Trapping of trifluoroacetonitrile imines with mercaptoacetaldehyde and mercaptocarboxylic acids: An access to fluorinated 1,3,4-thiadiazine derivatives via (3+3)-annulation

Article abstract of DOI:10.1016/j.jfluchem.2019.04.012

The in situ generated highly electrophilic nitrile imines derived from trifluoroacetonitrile are efficiently trapped by monomeric mercaptoacetaldehyde at room temperature in THF solution. The initially formed 1:1 adducts undergo spontaneous cyclization le

Full text of DOI:10.1016/j.jfluchem.2019.04.012

Accepted Manuscript
Title: Trapping of trifluoroacetonitrile imines with
mercaptoacetaldehyde and mercaptocarboxylic acids: an
access to fluorinated 1,3,4-thiadiazine derivatives via
(3+3)-annulation
Authors: Greta Utecht-Jarzy n´ ska, Aleksandra Michalak,
Justyna Bana s´ , Grzegorz Mlosto n´ , Marcin Jasi n´ ski
PII:
S0022-1139(19)30099-5
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2019.04.012
FLUOR 9315
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
25 March 2019
10 April 2019
10 April 2019
Please cite this article as: Utecht-Jarzy n´ ska G, Michalak A, Bana s´ J, Mlosto n´ G,
Jasi n´ ski M, Trapping of trifluoroacetonitrile imines with mercaptoacetaldehyde
and mercaptocarboxylic acids: an access to fluorinated 1,3,4-thiadiazine
derivatives via (3+3)-annulation, Journal of Fluorine Chemistry (2019),
https://doi.org/10.1016/j.jfluchem.2019.04.012
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th
Journal of Fluorine Chemistry, March 25 , 2019
th
Revised – April 10 , 2019
Trapping of trifluoroacetonitrile imines with mercaptoacetaldehyde and
mercaptocarboxylic acids: an access to fluorinated 1,3,4-thiadiazine derivatives via (3+3)-
annulation
Greta Utecht-Jarzyńska, Aleksandra Michalak, Justyna Banaś, Grzegorz Mlostoń, Marcin Jasiński*
Faculty
of
Chemistry,
University
of
Łódź,
Tamka
12,
91-403
Łódź,
Poland,
corresponding author: E-mail: mjasinski@uni.lodz.pl
Marcin Jasiński
Faculty of Chemistry, University of Łódź
Tamka 12, 91-403 Łódź, Poland
Tel.:
Fax:
+48 42 635 57 66
+48 42 665 51 62
e-mail: mjasinski@uni.lodz.pl
th
Dedicated to Professor Hans-Ulrich Reissig on the occasion of his 70 birthday
Graphical abstract:
Graphical abstract

nitrile imines derived from trifluoroacetonitrile can easily be trapped by bifunctional S-
nucleophiles

adducts obtained with mercaptoethanal undergo a spontaneous (3+3)-cyclisation to give 6-
membered products
1



oxidation of 1,3,4-thiadiazin-5-ols with PCC leads to the expected 1,3,4-thiadiazin-5-one
derivatives
1:1 adducts obtained with mercaptocarboxylic acids undergo cyclization only in the presence
of EDC methiodide
Abstract
The in situ generated highly electrophilic nitrile imines derived from trifluoroacetonitrile are efficiently
trapped by monomeric mercaptoacetaldehyde at room temperature in THF solution. The initially formed 1:1
adducts undergo spontaneous cyclization leading to 6-membered 5,6-dihydro-1,3,4-thiadiazin-5-ols bearing the
3 5 5 3
CF group at the C(2) atom in good yields. Subsequent oxidation of the latter products using C H N∙HCl∙CrO
(
PCC) led smoothly to the expected 1,3,4-thiadiazin-5-ones as final products. Alternatively, analogous 2-
trifluoromethylated heterocycles were obtained via trapping of the same nitrile imines with α-mercaptocarboxylic
acids followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC methiodide) induced
cyclisation of the initially formed 1:1 adducts. In general, efficiency of the second approach was lower and
depended on the type of substituent attached to phenyl ring in the starting 1,3-dipole.
Keywords: fluorinated nitrile imines, mercaptoacetaldehyde, α-mercaptocarboxylic acids, (3+3)-annulation,
trifluoromethylated 1,3,4-thiadiazines.
2

1. Introduction
According to Huisgen classification nitrile imines belong to the class of so-called propargyl-allenyl 1,3-
dipoles [1]. Over decades they have been widely applied in the (3+2)-cycloaddition reactions leading to diverse
nitrogen-containing five-membered heterocycles [2]. However, along with their tendency to react as 1,3-dipoles,
they are also known as electrophilic reagents, and the reactions with O-, N-, and S-nucleophiles are reported [3].
In our continuing studies on (3+2)-cycloadditions with fluorinated nitrogen-centered 1,3-dipoles [4-6], much
attention was paid to strongly electron-deficient nitrile imines 1 derived from trifluoroacetonitrile. For example,
we found that they react easily not only with aromatic and aliphatic thioketones but also with monomeric
thiochalcones yielding the 1,3,4-thiadiazole derivatives of type 2 in a fully regioselective manner [5]. In addition,
they underwent cycloadditions with less reactive electron-rich C=C dipolarophiles such as vinyl ethers and
alkoxyallenes leading to pyrazoles 3 and more complex spirobipyrazolines 4, respectively [6]; the latter products
being formed in a highly diastereoselective fashion via formal double (3+2)-cycloaddition (Scheme 1) [6b].
Mercaptoacetaldehyde (5), easily available from its stable dimer 1,4-dithiane-2,5-diol (6), is well known
as a versatile building block for the preparation of the S-containing organic products [7], and its reactions with
nitrile imines afforded 1,3,4-thiadiazine derivatives formed via spontaneous cyclisation of the initial 1:1 adducts
[
8].
The goal of the present work was to examine the course of the reactions between the in situ generated
nitrile imines 1 and mercaptoacetaldehyde under mild conditions. In addition, similar reactions with other
bifunctional substrates, e.g. -mercaptocarboxylic acids 7 were also of interest. Both procedures were expected to
open up an access to hitherto unknown trifluoromethylated 1,3,4-thiadiazin-6-ones 8 in a complementary approach
(
Scheme 1).
3

Scheme 1. Reactions of fluorinated nitrile imines 1 with thiocarbonyls (thioketones and thiochalcones), vinyl ethers, and
alkoxyallenes leading to (3+2)-cycloadducts 2-4, and (3+3)-annulations of 1 with bifunctional substrates 5 and 7 described
herein.
2
. Results and Discussion
A series of recent papers demonstrate that the title trifluoroacetonitrile imines 1 are readily available via
base-mediated dehydrohalogenation of the respective hydrazonoyl bromides of type 9 [5-6], and the requisite
precursors were prepared in a two-step protocol comprising condensation of fluoral hydrate with arylhydrazines
[
9] followed by bromination of the resulting hydrazones with NBS [5a]. In a test experiment the reaction of N’-
tolyl bromide 9a (X = CH ) and 1,4-dithiane-2,5-diol (6, 0.55 equiv.) was carried out in dry THF at room
temperature, in the presence of excess of Et
3
3
N (5.0 equiv.) (Scheme 2). The reaction progress was monitored by
1
TLC until the starting bromide 9a was fully consumed (2 hrs). The resulting mixture was examined by H NMR,
and only one set of signals attributed to the sole intermolecular product could be found in this spectrum. Subsequent
purification by flash column chromatography provided analytically pure material isolated as a fairly stable
colourless solid (78% yield), and the structure of the expected 5,6-dihydro-1,3,4-thiadiazin-5-ol derivative 10a
1
was confirmed by spectroscopic methods. For example, in the H NMR spectrum, the diagnostic absorptions of
the diastereotopic protons at C(6) were found at 2.93 (dd, J = 1.7, 12.9 Hz) and 3.18 (dd, J = 3.4, 12.9 Hz) ppm.
In addition, along with the characteristic pattern attributed to the p-tolyl group, the signals located at 3.06 (d, J =
1
0.7 Hz) and 5.64 (ddd, J = 1.7, 3.4, 10.7 Hz) ppm clearly evidenced the presence of the C(5)H(OH) group. In the
13C NMR spectrum two diagnostic quartets found at 119.7 (1JC-F = 273.0 Hz) and 120.7 (2J C-F = 38.9 Hz) ppm,
1
9
3
and a singlet located at 67.6 ppm in the F NMR spectrum confirmed the presence of the CF -C= unit. Moreover,

the (-)-ESI-MS spectrum showed the molecular peak of [M–H] at m/z = 273.5, which corresponded to the formula
C
11
H
11
F
3
N
2
OS.
In continuation of the study, a series of trifluoromethylated 5,6-dihydro-1,3,4-thiadiazinols of type 10
was prepared starting with differently substituted hydrazonoyl bromides 9, including representatives
functionalized with either strongly electron-donating (9c) or electron-withdrawing (9f,g) groups located at the para
position of the phenyl ring. In all the studied cases, the expected heterocyclic products 10 were isolated in fine
yields (64-92%), irrespective of the electronic properties of substituent X, although longer reaction times (up to
4
hr) were noticed for the transformations of nitrile imines 1 functionalized with EWGs attached to the phenyl ring.
The decrease in reaction rates can be explained by reduced nucleophilicity of NH group present in the initially
formed S-adduct. For that reason, the subsequent spontaneous cyclisation is expected to be a limiting step. Notably,
neither nitrile nor nitro and ester moieties interfered with the outcome of the developed (3+3)-annulation reaction.
4

Scheme 2. Synthesis of 1,3,4-thiadiazin-5-ols 10a-10h via (3+3)-annulation of mercaptoacetaldehyde (5) with the in situ
generated trifluoroacetonitrile imines 1a-1h.
The presence of the hemiaminal group in the newly synthesized 1,3,4-thiadiazine derivatives 10 offers
several possibilities for further functionalization of the core heterocycle. Particularly, taking into account the well
documented significance of the 1,3,4-thiadiazinone derivatives as biologically active compounds [10], we paid
some attention to oxidation protocols. Thus, the behavior of the model N-tolyl substituted 1,3,4-thiadiazin-5-ol
1
0a was briefly checked in reactions with selected mild oxidants. Unfortunately, neither treatment with activated
MnO nor with IBX under standard reaction conditions (CH Cl , 24 hr) provided the desired product. However,
the use of excess of pyridinium chlorochromate (PCC, 1.5 equiv.) as an oxidizing agent in CH Cl at room
2
2
2
2
2
temperature, afforded after 2h the expected thiadiazinone derivative 8a, which was isolated by flash column
chromatography in high yield of 83% (Scheme 3). Analogous transformations were also performed starting with
1
0a,b,e-g to give the expected 1,3,4-thiadiazin-5-one derivatives 8 in high yields of 63-91%.
Scheme 3. Oxidation of selected 5,6-dihydro-1,3,4-thiadiazin-5-ols 10 with PCC leading to 1,3,4-thiadiazin-5-ones 8.
In extension of the study, we turned our attention to -mercaptocarboxylic acids of type 7 as the
alternative bifunctional HS-nucleophiles for the preparation of target fluorinated 1,3,4-thiadiazine derivatives [11].
As shown in Scheme 4, the test experiment was performed using model N-tolylhydrazonoyl bromide 9a and
3
thioglycolic acid (7a), in dry THF, in the presence of excess of Et N. The reaction progress was monitored by
TLC, and after the nitrile imine precursor 9a was fully consumed, the resulting mixture was acidified with diluted
1
HCl followed by standard aqueous work-up. H NMR spectrum of mother liquor showed the presence two
2
diagnostic signals (singlets) located at 3.57 (2 H, CH ) and 9.60 (1 H, NH) ppm along with the characteristic
absorptions attributed to the p-tolyl group. That can serve as confirmation of the structure of acyclic adduct 11a
formed as the major component of the mixture. Following the general protocol for the synthesis of amides and
other carboxylic acid derivatives [12], 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC
5

methiodide) was examined as the coupling reagent for the subsequent cyclisation step. As expected, treatment of
crude 11a with EDC methiodide under standard reaction conditions (dry THF, room temperature) provided after
1
6hr the desired 1,3,4-thiadiazin-5-one derivative 8a in 27% yield (for 2 steps). Brief optimization of the final
annulation step with respect e.g. to the type of the solvent, and stoichiometry of substrates indicated that running
the reaction in dry CH Cl in the presence of slight excess EDC methiodide leads to product 8a in a satisfactory
2
2
overall yield of 50%. Next, a series of nitrile imines 1c-1g was tested in the reaction with thioglycolic acid (7a)
under analogous reaction conditions to provide the expected formal (3+3)-annulation products 8c-8g in moderate
yields.
Scheme 4. Synthesis of 1,3,4-thiadiazin-5-ones 8 via two-step (3+3)-annulation of nitrile imines 1 and -mercaptocarboxylic
acid 7a.
Finally, another three HS-nucleophiles functionalized with carboxylic groups, namely 2-
mercaptopropionic acid (7b), mercaptosuccinic acid (7c), and 3-mercaptopropionic acid (12) were involved into
the study, and their reactions with hydrazonoyl bromide 9f (X = NO
2
) provided solely the expected adducts of type
1 (Scheme 5). Subsequent treatment of compound 11h with EDC methiodide afforded 6-methylated derivative
h in fair overall yield of 55%. In contrast, the attempted cyclisation of 11i under analogous reaction conditions
1
8
led mainly to decomposition products formed, very likely, via competitive rearrangement of the first formed adduct
13]. Expected 7-membered 1,3,4-thiadiazepine derivative could not be found in the crude reaction mixture.
[
Similarly, the reaction of thiohydrazonate derivative 11j with the same coupling agent provided a complex mixture
of highly polar components, presumably the corresponding EDC-adducts of 11j, along with unidentified
decomposition products, although in this case, the formation of 6-membered product of type 8 in trace amounts
only was observed.
6

Scheme 5. Trapping of in situ generated nitrile imine 1f with 2-mercaptopropionic acid (7b), mercaptosuccinic acid (7c), and
3
-mercaptopropionic acid (12), and selected transformations of the initial adducts 11h-11j.
In order to test an alternative base-induced cyclisation approach [3d,11b], the first formed carboxylic
acids 11i and 11j were converted into their methyl esters 13i and 13j in overall 24% and 25% yield, respectively
Scheme 5). Unfortunately, attempted activation of the NH group in compounds 13 with K CO , LiOH, MeONa,
(
2
3
LDA, and NaH gave no satisfactory result, and either starting materials were recovered or decomposition products
were formed depending on the reaction conditions. Apparently, limited stability of 13 in the presence of hydroxide
and alkoxide reflect remarkably electrophilic character of esters 13, enhanced by the presence of the strongly
3
electron-withdrawing CF group, and the observed decomposition is presumably initiated by nucleophilic attack
onto the C atom of the thiohydrazonate group. Also, attempted cyclisation of 13i and 13j by heating either in
solution (refluxing EtOH or toluene) or neat (120 °C) was in vain.
3
. Conclusions
The presented study showed, that in situ generated electron-deficient fluorinated nitrile imines 1 can be
smoothly trapped by bifunctional HS-nucleophiles, and in the case of mercaptoacetaldehyde (5) spontaneous
cyclisation of the initial adducts leads to 1,3,4-thiadiazin-5-ols 10 as formal (3+3)-annulation products. The latter
compounds could be easily oxidized to 1,3,4-thidiazin-5-ones of type 8 by treatment with PCC. In contrast, the
analogous S-adducts derived from -mercaptocarboxylic acids 7 cyclized to a desired fluorinated 1,3,4-thidiazin-
5
-one 8 only upon treatment with the appropriate carbodiimide used as a coupling agent (EDC methiodide). The
presented complementary approaches leading to a novel fluorinated 1,3,4-thiadiazines 10 and 8 nicely supplement
protocols for the preparation of 1,3,4-thiadiazinones described in the literature [14], and other synthetic methods
7

towards fluoroalkylated N-heterocycles of practical applications [15]. In addition, the presented study emphasizes
the importance of nitrile imines as useful, versatile building blocks for the efficient preparation of not only 5-
membered heterocycles by (3+2)-cycloadditions with appropriate dipolarophiles but also larger, 6-membered ring
products formed via two-step (3+3)-annulation approach using bifunctional nucleophiles.
4
. Experimental Part
4
.1. General information
Solvents and reagents were purchased (Sigma-Aldrich, Acros) and used as received without further
purification. THF was dried over sodiumbenzophenone and freshly distilled before usage. Dichloromethane was
dried over CaH prior to use. If not stated otherwise, reactions were carried out under argon in flame-dried flasks
2
with addition of the reactants by using syringes; subsequent manipulations were conducted in air. Products were
purified by column chromatography on silica gel (230–400 mesh). Reported yields refer to analytically pure
1
13
samples. NMR spectra were measured on a Bruker AVIII 600 MHz ( H NMR [600 MHz]; C NMR [151 MHz];
19
19
F NMR [565 MHz]) or with a Varian Gemini 2000BB 200 MHz ( F NMR [188 MHz]) instruments. Chemical
1
]; 13C NMR: δ = 77.0 ppm
shifts are reported relative to solvent residual peaks ( H NMR: δ = 7.26 ppm [CDCl
3
3 3
CDCl ]) or to CFCl
(δ = 0.00 ppm) used as an external standard in 19F NMR measurements. For detailed peak
[
1
3
assignments in C NMR 2D spectra were taken (COSY, HMQC, HMBC). IR spectra were measured with a FTIR
NEXUS spectrometer (as thin film or KBr pellets). MS (ESI) were performed with a Varian 500-MS LC Ion Trap.
Elemental analyses were obtained with a Vario EL III (Elementar Analysensysteme GmbH) instrument. Melting
points were determined in capillaries with a MEL-TEMP II apparatus (Aldrich), and are uncorrected. Hydrazonoyl
bromides 9a-9h were obtained by treatment of the corresponding arylhydrazones with N-bromosuccinimide
(
NBS), in dry DMF, following the literature protocol [5a]. The latter trifluoroacetaldehyde hydrazones were
prepared by heating methanolic solutions of the appropriate hydrazine and excess fluoral hydrate in a closed
ampoule at 75 C overnight, in the presence of molecular sieves 4Å according to our earlier report [9].
4
.2. Synthesis of 1,3,4-thiadiazin-5-ones 8
Method A: To a solution of 5,6-dihydro-1,3,4-thiadiazin-5-ol 10 (1.0 mmol) in dichloromethane (10 mL)
was added PCC (323 mg, 1.5 mmol) and the resulting mixture was stirred at room temperature until the starting
0 was fully consumed (TLC monitoring, 2-10 h). The mixture was filtered through a short pad of Celite, and the
solvent was removed under reduced pressure. The crude product 8 was purified by flash column chromatography
SiO , CH Cl ).
Method B: To a solution of hydrazonoyl bromide 9 (1.0 mmol) and α-mercaptocarboxylic acid 7 (1.1
mmol) in dry THF (10 mL) was added dropwise Et N (2 mmol, 0.3 mL), and the resulting mixture was stirred at
room temperature overnight. Then, reaction was acidified with aq. HCl (5%) and extracted with Et O (3  15 mL).
The combined organic layers were dried (Na SO ), filtered, and the solvents were removed under reduced pressure.
The residue was dissolved in dry CH Cl (10 mL), solid EDC methiodide was added (171 mg, 1.1 mmol) and the
1
(
2
2
2
3
2
2
4
2
2
resulting mixture was stirred at room temperature overnight. The precipitate was filtered off, the solvents were
8

removed in vacuo, and the residue was purified by column chromatography (CC) to give 1,3,4-thiadiazin-5-one
derivatives 8.
4
.2.1. 4-(p-Tolyl)-2-(trifluoromethyl)-4H-1,3,4-thiadiazin-5(6H)-one (8a)
CC (SiO
2
, petroleum ether/CH
2
Cl
2
1:1), Method A: 227 mg (83%), Method B: 137 mg (50%), colourless
):  2.38 (s, 3 H, CH ), 3.64 (s, 2 H, 6-H ), 7.24, 7.30 (2 dbr, J ≈
, 151 MHz):  21.1 (q, CH
), 26.4 (t, C-6), 119.2 (q, 1JC-F = 275.0 Hz,
), 125.1, 129.5 (2 d, 4 CH), 135.9 (q, 2JC-F = 39.5 Hz, C-2), 137.7, 138.1 (2 s), 156.6 (s, C=O) ppm; 19F NMR
CDCl , 188 MHz):  –68.1 (s, CF ) ppm; IR (KBr): v 1694 (C=O), 1514, 1327, 1304, 1213, 1196, 1141, 1123,
014 cm ; ESI-MS (m/z): 297.1 (100, [M+Na] ), 275.1 (28, [M+H] ); elemental analysis calcd (%) for
OS (274.3): C 48.17, H 3.31, N 10.21, S 11.69; found: C 48.21, H 3.44, N 10.21, S 11.66.
1
solid, mp 4547 °C. H NMR (600 MHz, CDCl
3
3
2
8
.4 Hz, 2 H each) ppm; 13C NMR (CDCl
3
3
CF
3
(
3
3
-
1
+
+
1
11 9 3 2
C H F N
4
.2.2. 4-Phenyl-2-(trifluoromethyl)-4H-1,3,4-thiadiazin-5(6H)-one (8b)
1
CC (SiO
), 7.34-7.37, 7.43-7.46 (2 m, 1 H, 4 H) ppm; 13C NMR (CDCl
), 125.1, 128.0, 128.9 (3 d, 5 CH), 136.2 (q, 2JC-F = 39.5 Hz, C-2), 140.0 (s), 156.6 (s, C=O) ppm;
2
, CH
2
Cl
2
), Method A: 213 mg (82%), colourless oil. H NMR (600 MHz, CDCl
3
): δ 3.65 (s, 2
H, 6-H
2
, 151 MHz): δ 26.4 (t, C-6), 119.1 (q, 1JC-F
3
=
275.2 Hz, CF
3
19F NMR (CDCl
3
3
, 565 MHz): δ 68.1 (s, CF ) ppm; IR (KBr): ν 2930, 1690 (C=O), 1597, 1494, 1327, 1198, 1124,
-
1
+
1
4
016, 691 cm ; ESI-MS (m/z): 261.2 (100, [M+H] ); elemental analysis calcd (%) for C10
H
F
7 3
N
2
OS (260.2): C
6.15, H 2.71, N 10.76, S 12.32; found C 46.41, H 2.87, N 10.88, S 12.21.
4
.2.3. 4-(4-Methoxyphenyl)-2-(trifluoromethyl)-4H-1,3,4-thiadiazin-5(6H)-one (8c)
CC (SiO
2
, petroleum ether/CH
):  3.63 (s, 2 H, 6-H
, 151 MHz):  26.4 (t, C-6), 55.5 (q, OCH
), 126.6 (d, 2 CH), 133.1 (s), 135.8 (q, 2JC-F = 39.3 Hz, C-2), 156.6 (s, C=O), 159.2 (s, COMe) ppm;
19F NMR (CDCl
, 188 MHz):  68.1 (s, CF ) ppm; IR (KBr): v 1704 (C=O), 1513, 1333, 1254, 1193, 1143, 1020,
009 cm ; ESI-MS (m/z): 313.1 (100, [M+Na] ), 291.1 (89, [M+H] ); elemental analysis calcd (%) for
S (290.3): C 45.52, H 3.13, N 9.65, S 11.05; found: C 45.55, H 3.17, N 9.62, S 11.04.
2
Cl
2
1:1 gradient CH
), 3.83 (s, 3 H, OCH
), 114.2 (d, 2 CH), 119.2 (q, 1JC-F
2
Cl
2
), Method B: 122 mg (42%), colourless solid, mp
1
8
586 °C. H NMR (600 MHz, CDCl
3
2
3
), 6.95, 7.33 (2 dbr, J ≈ 9.1 Hz, 2
H each) ppm; 13C NMR (CDCl
=
3
3
2
75.1 Hz, CF
3
3
3
-
1
+
+
1
11 9 3 2 2
C H F N O
4
.2.4. 4-(4-Fluorophenyl)-2-(trifluoromethyl)-4H-1,3,4-thiadiazin-5(6H)-one (8d)
CC (SiO , petroleum ether/CH Cl 2:3), Method B: 69 mg (25%), thick colourless oil. H NMR (600
MHz, CDCl ):  3.64 (s, 2 H, 6-H , 151 MHz): 
), 7.10-7.14, 7.40-7.43 (2 m, 2 H each) ppm; 13C NMR (CDCl
6.3 (t, C-6), 115.8 (d, 2JC-F = 23.0 Hz, 2 CH), 119.1 (q, 1JC-F = 275.2 Hz, CF ), 127.0 (d, 3JC-F = 8.7 Hz, 2 CH),
36.1 (d, 4JC-F = 3.2 Hz, i-C), 136.5 (q, 2JC-F = 39.5 Hz, C-2), 156.7 (s, C=O), 161.8 (d, 1JC-F = 248.2 Hz, i-C) ppm;
1
2
2
2
3
2
3
2
1
3
19F NMR (CDCl
), –113.2 (m, Ar-F) ppm; IR (KBr): v 1697 (C=O), 1508, 1331, 1238,
3
, 188 MHz):  –68.1 (s, CF
3
-
1
+
1
4
199, 1124, 1020 cm ; ESI-MS (m/z): 279.2 (100, [M+H] ); elemental analysis (%) for C10
H
F
6 4
N
2
OS (278.2): C
3.17, H 2.17, N 10.07, S 11.52; found: C 43.13, H 2.24, N 10.01, S 11.51.
4
.2.5. 4-(4-Bromophenyl)-2-(trifluoromethyl)-4H-1,3,4-thiadiazin-5(6H)-one (8e)
9

CC (SiO
2
, petroleum ether/CH
Cl
2 2
1:1), Method A: 213 mg (63%), Method B: 98 mg (29%), colourless
):  3.64 (s, 2 H, 6-H ), 7.35, 7.56 (2 dbr, J ≈ 8.8 Hz, 2 H each)
, 151 MHz):  26.4 (t, C-6), 119.1 (q, 1JC-F = 275.3 Hz, CF
), 121.6 (s), 126.5, 132.0 (2 d,
CH), 136.8 (q, 2JC-F = 39.5 Hz, C-2), 139.0 (s), 156.6 (s, C=O) ppm; 19F NMR (CDCl
, 188 MHz):  –68.1 (s,
) ppm; IR (KBr): v 1698 (C=O), 1489, 1329, 1200, 1147, 1130, 1011 cm ; ESI-MS (m/z): 341.0 (97,
1
solid, mp 5456 °C. H NMR (600 MHz, CDCl
3
2
ppm; 13C NMR (CDCl
3
3
4
3
-
1
CF
3
81
+
79
+
[
M{ Br}+Na] ), 339.0 (100, [M{ Br}+H] ); elemental analysis calcd (%) for C10
6 3 2
H BrF N OS (339.1): C 35.42,
H 1.78, N 8.26, S 9.45; found: C 35.42, H 1.69, N 8.30, S 9.58.
4
.2.6. 4-(4-Nitrophenyl)-2-(trifluoromethyl)-4H-1,3,4-thiadiazin-5(6H)-one (8f)
CC (SiO
2
, petroleum ether/CH
2
Cl
2
1:3), Method A: 279 mg (91%), Method B: 220 mg (72%), colourless
):  3.70 (s, 2 H, 6-H ), 7.75, 8.29 (2 dbr, J ≈ 9.2 Hz, 2 H each)
, 151 MHz):  26.6 (t, C-6), 119.0 (q, 1JC-F = 275.6 Hz, CF
), 124.2, 124.7 (2 d, 4 CH),
38.4 (q, 2JC-F = 39.8 Hz, C-2), 144.8, 146.3 (2 s), 156.8 (s, C=O) ppm; 19F NMR (CDCl
, 188 MHz):  –68.2 (s,
1
solid, mp 98100 °C. H NMR (600 MHz, CDCl
3
2
ppm; 13C NMR (CDCl
3
3
1
3
-
1
CF
3
) ppm; IR (KBr): v 1701 (C=O), 1516, 1354, 1333, 1314, 1297, 1200, 1146, 1128 cm ; ESI-MS (m/z): 306.1
+
(
100, [M+H] ); elemental analysis calcd (%) for C10
H
F
6 3
N
3
O
3
S (305.2): C 39.35, H 1.98, N 13.77, S 10.50; found:
C 39.32, H 2.03, N 13.63, S 10.43.
4
.2.7. 4-(5-Oxo-2-(trifluoromethyl)-5,6-dihydro-4H-1,3,4-thiadiazin-4-yl)benzonitrile (8g)
CC (SiO
2
, petroleum ether/EtOAc 4:1), Method A: 248 mg (87%), Method B: 160 mg (56%), pale yellow
1
solid, mp 111112 °C. H NMR (600 MHz, CDCl
3 2
):  3.68 (s, 2 H, 6-H ), 7.67, 7.72 (2 dbr, J ≈ 8.1 Hz, 2 H each)
ppm; 13C NMR (CDCl
, 151 MHz):  26.5 (t, C-6), 111.1, 118.0 (2 s), 118.9 (q, 1JC-F = 275.6 Hz, CF
3
3
), 124.8,
32.7 (2 d, 4 CH), 138.1 (q, 2JC-F = 39.8 Hz, C-2), 143.4 (s), 156.7 (s, C=O) ppm; F NMR (CDCl
19
1
3
, 188 MHz): 
-
1
–
3
68.2 (s, CF ) ppm; IR (KBr): v 2229 (CN), 1707 (C=O), 1604, 1332, 1303, 1182, 1146, 1134, 1107 cm ; ESI-
+
+
MS (m/z): 308.0 (100, [M+Na] ), 286.1 (32, [M+H] ); elemental analysis calcd (%) for C11
H
6
F
3
N
3
OS (285.2): C
4
6.32, H 2.12, N 14.73, S 11.24; found: C 46.42, H 2.15, N 14.68, S 11.11.
4
.2.8. 6-Methyl-4-(4-nitrophenyl)-2-(trifluoromethyl)-4H-1,3,4-thiadiazin-5(6H)-one (8h)
1
CC (SiO
2
, petroleum ether/CH
):  1.62 (d, J = 7.1 Hz, 3 H, CH
.2 Hz, 2 H each) ppm; 13C NMR (CDCl
, 151 MHz):  15.9 (q, CH
), 124.2, 124.7 (2 d, 4 CH), 137.5 (q, 2JC-F = 39.8 Hz, C-2), 145.2, 146.2 (2 s), 160.6 (s, C=O) ppm; 19F NMR
2
Cl
2
1:4), Method B: 175 mg (55%), light orange solid, mp 6971 °C. H
NMR (600 MHz, CDCl
3
3
), 3.81 (q, J = 7.1 Hz, 1 H, 6-H), 7.73, 8.29 (2 dbr, J ≈
9
3
3
), 34.3 (d, C-6), 119.1 (q, 1JC-F = 275.3 Hz,
CF
3
-
1
(
(
CDCl
3
, 188 MHz):  68.4 (s, CF
3
) ppm; IR (KBr): v 1708 (C=O), 1602, 1516, 1353, 1329, 1115 cm ; ESI-MS
S (319.3): C 41.38, H 2.53, N 13.16,
+
m/z): 342.0 (100, [M+Na] ); elemental analysis calcd (%) for C11
H
8 3
F N
3
O
3
S 10.04; found: C 41.56, H 2.73, N 13.29, S 10.10.
4
.3. Synthesis of 1,3,4-thiadiazin-5-ols 10; general procedure
To a solution of the respective hydrazonoyl bromide 9 (1.0 mmol) and 1,4-dithiane-2,5-diol (6, 84 mg,
.55 mmol) in dry THF (10 mL) was added dropwise Et N (0.7 mL) and the resulting mixture was stirred at
0
3
ambient temperature until the starting bromide was fully consumed (TLC monitoring). The precipitate
1
0

triethylammonium salt was filtered off, and the solvents were removed in vacuo. The resulting material was
purified by column chromatography (CC) to afford 1,3,4-thiadiazin-5-ols 10.
4
.3.1. 4-(p-Tolyl)-2-(trifluoromethyl)-5,6-dihydro-4H-1,3,4-thiadiazin-5-ol (10a):
Reaction time 2h; CC (SiO , CH Cl ), 215 mg (78%), colourless solid, mp 8384 °C. H NMR (600 MHz,
): δ 2.33 (s, 3 H, Me), 2.93 (dd, J = 1.7, 12.9 Hz, 1 H, 6-H), 3.06 (d, J = 10.7 Hz, 1 H, OH), 3.18 (dd, J =
1
2
2
2
CDCl
3
3
.4, 12.9 Hz, 1 H, 6-H), 5.64 (ddd, J = 1.7, 3.4, 10.7 Hz, 1 H, 5-H), 7.16, 7.29 (2 d, J = 8.4 Hz, 2 H each) ppm;
13C NMR (CDCl , 151 MHz): δ 20.6 (q, Me), 28.5 (t, C-6), 71.1 (d, C-5), 116.6 (d, 2 CH), 119.7 (q, 1JC-F = 273.0
Hz, CF , 565 MHz):
), 120.7 (q, 2JC-F = 38.9 Hz, C-2), 129.7 (d, 2 CH), 133.2, 143.0 (2 s) ppm; 19F NMR (CDCl
δ 67.6 (s, CF
3
3
3
-
1
3
) ppm; IR (KBr): ν 3416 (OH), 1578, 1511, 1331, 1263, 1188, 1137, 999, 813 cm ; (-)-ESI-MS

(
m/z): 275.3 (100, [MH] ); elemental analysis calcd (%) for C11
H
11
F
3
N
2
OS (276.3): C 47.82, H 4.01, N 10.14, S
1
1.60; found: C 47.80, H 4.15, N 10.47, S 11.56.
4
.3.2. 4-Phenyl-2-(trifluoromethyl)-5,6-dihydro-4H-1,3,4-thiadiazin-5-ol (10b):
2 2 2 2
Reaction time 2h; CC (petroleum ether/CH Cl 1:1 gradient CH Cl ), 199 mg (76%), colourless solid, mp
1
4
6
4
547 °C. H NMR (600 MHz, CDCl
3
): δ 2.92 (dd, J = 1.7, 12.9 Hz, 1 H, 6-H), 3.16 (dd, J = 3.4, 12.9 Hz, 1 H,
-H), 3.21 (d, J = 10.4 Hz, 1 H, OH), 5.66 (ddd, J = 1.7, 3.4, 10.4 Hz, 1 H, 5-H), 7.10-7.13, 7.35-7.42 (2 m, 1 H,
1
3
, 151 MHz): δ 28.5 (t, C-6), 70.8 (d, C-5), 116.4 (d, 2 CH), 119.6 (q, 1JC-F = 273.1 Hz,
3
H) ppm; C NMR (CDCl
), 121.6 (q, 2JC-F = 38.9 Hz, C-2), 123.5 (d, CH), 129.2 (d, 2 CH), 145.0 (s) ppm; F NMR (CDCl
19
CF
3
3
, 565 MHz):
-
1
δ 67.7 (s, CF
3
) ppm; IR (KBr): ν 3408 (OH), 2359, 1599, 1493, 1327, 1263, 1190, 1134, 1014, 758 cm ; ESI-
+
MS (m/z): 263.1 (100, [M+H] ); elemental analysis calcd (%) for C10
H
9
F
3
N
2
OS (262.3): C 45.80, H 3.46, N 10.68,
S 12.22; found: C 45.71, H 3.52, N 10.64, S 12.07.
4
.3.3. 4-(4-Methoxyphenyl)-2-(trifluoromethyl)-5,6-dihydro-4H-1,3,4-thiadiazin-5-ol (10c):
Reaction time 2h; CC (SiO , petroleum ether/CH Cl 1:1 gradient CH Cl ), 187 mg (64%), red oil. H
NMR (600 MHz, CDCl ): δ 2.91 (dd, J = 1.7, 12.8 Hz, 1 H, 6-H), 3.14 (dd, J = 3.4, 12.8 Hz, 1 H, 6-H), 3.26 (sbr
H, OH), 3.78 (s, 3 H, OMe), 5.55 (ddbr, J ≈ 1.7, 3.4 Hz, 1 H, 5-H), 6.86-6.89, 7.28-7.31 (2 m, 2 H each) ppm;
13C NMR (CDCl
, 151 MHz): δ = 28.4 (t, C-6), 55.5 (q, OMe), 71.4 (d, C-5), 114.4, 118.5 (2 d, 2 CH each), 119.7
q, 1JC-F = 272.9 Hz, CF ), 120.5 (q, 2JC-F = 38.7 Hz, C-2), 139.3, 156.2 (2 s) ppm; 19F NMR (CDCl
, 565 MHz):
1
2
2
2
2
2
3
,
1
3
(
3
3
-
1
δ 67.6 (s, CF
3
) ppm; IR (film): ν 3463 (OH), 2973, 1593, 1575, 1515, 1324, 1247, 1143, 1014, 822 cm ; ESI-
+
MS (m/z): 293.1 (100, [M+H] ); elemental analysis calcd (%) for C11
H
11
F
3
N
2
O
2
S (292.3): C 45.20, H 3.79, N 9.58,
S 10.97; found: C 45.35, H 3.97, N 9.67, S 10.80.
4
.3.4. 4-(4-Fluorophenyl)-2-(trifluoromethyl)-5,6-dihydro-4H-1,3,4-thiadiazin-5-ol (10d):
Reaction time 3h; CC (SiO , petroleum ether/CH Cl 1:1), 185 mg (66%), yellow oil. H NMR (600 MHz,
): δ 2.96 (dd, J = 1.7, 12.9 Hz, 1 H, 6-H), 3.08 (sbr, 1 H, OH), 3.20 (dd, J = 3.4, 12.9 Hz, 1 H, 6-H), 5.61
1
2
2
2
CDCl
3
1
3
(
(
3
ddbr, J ≈ 1.7, 3.4 Hz, 1 H, 5-H), 7.03-7.07, 7.34-7.37 (2 m, 2 H each) ppm; C NMR (CDCl , 151 MHz): δ 28.7
t, C-6), 71.4 (d, C-5), 115.8 (d, 2JC-F = 22.7 Hz, 2 CH), 118.3 (d, 3JC-F = 8.0 Hz, 2 CH), 119.6 (q, 1JC-F = 273.1 Hz,
), 121.5 (q, 2JC-F = 39.0 Hz, C-2), 141.6 (d, 4JC-F = 2.5 Hz, i-C), 159.4 (d, 1JC-F = 242.9 Hz, i-C) ppm; F NMR
19
CF
3
1
1

(
CDCl
230, 1190, 1134, 1014, 831 cm ; ESI-MS (m/z): 281.0 (37, [M+H] ), 280 (100, M ), 263 (28). elemental analysis
calcd (%) for C10 OS (280.2): C 42.86, H 2.88, N 10.00, S 11.44; found: C 43.03, H 2.96, N 10.21, S 11.52.
3
, 565 MHz): δ 67.7 (s, CF
3
), 120.0 (m, Ar-F) ppm; IR (film): ν 3421 (OH), 2362, 1508, 1331, 1267,
-
1
+
+
1
8 4 2
H F N
4
.3.5. 4-(4-Bromophenyl)-2-(trifluoromethyl)-5,6-dihydro-4H-1,3,4-thiadiazin-5-ol (10e):
Reaction time 3h; CC (SiO , petroleum ether/CH Cl 1:1), 239 mg (70%), colourless solid, mp 7475 °C.
1H NMR (600 MHz, CDCl
): δ 2.96 (dd, J = 1.7, 12.9 Hz, 1 H, 6-H), 3.05 (dbr, J ≈ 11.1 Hz, 1 H, OH), 3.22 (dd, J
3.4, 12.9 Hz, 1 H, 6-H), 5.63 (dddbr, J ≈ 1.7, 3.4, 11.1 Hz, 1 H, 5-H), 7.27-7.30, 7.44-7.47 (2 m, 2 H each) ppm;
2
2
2
3
=
13C NMR (CDCl
, 151 MHz): δ 28.7 (t, C-6), 70.9 (d, C-5), 116.4 (s, CBr), 117.9 (d, 2 CH), 119.5 (q, 1JC-F = 273.8
), 122.3 (q, 2JC-F = 39.0 Hz, C-2), 132.1 (d, 2 CH), 144.1 (s) ppm; 19F NMR (CDCl
, 565 MHz): δ 67.8
3 3
3
Hz, CF
s, CF ) ppm; IR (KBr): ν 3493 (OH), 2924, 2853, 1571, 1493, 1329, 1264, 1139, 1116, 1014, 824 cm ; (-)-ESI-
MS (m/z): 339.3 (100, [M{ Br}H] ), 341.3 (94, [M{ Br}H] ); elemental analysis calcd (%) for
BrF OS (341.1): C 35.21, H 2.36, N 8.21, S 9.40; found: C 35.37, H 2.54, N 8.48, S 9.60.
-
1
(
3
7
9

81

C
10
H
8
3 2
N
4
.3.6. 4-(4-Nitrophenyl)-2-(trifluoromethyl)-5,6-dihydro-4H-1,3,4-thiadiazin-5-ol (10f):
Reaction time 3h; CC (SiO , petroleum ether/CH Cl 1:1), 218 mg (71%), brown solid, mp 135136 °C.
1H NMR (600 MHz, CDCl
): δ 3.08 (dd, J = 1.7, 13.1 Hz, 1 H, 6-H), 3.09 (d, J = 11.3 Hz, 1 H, OH), 3.32 (dd, J
3.4, 13.1 Hz, 1 H, 6-H), 5.79 (ddd, J = 1.7, 3.4, 11.3 Hz, 1 H, 5-H), 7.52, 8.24 (2 d, J = 9.3 Hz, 2 H each) ppm;
13C NMR (CDCl , 151 MHz): δ 29.2 (t, C-6), 70.7 (d, C-5), 115.3 (d, 2 CH), 119.2 (q, 1JC-F = 274.0 Hz, CF
),
25.4 (d, 2 CH), 126.0 (q, 2JC-F = 39.4 Hz, C-2), 143.2, 149.3 (2 s) ppm; F NMR (CDCl
, 565 MHz): δ 68.1 (s,
), 1511, 1431, 1343, 1311, 1260, 1195, 1140, 1113, 1014, 823 cm-
S (307.2): C 39.09, H 2.62,
2
2
2
3
=
3
3
19
1
3
CF
3
) ppm; IR (KBr): ν 3428 (OH), 1591 (NO
2
1;
ESI-MS (m/z): 308.1 (100, [M+H] ); elemental analysis calcd (%) for C10
+
H
F
3
N
8
3
O
3
N 13.68, S 10.43; found: C 39.21, H 2.85, N 13.69, S 10.41.
4
.3.7. 4-(5-Hydroxy-2-(trifluoromethyl)-5,6-dihydro-4H-1,3,4-thiadiazin-4-yl)benzonitrile (10g):
Reaction time 3h; CC (SiO , petroleum ether/AcOEt 1:1), 264 mg (92%), colourless solid, mp 155156
C. H NMR (600 MHz, CDCl ): δ 3.04 (dd, J = 1.7, 13.1 Hz, 1 H, 6-H), 3.15 (sbr, 1 H, OH), 3.29 (dd, J = 3.4,
2
1
°
3
1
3
1
3.1 Hz, 1 H, 6-H), 5.74 (m
c
, 1 H, 5-H), 7.47-7.52, 7.61-7.66 (2 m, 2 H each) ppm; C NMR (CDCl
3
, 151 MHz):
), 125.2 (q,
, 565 MHz): δ 68.1 (s, CF ) ppm; IR
δ 29.0 (t, C-6), 70.6 (d, C-5), 106.2 (s, CN), 115.9 (d, 2 CH), 118.9 (s), 119.3 (q, 1JC-F = 273.9 Hz, CF
2JC-F = 39.3 Hz, C-2), 133.5 (d, 2 CH), 147.8 (s) ppm; 19F NMR (CDCl
3
3
3
-
1
(
(
KBr): ν = 3371 (OH), 2234 (CN), 1605, 1506, 1340, 1265, 1122, 1068, 1008, 829 cm ; (-)-ESI-MS (m/z): 286.0

100, [MH] ); elemental analysis calcd (%) for C11
8 3 3
H F N OS (287.3): C 45.99, H 2.81, N 14.63, S 11.16; found:
C 46.15, H 3.04, N 14.67, S 11.30.
4
.3.8. 4-(5-Hydroxy-2-(trifluoromethyl)-5,6-dihydro-4H-1,3,4-thiadiazin-4-yl)phenyl benzoate (10h):
Reaction time 4h; CC (SiO , CH Cl /AcOEt 95:5), 271 mg (71%), colourless solid, mp 131133 °C. H
NMR (600 MHz, CDCl ): δ 2.97 (dd, J = 1.6, 12.8 Hz, 1 H, 6-H), 3.10 (d, J = 11.0 Hz, 1 H, OH), 3.23 (dd, J =
.5, 12.8 Hz, 1 H, 6-H), 5.68 (ddd, J = 1.6, 3.5, 11.0 Hz, 1 H, 5-H), 7.19-7.23, 7.44-7.48, 7.49-7.54, 7.62-7.66,
.19-8.22 (5 m, 3  2 H, 1 H, 2 H) ppm; 13C NMR (CDCl
, 151 MHz): δ 28.7 (t, C-6), 71.3 (d, C-5), 117.5 (d, 2
1
2
2
2
3
3
8
3
1
2

CH), 119.6 (q, 1JC-F = 273.1 Hz, CF ), 121.8 (q, 2JC-F = 39.0 Hz, C-2), 122.4, 128.6 (2 d, 2 CH each), 129.4 (s),
3
19
1
3
30.2 (d, 2 CH), 133.6 (d, CH), 143.0, 147.0 (2 s), 165.4 (s, C=O) ppm; F NMR (CDCl , 565 MHz): δ 67.7 (s,
-
1
3
CF ) ppm; IR (KBr): ν 3416 (OH), 2829, 1702 (C=O), 1452, 1504, 1320, 1265, 1126, 1008, 710 cm ; ESI-MS
+
+
(
m/z): 405.1 (100, [M+Na] ), 383.1 (7, [M+H] ); elemental analysis calcd (%) for C17
13 3 2 3
H F N O S (382.4): C 53.40,
H 3.43, N 7.33, S 8.38; found: C 53.45, H 3.56, N 7.42, S 8.38.
4
.4. Synthesis of thiohydrazonates 13i and 13j
To a solution of hydrazonoyl bromide 9f (312 mg, 1.0 mmol) and 3-mercaptopropionic acid (12, 117 mg,
3
.1 mmol) or mercaptosuccinic acid (7c, 165 mg, 1.1 mmol) in dry THF (10 mL) was added dropwise excess Et N
1
(
2 mmol, 0.3 mL) at room temperature, and the stirring was continued overnight. The resulting mixture was
acidified with aq. HCl (5%), then extracted with Et O (3  15 mL), and the combined organic layers were dried
over Na SO . After the solvents were removed under reduced pressure, the crude carboxylic acid 11i or 11j was
dissolved in dry MeOH (10 mL), two drops of conc. H SO were added, and the solution was refluxed overnight.
The mixture was cooled to room temperature, quenched with NaHCO (5%, 10 mL) and extracted with Et O (3 
5 mL). Combined organics were dried (Na SO ), filtered, the solvents were removed in vacuo, and the crude
product 13i or 13j was purified by chromatography column.
2
2
4
2
4
3
2
1
2
4
4
.4.1. Methyl 3-((2,2,2-trifluoro-1-(2-(4-nitrophenyl)hydrazono)ethyl)sulfanyl)propanoate (13i)
CC (SiO , petroleum ether/CH Cl gradient CH Cl ), 86 mg (24%), pale orange solid, mp 8789 °C. H
NMR (600 MHz, CDCl ):  2.68 (t, J = 6.1 Hz, 2 H, CH ), 3.08 (t, J = 6.1 Hz, 2 H, S-CH ), 3.82 (s, 3 H, OMe),
.39, 8.23 (2 dbr, J ≈ 9.1 Hz, 2 H each), 10.12 (sbr, 1 H, NH) ppm; C NMR (CDCl , 151 MHz):  27.4, 33.1 (2 t,
CH CH
-), 52.5 (q, OMe), 114.0 (d, 2 arom. CH), 120.8 (q, 1JC-F = 272.5 Hz, CF ), 124.7 (q, 2JC-F = 38.6 Hz, C-
), 125.8 (d, 2 arom. CH), 142.6, 147.5 (2 s), 172.8 (s, C=O) ppm; 19F NMR (CDCl
, 188 MHz):  –66.4 (s,
) ppm; ESI-MS (m/z): 374 (23, [M+Na] ), 352.3 (100, [M+H] ); elemental analysis calcd (%) for
S (351.3): C 41.03, H 3.44, N 11.96, S 9.13; found: C 41.19, H 3.51, N 11.87, S 9.31.
1
2
2
2
2
2
3
2
2
13
7
3
-
2
2
3
CF
3
3
3
+
+
CF
12 12 3 3 4
C H F N O
4
.4.2. Dimethyl 2-((2,2,2-trifluoro-1-(2-(4-nitrophenyl)hydrazono)ethyl)sulfanyl)succinate (13j)
1
CC (SiO
.91 (dd, J = 9.9, 18.3 Hz, 1 H, -CH
.00 (dd, J = 4.3, 9.9 Hz, 1 H, S-CH), 7.43, 8.24 (2 dbr, J ≈ 9.1 Hz, 2 H each), 10.48 (sbr, 1 H, NH) ppm; C NMR
, 151 MHz):  35.1 (t, -CH -), 42.3 (d, S-CH), 52.8, 53.2 (2 q, 2 OMe), 114.2 (d, 2 arom. CH), 120.5 (q,
1JC-F = 272.6 Hz, CF ), 122.4 (q, 2JC-F = 39.0 Hz, C-CF
), 125.8 (d, 2 arom. CH), 142.9, 147.4 (2 s), 170.8, 171.8
2
, CH
2
Cl
2
), 102 mg (25%), pale yellow solid, mp 113114 °C. H NMR (600 MHz, CDCl
3
): 
2
4
2 2
-), 3.06 (dd, J = 4.3, 18.3 Hz, 1 H, -CH -), 3.77, 3.84 (2 s, 2  3 H, 2 OMe),
13
(
CDCl
3
2
3
3
1
9
(
(
2 s, 2 C=O) ppm; F NMR (CDCl
3
, 188 MHz):  –66.4 (s, CF
3
) ppm; IR (KBr): v 3210 (N-H), 1737 (C=O), 1719
-
1
+
C=O), 1603, 1552, 1339, 1252, 1148, 1125, 1108, 988 cm ; ESI-MS (m/z): 432.0 (100, [M+Na] ); elemental
14 3 3 6
analysis calcd (%) for C14H F N O S (409.3): C 41.08, H 3.45, N 10.27, S 7.83; found: C 41.30, H 3.40, N 10.46,
S 7.73.
Acknowledgements
1
3

The authors thank the National Science Center (NCN, Cracow, Poland) for financial support in the
framework of Preludium grant #2016/21/N/ST5/01254 (GUJ).
References
[1]
[2]
[3]
(a) R. Huisgen, 1,3-Dipolar Cycloadditions. Past and Future, Angew. Chem. Int. Ed. Engl. 2 (1963) 565‒
98; 1,3-Dipolare Cycloadditionen, Rückschau und Ausblick, Angew. Chem. 75 (1963) 604637;
b) R. Huisgen, 1,3-Dipolar Cycloadditions – Introduction, Survey, Mechanism, in: 1,3-Dipolar
5
(
Cycloaddition Chemistry, A. Padwa (Ed.), Wiley-Interscience, New York, 1984, Volume 1, Chapter 1,
pp. 1‒176.
(a) J.T. Sharp, Nitrile Ylides and Nitrile Imines, in: Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products, A. Padwa, W.H. Pearson (Eds.), John Wiley &
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