J =
CDCl3) δ 7.51 (d, J = 45.3 Hz, 1H), 7.31 – 7.24 (m, 3H), 47.0 Hz, 1H), 6.93 (d, J = 2.7 Hz, 1H), 6.82 (d, J = 2.7 Hz,
7.17 (d, J = 7.7 Hz, 1H), 5.67 – 5.58 (m, 2H), 4.38 – 4.28 1H), 4.84 (s, 2H), 4.38 – 4.28 (m, 2H), 4.23 (q, J = 7.2 Hz,
(m, 2H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, 2H), 1.31 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13C
CDCl3) δ 171.9, 164.3 (d, JC-F = 34.7 Hz, 1C), 144.5 (dm, NMR (151 MHz, CDCl3) δ 167.1, 166.8, 164.0 (d, JC-F
=
JC-F = 251.1 Hz; 146.4 – 146.3, 144.8 – 144.6, 1C), 141.4 34.7 Hz, 1C), 119.1, 114.2, 88.1 (d, JC-F = 214.4 Hz, 1C),
(dm, JC-F = 255.9 Hz; 142.4 – 142.1, 140.7 – 140.4, 1C), 63.2, 62.1, 48.6, 14.1, 14.0. IR (KBr, cm-1): 3175, 3105,
137.6 (dm, JC-F = 253..3 Hz; 138.6 – 138.4, 136.9 – 136.7, 2980, 2915, 2845, 1745, 1439, 1281, 1216, 1017, 734.
1C), 131.5, 129.3 (d, JC-F = 2.3 Hz, 1C), 108.2 (td, JC-F
=
LRMS (EI, 70 eV) m/z (%): 290 (76), 218 (27), 146 (100),
16.6, 4.5 Hz, 1C), 88.0 (d, JC-F = 212.9 Hz, 1C), 63.2, 37.7, 81 (13). HRMS (ESI) for C11H16FN2O4S+ (M+H)+: calcd
13.9. IR (KBr, cm-1): 2980, 2915, 2845, 1759, 1499, 1411, 291.0809, found 291.0812.
1322, 1119, 1011, 947, 742. LRMS (EI, 70 eV) m/z (%):
434 (85), 362 (19), 343 (12), 329 (15), 181 (100), 161 (31).
Ethyl
2-(3-(2-(ethylamino)-2-oxoethyl)-2-thioxo-2,3-
HRMS (ESI) for C18H13F6N2O2S+ (M+H)+: calcd 435.0596,
found 435.0599.
dihydro-1H-imidazol-1-yl)-2-fluoroacetate (34). Yellow
1
oil. 67% yield (77.5 mg). H NMR (600 MHz, CDCl3) δ
7.11 (d, J = 46.8 Hz, 1H), 6.95 (dd, J = 15.8, 2.7 Hz, 2H),
Ethyl
2-(6-bromo-3-methyl-2-thioxo-2,3-dihydro-1H- 6.69 (s, 1H), 4.77 – 4.64 (m, 2H), 4.37 (qq, J = 10.6, 7.0
imidazo[4,5-b]pyridin-1-yl)-2-fluoroacetate (29). White Hz, 2H), 3.34 – 3.26 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H), 1.15
solid. Mp. 139.1 – 140.3 C. 66% yield (91.9 mg). H (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 166.1,
1
NMR (600 MHz, CDCl3) δ 8.34 (d, J = 1.9 Hz, 1H), 7.67 165.9, 163.9 (d, JC-F = 33.2 Hz, 1C), 119.2, 114.9, 88.1 (d,
(d, J = 1.9 Hz, 1H), 7.52 (d, J = 45.1 Hz, 1H), 4.44 – 4.32 JC-F = 214.4 Hz, 1C), 63.32, 51.6, 34.7, 14.6, 14.0. IR (KBr,
(m, 2H), 3.82 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR cm-1): 3175, 3105, 2980, 2915, 2845, 1745,1650, 1562,
(151 MHz, CDCl3) δ 172.8, 163.8 (d, JC-F = 34.7 Hz, 1C), 1439, 1281, 1225, 1017, 765. LRMS (EI, 70 eV) m/z (%):
144.8, 144.4, 123.7 (d, JC-F = 2.2 Hz, 1C), 119.8, 114.6, 289 (100), 256 (15), 244 (33), 217 (11)159 (24), 146 (62),
87.3 (d, JC-F = 214.4 Hz, 1C), 63.6, 30.3, 14.0. IR (KBr, 112 (11), 86 (12). HRMS (ESI) for C11H17FN3O3S+
cm-1): 3077, 2980, 2933, 1764, 1597, 1471, 1430, 1374, (M+H)+: calcd 290.0969, found 290.0975.
1304, 1225, 1091, 1063, 863, 720. LRMS (EI, 70 eV) m/z
(%): 347 (94), 349 (96), 275 (100), 277 (99), 242 (16), 244
Ethyl
2-(3-(4-acetyl-2-fluorophenyl)-2-thioxo-2,3-
(14), 201 (13), 203 (13), 174 (36), 176 (36), 95 (12).
HRMS (ESI) for C11H12BrFN3O2S+ (M+H)+: calcd
347.9812, found 347.9815.
dihydro-1H-imidazol-1-yl)-2-fluoroacetate (35). White
1
solid. Mp. 102.8 – 103.9 C. 72% yield (98.0 mg). H
NMR (600 MHz, CDCl3) δ 7.89 – 7.82 (m, 3H), 7.20 (d, J
= 46.7 Hz, 1H), 7.09 (d, J = 2.7 Hz, 1H), 6.89 (t, J = 2.2 Hz,
Ethyl 2-fluoro-2-(1-isobutyl-2-thioxo-1,2-dihydro-3H- 1H), 4.44 – 4.30 (m, 2H), 2.63 (s, 3H), 1.36 (t, J = 7.1 Hz,
imidazo[4,5-c]quinolin-3-yl)acetate (30). Light yellow 3H). 13C NMR (151 MHz, CDCl3) δ 195.6, 167.5, 164.0 (d,
1
solid. Mp. 112.1 – 113.5 C. 60% yield (86.7 mg). H JC-F = 33.2 Hz, 1C), 156.6 (d, JC-F = 255.2 Hz, 1C), 139.2
NMR (600 MHz, CDCl3) δ 8.93 (s, 1H), 8.23 (d, J = 8.4 Hz, (d, JC-F = 5.9 Hz, 1C), 129.8, 128.9 (d, JC-F = 11.9 Hz, 1C),
1H), 8.14 (dd, J = 8.5, 1.4 Hz, 1H), 7.78 – 7.61 (m, 3H), 124.5 (d, JC-F = 3.7 Hz, 1C), 119.3, 116.6 (d, JC-F = 21.1 Hz,
4.71 (s, 2H), 4.36 (qq, J = 10.9, 7.1 Hz, 2H), 2.52 – 2.40 1C), 115.1, 88.1 (d, JC-F = 212.9 Hz, 1C), 63.4, 26.7, 14.0.
(m, 1H), 1.27 (t, J = 7.11 Hz, 3H), 1.10 – 1.07 (m, 6H). 13
C
IR (KBr, cm-1): 2989, 2923, 2849, 1752, 1683, 1514, 1422,
NMR (151 MHz, CDCl3) δ 172.5, 164.1 (d, JC-F = 33.2 Hz, 1395, 1253, 1191, 1027, 878. LRMS (EI, 70 eV) m/z (%):
1C), 145.6, 133.7, 132.9, 130.9, 128.5, 127.9, 123.3, 120.7, 340 (100), 321 (10), 293 (12), 267 (39), 249 (60), 225 (32),
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801166
Advanced Synthesis & Catalysis
164 (10). HRMS (ESI) for C15H15F2N2O3S+ (M+H)+: calcd 128.7, 127.8, 120.0, 113.4, 87.9 (d, JC-F = 214.4 Hz, 1C),
341.0766, found 341.0769.
75.0, 70.6, 63.2, 52.0, 14.0. IR (KBr, cm-1): 3179, 3138,
3110, 2975, 2915, 2896, 1764, 1444, 1402, 1239, 1086,
789. HRMS (ESI) for C22H21Cl3FN2O3S+ (M+H)+: calcd
517.0317, found 517.0319.
Ethyl
2-fluoro-2-(3-methyl-5-phenyl-2-thioxo-2,3-
dihydro-1H-imidazol-1-yl)acetate (36). White solid. Mp.
1
133.4 – 134.2 C. 81% yield (95.4 mg). H NMR (600
MHz, CDCl3) δ 7.42 (s, 5H), 7.25 (d, J = 47.5 Hz, 1H), Diethyl 2,2'-((2-(2,4-difluorophenyl)-2-hydroxypropane-
6.69 (s, 1H), 3.91 – 3.82 (m, 2H), 3.70 (s, 3H), 1.03 (t, J = 1,3-diyl)bis(5-thioxo-1,5-dihydro-4H-1,2,4-triazole-1,4-
7.2 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 167.1, 164.0 diyl))bis(2-fluoroacetate) (40). White solid. Mp. 117.7 –
1
(d, JC-F = 31.7 Hz, 1C), 130.6 (d, JC-F = 2.9 Hz, 1C), 129.7, 119.0 C. 48% yield (111.1 mg). H NMR (600 MHz,
129.4 (d, JC-F = 2.7 Hz, 1C), 128.8, 127.0, 116.6, 88.0 (d, CDCl3) δ 8.05 – 7.98 (m, 2H), 7.63 – 7.58 (m, 1H), 6.87 –
JC-F = 215.9 Hz, 1C), 62.7, 35.4, 13.6. IR (KBr, cm-1): 3105, 6.81 (m, 2H), 6.84 (d, J = 46.4 Hz, 2H) 5.02 – 4.91 (m, 3H),
3049, 2915, 2850, 1754, 1448, 1402, 1263, 1225, 1193, 4.81 – 4.72 (m, 2H), 4.40 – 4.35 (m, 4H), 1.36 (t, J = 7.1
1063, 1040, 817, 761, 696. LRMS (EI, 70 eV) m/z (%): Hz, 6H). 13C NMR (151 MHz, CDCl3) δ169.2 (d, JC-F
=
294 (100), 222 (48), 221 (36), 201 (43), 131 (30), 101 (10). 10.6 Hz, 2C), 163.2 (dd, JC-F = 250.7, 12.1 Hz, 1C), 163.1
HRMS (ESI) for C14H16FN2O2S+ (M+H)+: calcd 295.0911, (d, JC-F = 30.2 Hz, 2C), 159.4 (dd, JC-F = 249.2, 12.1 Hz,
found 295.0915.
1C), 137.2 (d, JC-F = 6.0 Hz, 2C), 129.9 –129.7 (m, 1C),
123.1 – 123.0 (m, 1C), 111.4 (dd, JC-F = 21.1, 3.0 Hz, 1C),
104.3 (t, JC-F = 26.4 Hz, 1C), 87.1 (dd, JC-F = 214.4, 6.8 Hz,
2C), 77.7 (m, 1C), 63.9, 55.1, 13.9. IR (KBr, cm-1): 3351,
2915, 2850, 1759, 1652, 1634, 1439, 1327, 1276, 1216,
Ethyl
2-fluoro-2-(1-methyl-5-thioxo-1,5-dihydro-4H-
1,2,4-triazol-4-yl)acetate (37). Light yellow oil. 79% yield
(69.3 mg). 1H NMR (600 MHz, CDCl3) δ 8.04 (s, 1H), 6.89
(d, J = 46.5 Hz, 1H), 4.41 – 4.31 (m, 2H), 3.79 (s, 3H),
1.34 (t, J = 7.2 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ
+
1086, 1007, 961, 854. HRMS (ESI) for C21H23F4N6O5S2
(M+H)+: calcd 579.1102, found 579.1107.
167.4, 163.3 (d, JC-F = 31.7 Hz, 1C), 136.8, 87.0 (d, JC-F
=
214.4 Hz, 1C), 63.8, 36.7, 13.9. IR (KBr, cm-1): 3124, 2919, 1-allyl-3-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-
2855, 1763, 1541, 1467, 1397, 1318, 1220, 1081, 1007, thione (41)[19]. Light yellow solid. Mp. 76.2 – 76.6 C.
1
868, 784. LRMS (EI, 70 eV) m/z (%): 219 (96), 147 (100), 92% yield (75.2 mg). (CAS 19382-44-6) H NMR (600
87 (21), 73 (23), 60 (13). HRMS (ESI) for C7H11FN3O2S+ MHz, CDCl3) δ 7.28 – 7.17 (m, 4H), 6.01 – 5.87 (m, 1H),
(M+H)+: calcd 220.0551, found 220.0552.
5.28 – 5.17 (m, 2H), 5.01 (dt, J = 5.6, 1.6 Hz, 2H), 3.81 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 169.8, 132.6, 131.8,
131.1, 123.0, 123.0, 118.1, 109.5, 108.9, 47.2, 31.3. IR
(KBr, cm-1): 3049, 2919, 2845, 1652, 1559, 1485, 1434,
1402, 1351, 1202, 1123, 738. LRMS (EI, 70 eV) m/z (%):
204 (60), 189 (100), 171 (19), 119(16). HRMS (ESI) for
C11H13N2S+ (M+H)+: calcd 205.0794, found 205.0795.
Ethyl
2-(3-(((2R,4S)-4-((4-(4-acetylpiperazin-1-
yl)phenoxy)methyl)-2-(2,4-dichlorophenyl)-1,3-
dioxolan-2-yl)methyl)-2-thioxo-2,3-dihydro-1H-
imidazol-1-yl)-2-fluoroacetate (38). Yellow oil. 37%
1
yield (98.8 mg). H NMR (600 MHz, DMSO-d6) δ 7.62 –
7.59 (m, 1H), 7.49 (dd, J = 8.5, 3.9 Hz, 1H), 7.41 – 7.38 (m,
1H), 7.21 (dd, J = 4.7, 2.7 Hz, 1H), 7.13 (t, J = 3.0 Hz, 1H), 1-(but-3-yn-1-yl)-3-methyl-1,3-dihydro-2H-
6.98 (dd, J = 47.5, 2.8 Hz, 1H), 6.91 (dd, J = 9.1, 2.3 Hz, benzo[d]imidazole-2-thione (42). Brown solid. Mp. 81.1 –
2H), 6.88 – 6.85 (m, 2H), 4.76 – 4.61 (m, 2H), 4.39 – 4.34 82.0 C. 76% yield (216.3 mg). 1H NMR (600 MHz,
(m, 1H), 4.25 – 4.18 (m, 2H), 3.98 – 3.83 (m, 4H), 3.56 (dt, CDCl3) δ 7.36 – 7.32 (m, 1H), 7.27 – 7.24 (m, 2H), 7.21 –
J = 9.8, 5.0 Hz, 4H), 3.01 (t, J = 5.1 Hz, 2H), 2.95 (t, J = 7.18 (m, 1H), 4.50 (t, J = 7.1 Hz, 2H), 3.81 (s, 3H), 2.80 (td,
5.2 Hz, 2H), 2.03 (s, 3H), 1.18 (td, J = 7.1, 4.9 Hz, 3H). 13C J = 7.1, 2.7 Hz, 2H), 1.97 (t, J = 2.7 Hz, 1H). 13C NMR
NMR (151 MHz, DMSO-d6) δ 168.7, 166.9 (d, JC-F = 4.2 (151 MHz, CDCl3) δ 169.5, 132.5, 132.0, 123.0, 122.9,
Hz, 1C), 164.1 (d, JC-F = 33.2 Hz, 1C), 152.6, 146.0, 135.4, 109.4, 108.9, 80.7, 70.6, 43.5, 31.1, 17.8. IR (KBr, cm-1):
134.9, 133.5, 131.0, 130.4, 127.5, 120.9, 120.9, 118.36, 3282, 2952, 2919, 2845, 1615, 1490, 1434, 1411, 1338,
115.8, 115.7, 115.4, 108.2, 88.6 (d, JC-F = 211.4 Hz, 1C), 1188, 733. LRMS (EI, 70 eV) m/z (%): 216 (100), 183 (52),
75.0 (d, JC-F = 2.8 Hz, 1C), 68.5 (d, JC-F = 11.2 Hz, 1C), 164 (64), 131 (42), 118 (16), 77 (12). HRMS (ESI) for
67.0, 62.9, 51.1, 50.6, 50.2, 46.1, 41.3, 21.6, 14.2 (d, JC-F
=
C12H13N2S+ (M+H)+: calcd 217.0794, found 217.0797.
2.7 Hz, 1C). IR (KBr, cm-1): 2915, 2855, 1861, 1745, 1643,
1509, 1411, 1225, 1035, 826, 687. HRMS (ESI) for
C30H34Cl2FN4O6S+ (M+H)+: calcd 667.1555, found
667.1558.
3-(3-methyl-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-
1-yl)propanenitrile (43)[20]. Light yellow solid. Mp. 144.8
1
– 145.5 C. 63% yield (54.8 mg). (CAS 77484-07-2) H
NMR (600 MHz, CDCl3) δ 7.35 – 7.28 (m, 3H), 7.24 –
Ethyl
2-(3-(2-((4-chlorobenzyl)oxy)-2-(2,4- 7.21 (m, 1H), 4.61 (t, J = 6.7 Hz, 2H), 3.81 (s, 3H), 3.03 (t,
dichlorophenyl)ethyl)-2-thioxo-2,3-dihydro-1H-
J = 6.7 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ 169.5,
imidazol-1-yl)-2-fluoroacetate (39):
a
mixture of 132.5, 131.4, 123.6, 123.5, 117.4, 109.3, 108.9, 40.5, 31.2,
diastereomers. White solid. Mp. 98.5 – 100.1 C. 65% 16.4. IR (KBr, cm-1): 2958, 2924, 2850, 2246, 1652, 1611,
1
yield (134.6 mg). Diastereomer 1: H NMR (600 MHz, 1495, 1443, 1397, 1346, 1155, 1127, 733. LRMS (EI, 70
CDCl3) δ 7.47 (d, J = 2.2 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), eV) m/z (%): 217 (100), 177 (15), 164 (94) 131 (37), 118
7.31 (t, J = 2.2 Hz, 1H), 7.30 – 7.25 (m, 2H), 7.17 (d, J = (14), 77 (12). HRMS (ESI) for C11H12N3S+ (M+H)+: calcd
47.3 Hz, 1H), 7.13 – 7.09 (m, 2H), 6.86 (d, J = 2.6 Hz, 1H), 218.0746, found 218.0745.
6.74 (d, J = 2.6 Hz, 1H), 5.29 – 5.20 (m, 1H), 4.47 – 4.32
(m, 4H), 4.24 (d, J = 5.1 Hz, 1H), 4.20 – 4.09 (m, 1H), 1.34
1-benzyl-3-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-
(t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ164.3 (d,
thione (44)[21]. White solid. Mp. 134.0 – 135.0 C. 92%
1
JC-F = 33.2 Hz, 1C), 135.6, 135.0, 134.4, 134.1, 133.8,
yield (93.6 mg). (CAS 26069-99-8) H NMR (600 MHz,
129.8, 129.1, 128.8, 128.7, 127.8, 119.8, 113.6, 88.0 (d, JC-
CDCl3) δ 7.37 (d, J = 7.4 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H),
= 214.4 Hz, 1C), 75.0, 70.5, 63.1, 52.0, 14.0. IR (KBr,
Fcm-1): 3179, 3138, 3110, 2975, 2915, 2896, 1764, 1444,
7.28 – 7.18 (m, 3H), 7.15 (t, J = 7.6 Hz, 1H), 7.08 (d, J =
7.9 Hz, 1H), 5.60 (s, 2H), 3.86 (s, 3H). 13C NMR (151
1402, 1239, 1086, 789. HRMS (ESI) for C22H21Cl3FN2O3S+
MHz, CDCl3) δ 170.5, 135.7, 132.7, 131.8, 128.7, 127.8,
(M+H)+: calcd 517.0317, found 517.0319. Diastereomer 2:
1H NMR (600 MHz, CDCl3) δ 7.46 (d, J = 2.2 Hz, 1H),
7.41 (d, J = 2.1 Hz, 1H), 7.32 (t, J = 2.2 Hz, 1H), 7.30 –
7.25 (m, 2H), 7.18 (d, J = 47.0 Hz, 1H), 7.13 – 7.09 (m,
2H), 6.85 (d, J = 2.6 Hz, 1H), 6.75 (d, J = 2.6 Hz, 1H), 5.29
– 5.20 (m, 1H), 4.47 – 4.32 (m, 4H), 4.26 (d, J = 5.1 Hz,
1H), 4.20 – 4.09 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H). 13C
NMR (151 MHz, CDCl3) δ166.6 (d, JC-F = 27.2 Hz, 1C),
135.6, 134.9, 134.5, 134.2, 133.8, 129.8, 129.1, 128.8,
127.6, 123.0, 123.0, 109.6, 108.9, 48.4, 31.5. IR (KBr, cm-
1): 3063, 3022, 2924, 1601, 1485, 1439, 1402, 1332, 1198,
738, 705. LRMS (EI, 70 eV) m/z (%): 254 (100), 221 (62),
163 (16), 145 (10), 119 (12), 91 (66), 65 (10). HRMS (ESI)
for C15H15N2S+ (M+H)+: calcd 255.0951, found 255.0951.
2-(3-methyl-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-
1-yl)ethyl acetate (45)[5a]. Colorless oil. 85% yield (85.1
1
mg). (CAS 2101845-30-9) H NMR (600 MHz, CDCl3) δ
9
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10.1002/adsc.201801166
Advanced Synthesis & Catalysis
7.29 – 7.25 (m, 3H), 7.22 – 7.19 (m, 1H), 4.74 – 4.59 (m, 127.8, 122.0, 115.7, 89.8 (d, JC-F = 214.4 Hz, 1C), 75.2,
2H), 4.53 – 4.38 (m, 2H), 3.82 (s, 3H), 1.98 (s, 3H). 13C 70.6, 63.3, 53.9, 14.0. IR (KBr, cm-1): 3140, 3110, 2929,
NMR (151 MHz, CDCl3) δ 170.8, 169.9, 132.5, 132.4, 2915, 2896, 1767, 1464, 1402, 1239, 1086, 754. HRMS
123.0, 123.0, 109.1, 109.0, 61.6, 43.6, 31.2, 20.8. IR (KBr, (ESI) for C22H21Cl3FN2O3Se+ (M+H)+: calcd 564.9762,
cm-1): 2929, 2845, 1741, 1481, 1406, 1332, 1225, 1049, found 564.9763. Diastereomer 2: 1H NMR (600 MHz,
743. LRMS (EI, 70 eV) m/z (%): 250 (90), 207 (40), 190 CDCl3) δ 7.47 (d, J = 8.4 1H), 7.44 (d, J = 2.1 Hz 1H), 7.37
(43), 164 (100), 131 (31), 118 (13), 77 (11). HRMS (ESI) (d, J = 32.0 1H), 7.34 – 7.31 (m, 1H), 7.31 – 7.28 (m, 2H),
for C12H15N2O2S+ (M+H)+: calcd 251.0849, found 7.14 – 7.10 (m, 2H), 7.06 (d, J = 2.5 Hz 1H), 6.91 (d, J =
251.0850.
2.5 Hz 1H), 5.30 (t, J = 8.6 Hz 1H), 4.62 – 4.53 (m, 1H),
4.45 – 4.34 (m, 3H), 4.32 – 4.21 (m, 2H), 1.36 (t, J = 7.1
Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 164.0 (d, JC-F
=
Ethyl
2-(3-methyl-2-thioxo-2,3-dihydro-1H-
31.7 Hz, 1C), 135.6, 135.1, 134.5, 134.0, 133.8, 130.0,
benzo[d]imidazol-1-yl)acetate (46). White solid. Mp.
1
129.1, 128.8, 128.7, 127.8, 121.8, 115.9, 89.8 (d, JC-F
=
141.6 – 142.2 C. 56% yield (56.1 mg). H NMR (600
214.4 Hz, 1C), 75.2, 70.6, 63.3, 53.8, 14.0. IR (KBr, cm-1):
3140, 3110, 2929, 2915, 2896, 1767, 1464, 1402, 1239,
1086, 754. HRMS (ESI) for C22H21Cl3FN2O3Se+ (M+H)+:
calcd 564.9762, found 564.9763.
MHz, CDCl3) δ 7.28 – 7.22 (m, 2H), 7.22 – 7.18 (m, 1H),
7.09 – 7.07 (m, 1H), 5.12 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H),
3.81 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz,
CDCl3) δ 170.7, 167.1, 132.5, 131.9, 123.3, 123.2, 109.1,
108.8, 61.9, 45.7, 31.4, 14.1. IR (KBr, cm-1): 2975, 2929,
2850, 1736, 1485, 1416, 1337, 1225, 1198, 1040, 1021, Ethyl 2-fluoro-2-(1-methyl-5-selenoxo-1,5-dihydro-4H-
747. LRMS (EI, 70 eV) m/z (%): 250 (100), 178 (100), 145 1,2,4-triazol-4-yl)acetate (51). Yellow oil. 55% yield
(32), 132 (23), 118 (18), 77(11). HRMS (ESI) for (58.5 mg). 1H NMR (600 MHz, CDCl3) δ 8.20 (s, 1H), 7.09
C12H15N2O2S+ (M+H)+: calcd 251.0849, found 251.0850.
(d, J = 45.9 Hz, 1H), 4.45 – 4.35 (m, 2H), 3.93 (s, 3H),
1.39 (t, J = 7.2 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ
163.3, 163.2 (d, JC-F = 34.7 Hz, 1C), 138.7, 88.7 (d, JC-F
=
Ethyl
(E)-4-(3-methyl-2-thioxo-2,3-dihydro-1H-
214.4 Hz, 1C), 63.9, 38.4, 13.9. IR (KBr, cm-1): 3124, 2919,
2855, 1763, 1525, 1467, 1397, 1318, 1220, 1081, 1007,
890, 754. LRMS (EI, 70 eV) m/z (%): 267 (100), 239 (10),
195 (71), 121 (32), 87 (77), 55 (13). HRMS (ESI) for
C7H11FN3O2Se+ (M+H)+: calcd 267.9995, found 267.9996.
benzo[d]imidazol-1-yl)but-2-enoate (47). Brown solid.
Mp. 107.1 – 108.0 C. 51% yield (56.4 mg). 1H NMR (600
MHz, CDCl3) δ 7.28 – 7.20 (m, 3H), 7.10 – 7.08 (m, 1H),
7.01 (dt, J = 15.7, 4.9 Hz, 1H), 5.73 (dt, J = 15.7, 1.9 Hz,
1H), 5.15 (dd, J = 4.9, 1.9 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H),
3.81 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz,
CDCl3) δ 170.1, 165.5, 140.3, 132.6, 131.4, 123.3, 123.3, 2-fluoro-2-(3-methyl-2-thioxo-2,3-dihydro-1H-
123.2, 109.1, 109.1, 60.6, 45.2, 31.4, 14.2. IR (KBr, cm-1): benzo[d]imidazol-1-yl)acetic acid (52). White solid. Mp.
1
2975, 2924, 2896, 1717, 1657, 1490, 1420, 1337, 1281, 130.2 – 131.4 C. 96% yield (92.3 mg). H NMR (600
1170, 1026, 733. LRMS (EI, 70 eV) m/z (%): 276 (42), 231 MHz, DMSO-d6) δ 14.50 (s, 1H), 7.55 (d, J = 7.5, 1H),
(12), 203 (45), 189 (100), 164 (12), 119 (11), 77 (9). 7.41 (d, J = 46.2 Hz, 1H), 7.37 – 7.29 (m, 3H), 3.76 (s, 3H).
HRMS (ESI) for C14H17N2O2S+ (M+H)+: calcd 277.1005, 13C NMR (151 MHz, DMSO-d6) δ 171.0, 165.9 (d, JC-F
=
found 277.1008.
31.7 Hz, 1C), 132.7, 129.5 (d, JC-F = 2.2 Hz, 1C), 124.6,
124.3, 110.9, 109.9, 87.9 (d, JC-F = 211.4 Hz, 1C), 32.0. IR
(KBr, cm-1): 3637, 3071, 2942, 1773, 1723, 1442, 1397,
1334, 1200, 1068, 738. HRMS (ESI) for C10H10FN2O2S+
(M+H)+: calcd 241.0442, found 241.0441.
1-methyl-3-(3,4,4-trifluorobut-3-en-1-yl)-1,3-dihydro-
2H-benzo[d]imidazole-2-thione (48). Yellow oil. 84%
yield (81.5 mg). 1H NMR (600 MHz, CDCl3) δ 7.29 – 7.26
(m, 2H), 7.24 – 7.18 (m, 2H), 4.53 (t, J = 6.9 Hz, 2H), 3.81
(s, 3H), 2.93 – 2.86 (m, 2H). 13C NMR (151 MHz, CDCl3) 2-fluoro-2-(3-methyl-2-thioxo-2,3-dihydro-1H-
δ 169.7, 153.5 (td, JC-F = 281.6, 46.8, 13.6 Hz, 1C), 132.5, benzo[d]imidazol-1-yl)-N-(thiazol-2-yl)acetamide (53).
131.7, 126.1 (ddd, JC-F = 234.1, 52.9, 16.6 Hz, 1C), 123.2, White solid. Mp. 215.3 – 215.9 C. 85% yield (109.6 mg).
123.2, 109.1, 108.5, 40.7, 31.1, 24.6 (dd, JC-F = 21.1, 3.0 1H NMR (600 MHz, DMSO-d6) δ 13.13 (s, 1H), 7.62 (d, J
Hz, 1C). IR (KBr, cm-1): 3054, 2915, 2850, 1792, 1485, = 46.7 Hz, 1H), 7.56 – 7.53 (m, 1H), 7.52 (d, J = 3.8 Hz,
1406, 1332, 1295, 1257, 1114, 1003, 743. LRMS (EI, 70 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.28 (d, J = 3.8 Hz, 1H), 7.24
eV) m/z (%): 272 (41), 190 (43), 171 (19), 164 (100) 131 (t, J = 7.7 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 3.77 (s, 3H).
(37), 118 (14), 77 (12). HRMS (ESI) for C12H12F3N2S+ 13C NMR (151 MHz, DMSO-d6) δ 171.4, 132.9, 129.7 (d,
(M+H)+: calcd 273.0668, found 273.0670.
JC-F = 2.4 Hz, 1C), 124.5, 124.2, 114.4, 114.3, 110.8, 110.1,
89.4 (d, JC-F = 211.4 Hz, 1C), 32.0. IR (KBr, cm-1): 3161,
3005, 2942, 1692, 1542, 1444, 1402, 1335, 1291, 1025,
Ethyl 2-fluoro-2-(3-methyl-2-selenoxo-2,3-dihydro-1H-
benzo[d]imidazol-1-yl)acetate (49). White solid. Mp.
154.3 – 155.7 C. 62% yield (78.2 mg). H NMR (600
+
824, 745. HRMS (ESI) for C13H12FN4OS2 (M+H)+: calcd
1
323.0431, found 323.0430.
MHz, CDCl3) δ 7.76 (d, J = 45.0 Hz, 1H), 7.37 – 7.26 (m,
4H), 4.38 – 4.29 (m, 2H), 3.94 (d, J = 0.8 Hz, 3H), 1.25 (t,
J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 170.1,
164.3 (d, JC-F = 34.7 Hz, 1C), 133.7, 130.4, 124.6, 124.3,
110.7, 109.8, 89.8 (d, JC-F = 214.4 Hz, 1C), 63.2, 33.8, 14.0.
IR (KBr, cm-1): 2943, 2855, 1758, 1488, 1444, 1387, 1333,
1292, 1217, 1178, 1051, 751. LRMS (EI, 70 eV) m/z (%):
316 (86), 244 (61), 223 (10), 208 (11), 163 (100), 143 (14),
131 (22), 102 (17), 75 (10). HRMS (ESI) for
C12H14FN2O2Se+ (M+H)+: calcd 317.0199, found 317.0198.
Acknowledgements
We gratefully thank the South China Agricultural University,
Science Technology Program Project of Guangdong Province
(No. 2016B020204005), and the Open Fund of the Key
Laboratory of Functional Molecular Engineering of Guangdong
Province (2017kf03) (South China University of Technology) for
their financial support. I also thank Prof. Jin-Heng Li for fruitful
discussions.
Ethyl
2-(3-(2-((4-chlorobenzyl)oxy)-2-(2,4-
dichlorophenyl)ethyl)-2-selenoxo-2,3-dihydro-1H-
imidazol-1-yl)-2-fluoroacetate (50):
diastereomers, Yellow oil, 43%
a
mixture of
yield (97.1 mg).
References
Diastereomer 1: 1H NMR (600 MHz, CDCl3) δ 7.47 (d, J =
8.4 1H), 7.44 (d, J = 2.1 Hz 1H), 7.37 (d, J = 32.0 1H),
7.34 – 7.31 (m, 1H), 7.31 – 7.28 (m, 2H), 7.14 – 7.10 (m,
2H), 7.05 (d, J = 2.5 Hz, 1H), 6.92 (d, J = 2.5 Hz 1H), 5.29
(t, J = 8.6 Hz 1H), 4.62 – 4.53 (m, 1H), 4.45 – 4.34 (m, 3H),
4.32 – 4.21 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR
(151 MHz, CDCl3) δ 162.0 (d, JC-F = 31.7 Hz, 1C), 135.5,
135.1, 134.6, 134.1, 133.9, 130.0, 129.1, 128.8, 128.7,
[1] D. C. Blakemore, L. Castro, I. Churcher, D. C. Rees, A.
W. Thomas, D. M. Wilson, A. Wood, Nature
Chem. 2018, 10, 383–394.
10
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10.1002/adsc.201801166
Advanced Synthesis & Catalysis
[2] a) Y.-J. Wu, Progress Heterocyclic Chem. 2012, 24, 1–
53. b) K. K. Biron, Antiviral Res. 2006, 71, 154–163. c)
G. Gece, Corros. Sci. 2011, 53, 3873–3898.
Res. 2007, 40, 303–313. b) J. Tauber, D. Imbri, T.
Opatz, Molecules 2014, 19, 16190–16222.
[16] Reviews for carbene, see: a) W. A. Herrmann, C.
Köcher, Angew. Chem. Int. Ed. 1997, 36, 2162–2187. b)
D. J. Nelson, S. P. Nolan, Chem. Soc. Rev. 2013, 42,
6723–6753.
[3] a) K. P. Bhabak, G. Mugesh, Chem. -Eur. J. 2010, 16,
1175–1185. b) D. Das, G. Roy, G. Mugesh, J. Med.
Chem. 2008, 51, 7313–7317.
[4] a) A. Guan, L. Li, C. Liu, Nongyao 2003, 42, 42–43, 41. [17] A review on the application of elemental sulfur in
b) M. Jautelat, H.-L. Elbe, J. Benet-Buchholz, W. Etzel,
Pflanzenschutz-Nachrichten Bayer 2004, 57, 145–162.
organic synthesis, see: T. B. Nguyen, Adv. Synth. Catal.
2017, 359, 1066–1130.
[5] a) M. Banerjee, R. Karri, A. Chalana, R. Das, R. K. Rai, [18] Our work for the direct sulfurization of
K. S. Rawat, B. Pathak, G. Roy, Chem. -Eur. J. 2017,
23, 5696–5707. b) M. Banerjee, R. Karri, K. S. Rawat,
K. Muthuvel, B. Pathak, G. Roy, Angew. Chem. Int. Ed.
2015, 54, 9323–9327.
imidazoheterocycles, see: a) J.-R. Zhang, L.-Z. Zhan, L.
Wei, Y.-Y. Ning, X.-L. Zhong, J.-X. Lai, L. Xu, R.-Y.
Tang, Adv. Synth. Catal. 2018, 360, 533–543. b) J.-R.
Zhang, Y.-Y. Liao, J.-C. Deng, K.-Y. Feng, M. Zhang,
Y.-Y. Ning, Z.-W. Lin, R.-Y. Tang, Chem. Commun.
2017, 53, 7784–7787. c) J.-C. Deng, S.-B. Zhuang, Q.-
Z. Liu, Z.-W. Lin, Y.-L. Su, J.-H. Chen, R.-Y Tang,
RSC Adv. 2017, 7, 54013–54016. d) J. Jiao, L. Wei, X.-
M. Ji, M.-L. Hu, R.-Y. Tang, Adv. Synth. Catal. 2016,
358, 268–275.
[6] Q. Xu, C. H. Heo, G. Kim, H. W. Lee, H. M. Kim, J.
Yoon, Angew. Chem. Int. Ed. 2015, 54, 4890–4894.
[7] K. Mebrouk, F. Camerel, O. Jeannin, B. Heinrich, B.
Donnio, M. Fourmiguꢀ, Inorg. Chem. 2016, 55,
1296−1303.
[19] T. Takahashi, A. Kaji, J. Hayami, Bull. Inst. Chem.
Res. 1973, 51, 163-172.
[8] B. M. Neilson, V. M. Lynch, C. W. Bielawski, Angew.
Chem. Int. Ed. 2011, 50, 10322–10326.
[20] Jpn. Kokai Tokkyo Koho, JP Patent, 55118468A,
[9] a) H. R. Kim, I. G. Jung, K. Yoo, K. Jang, E. S. Lee, J.
Yun, S. U. Son, Chem. Commun. 2010, 46, 758–760. b)
L.-M. Zhang, H.-Y. Li, H.-X. Li, D. J. Young, Y. Wang,
J.-P. Lang, Inorg. Chem. 2017, 56, 11230−11243. c) E.
Alvarado, A. C. Badaj, T. G. Larocque, G. G.
Lavoie, Chem. –Eur. J. 2012, 18, 12112−12121.
1980.
[21] K. M. Krivozheiko, M. B. Kolesova, A. V. El'tsov,
Biol. Aktiv. Soedin. 1968, 300-308.
[10] A. Wohl, W. Marckwald, Ber. Dtsch. Chem. Ges.
1889, 22, 568–580.
[11] a) K. Matsuda, I. Yanagisawa, Y. Isomura, T. Mase, T.
Shibanuma, Synth. Commun. 1997, 27, 3565–3571. b)
B. Batanero, J. Escudero, F. Barba, Synthesis 1999,
1809–1813. c) D. M. Wolfe, P. R. Schreiner, Eur. J.
Org. Chem. 2007, 2825–2838. d) A. Ranjan, R.
Yerande, P. B. Wakchaure, S. G. Yerande, D. H. Dethe,
Org. Lett. 2014, 16, 5788−5791. e) G. S. Yellol, C.-T.
Chou, W.-J. Chang, B. Maiti, C.-M. Sun, Adv. Synth.
Catal. 2012, 354, 187–196. f) R.-S. Zeng, J.-P. Zou, S.-
J. Zhi, J. Chen, Q. Shen, Org. Lett. 2003, 5, 1657–1659.
[12] a) A. J. Arduengo, U.S. Patent 5,104,993, 1992. b) C.
O. Yang, D. M. Rotstein, S. S. Labadie, K. A. M.
Walker, Synlett 1995, 1995, 655–658. c) X.-L. Tao, M.
Lei, Y.-G. Wang, Synth. Commun. 2007, 37, 399–408.
d) M. Feroci, M. Orsini, A. Inesi, Adv. Synth. Catal.
2009, 351, 2067–2070.
[13] a) C.-P. Zhang, Q.-Y. Chen, Y. Guo, J.-C. Xiao, Y.-C.
Gu, Chem. Soc. Rev. 2012, 41, 4536–4559. b) B.-N.
Huang, W.-Y. Huang, C.-M. Hu, Acta Chim. Sinica.
1981, 39, 481–483.
[14] Compound 2a has been used as a linker for the
template of meta-C-H activation, see: R.-Y. Tang, G. Li,
J.-Q. Yu, Nature 2014, 507, 215–220.
[15] Reviews for radical addition of imines, see: a) C. H.
Schiesser, U. Witle, H. Matsubara, I. Ryu, Acc. Chem.
11
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10.1002/adsc.201801166
Advanced Synthesis & Catalysis
FULL PAPER
Sulfite-Induced N-Alkylation and Thioketonization
of Azoles Enable Access to Diverse Azole Thiones
Adv. Synth. Catal. Year, Volume, Page – Page
Jian-Chao Deng,a Jia-Hao Chen,a Jun-Rong Zhang,a
Ting-Ting Lu,a and Ri-Yuan Tang*abc
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This article is protected by copyright. All rights reserved.