Regioselective N(2)-H-functionalization of thiosemicarbazones of aromatic and heteroaromatic aldehydes with acrylonitrile

Article abstract of DOI:10.1080/00397911.2016.1257723

Regioselective N(2)-H-cyanoethylation of thiosemicarbazones of aromatic and heteroaromatic aldehydes with acrylonitrile proceeds under mild conditions (14% KOH, acetone/H₂O, 35 °C, 6–21 h) to afford 1-(2-сyanoethyl)-2-[(E)-aryl(heteroaryl)methylidene]-1-hydrazinecarbothioamides in up to 74% yields. The synthesized thioamides are promising precursors of novel families of functionalized thiosemicarbazones as exemplified by hydrolysis of their cyano group to the corresponding amido function (46.5–60% yields).

Full text of DOI:10.1080/00397911.2016.1257723

Regioselective N(2)-H-Functionalization of Thiosemicarbazones of Aromatic and
Heteroaromatic Aldehydes with Acrylonitrile
Anastasiya G. Mal'kina1, Valentina V. Nosyreva1, Alexander I. Albanov1, Andrei V.
Afonin1, Alexander V. Vashchenko1, Svetlana V. Amosova1, Boris A. Trofimov1
1A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of
Sciences, Irkutsk, Russian Federation
Address correspondence to Boris A. Trofimov, A. E. Favorsky Irkutsk Institute of
Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033
Irkutsk, Russian Federation E-mail: boris_trofimov@irioch.irk.ru
Abstract
Regioselective N(2)-H-cyanoethylation of thiosemicarbazones of aromatic and
heteroaromatic aldehydes with acrylonitrile proceeds under mild conditions (14% KOH,
acetone/H2O, 35 oC, 6-21 h) to afford 1-(2-сyanoethyl)-2-[(Е)-
aryl(heteroaryl)methylidene]-1-hydrazinecarbothioamides in up to 74% yields. The
synthesized thioamides are promising precursors of novel families of functionalized
thiosemicarbazones as exemplified by hydrolysis of their cyano group to the
corresponding amido function (46.5-60% yields).
Graphical Abstract
KEYWORDS: thiosemicarbazone; acrylonitrile; nucleophilic addition; N(2)-H-
cyanoethylation; thioamide
1

INTRODUCTION
Thiosemicarbazones of aromatic and heteroaromatic aldehydes exhibit a great variety of
biological activities and, therefore, attract ever-increasing interest as pharmaceuticals and
their precurors.[1-4] Among them were found the compounds possessing antitumor,[2,5-10]
antibacterial,[3,4,11-15] anticonvulsant,[16] antioxidant,[17] antifungal[14] and antihelminthic[18-
21] actions and also urease inhibitors.[22] A number of popular drugs are thiosemicarbazone
derivatives, e.g. thioacetazone[23,24] and perchlozone[25-29] (antituberculosis medicines)
and аmbazone (antiseptic, disinfectant and antineoplastic),[30] Figure 1.
A rich chemistry of thiosemicarbazones, their availability and importance of the
heterocycles,[31-34] metal complexes[8,33,35-40] and pharmaceuticals, being steadily derived
therefrom, instigate the further development of the synthetic methods in this field. A
common route to thiosemicarbazones, which remains a major one, is a condensation of
aldehydes with thiosemicarbazides.[21,22,31,41-48] However, the functionalization of
thiosemicarbazones, which might greatly diversify and multiply their pharmaceutical
value, still represents a synthetic challenge. In this line, the reactions of
thiosemicarbazones with activated unsaturated compounds are intensively explored. The
reactions of thiosemicarbazones with maleic anhydride[21] and arylidenemalononitrile[49]
proceed over the thioamide moiety to form 4-thiazolidinone and piperidine substituted
heterocycles, while 1,1,2,2-tetracyanoethylene[50] and diethyl 2,3-dicyanofumarate[33] and
phenyl substituted thiosemicarbazone with simultaneous participation of both N(2) and S
and N(1) and N(2) atoms to close the amino-1,3-thiazole or dihydropyrazole cycles.
2

Electron-deficient acetylenes (methylpropiolate,[51] dialkyl acetylenedicarboxylate,[31,52-55]
3-phenyl-2-propynoate,[56,57] acylacetylenes[58]) cyclize with thiosemicarbazones
involving both thione and amide functions to deliver 1,3-thiazolidin-4-ones or 1,3-
thiazin-4-ones.[31,52-55] The initial intermediates of these reactions were proved to be S-
adducts.[51]
To our knowledge, among scare examples of the initial NH2 function attack at the triple
bond is a reaction of isatin-3-thiosemicarbazone with acetylenic esters (NaOEt/EtOH),
which finally leads to 3-[2-oxo-2H,3H-benzo(b-pyrrolidine-3-iminyl]-4-oxo-2-thioxo-
1,2,4-trihydropyrimidine.[56,57] At the same time, just one evidence of N(2)-H-
functionalization of thiosemicarbazones with activated unsaturated compounds is known.
As shown in the work,[59] the cyanoethylation of 1-benzylidenethiosemicarbazone
proceeds at N(2)-H site to afford the corresponding 2-(β-cyanoethyl) derivatives.
Here we report the base-catalyzed regioselective addition of thiosemicarbazones of
aromatic and heteroaromatic aldehydes 1а-е to acrylonitrile 2 to give N(2)-H-
cyanoethylated thiosemicarbazones, 1-(2-cyanoethyl)-2-[(Е)-
aryl(heteroaryl)methylidene]-1-hydrazinecarbothioamides 3а-e.
RESULTS AND DISCUSSION
In order to find synthetically suitable conditions for this reaction, we have tested various
bases (NaOH, KOH, t-BuOK and piperidine) both in solvents (acetone, acetonitrile,
3

DMSO, DMF) and under solvent-free conditions at a temperature within 30-70 oC using
2-[(E)-4-pyridinylmethylidene]-1-hydrazinecarbothioamide (1e) as a standard compound
(Table 1).
As follows from Table 1, where some selected results of screening of the reaction
conditions are given, the best yields (60-64%) of adduct 3e are attained using 14 mol%
KOH in acetone/water solution at 30-35 0C with 3-fold excess of acrylonitrile for 7-8 h
(entries 5-6). It should be underlined that other combination of bases, solvents and
reactant ratios gives much inferior results, even with such strong base systems as t-
BuOK/MeCN or t-BuOK/DMSO (Table 1, entries 8-10) that is due to rapid
polymerization of acrylonitrile in the presence of these catalysts. Addition of water,
which decrease the basicity of the reaction mixture, allow the N(2)-H-functionalization
efficiency to be considerably improved (Table 1, entries 1-6) with simultaneous decrease
of acrylonitrile excess. However, application of piperidine in DMF as a basic catalyst
appeared to be entirely unsuccessful (entry 12): the starting material was recovered along
with considerable amounts of acrylonitrile polymer. Interestingly, the positive effect of
acetone as a co-solvent on the yields proved to be the most pronounced (Table 1, entries
5-6) probably because of a better solubility of the starting thiosemicarbazone.
Further on, we have transferred the best conditions found for N(2)-H-cyanoethylation of
thiosemicarbazone 1e (Table 1, entries 5-6) to other representatives of this series and the
corresponding cyanoethyl derivatives 3a-d have been synthesized in 37-74% yields
(Figure 2).
4

As expected some additional tuning of the experimental conditions for each
thiosemicarbazone to reach better yields has been required (Table 2).
The additional adjustment of the experimental conditions included the alteration of 1a-e:2
molar ratio, acetone amount and time. Generally, the reactions proceeded more efficiently
at a lower excess of acrylonitrile and a higher dilution in acetone (Table 2).
The synthesized compounds 3a-e, due to their CH2CH2CN substituent with its rich
chemistry and high reactivity, are promising intermediates for further synthesis of novel
families of diverse thiosemicarbazones, e.g. having such biologically important
functionalities as the amide, ester, acid or amine groups. To illustrate these possibilities,
we have implemented hydrolysis of the nitriles 3a-e to the corresponding amides 4a-e, 3-
{1-(aminocarbothioyl)-2-[(E)-aryl(heteroaryl)methylidene]hydrazino}propanamides (4а-
с,e) and 3-{1-(aminocarbothioyl)-2-[(E)-2-furylmethylidene]hydrazino}propanamide
(4d), (30-100 mol% KOH, ethanol with traces of water, 50-52 oC, 3-11 h, Table 3). In
some cases, the hydrolysis was accompanied by the formation of the starting
thiosemicarbazones 1a,c-e (isolated in 2-28% yields) that is likely resulted from the retro-
cyanoethylation reaction.[60] The reaction completion was controlled by the IR
spectroscopy (following the disappearance of the CN absorption band at 2247-2252 cm-1)
and TLC.
5

For pharmaceutical application, the pyridinium salts of thiosemicarbazone 3e are of
special interest. Therefore, we have demonstrated the easy formation of such salts by the
synthesis of the corresponding hydrochloride 5 in 85% yield (Scheme 1).
Noteworthy, during the above transformations other functionalities (thioamide, thione,
C=N hydrozone groups) of the starting nitriles remained intact thus confirming the
capacity of the functionalized nitriles to be precursors of various new families of
thiosemicarbazones of aromatic and heteroaromatic aldehydes.
The molecular structure of compounds 3a,b was established by single crystal X-ray
analysis, which evidences that they are Е-isomers. In thiosemicarbazone 3b, the nitro-
group has anti-orientation relative to the azomethine moiety (Figure 1, 2, see
Supplementary Information, CCDC 1498046 and CCDC 1496047).
The structures of all compounds was also been confirmed by 1H, 13C, 15N and 2D
(NOSY, COSY, HMBC HSQC) NMR techniques and IR spectroscopy (See
Supplementary Information).
CONCLUSIONS
In conclusion, regioselective N(2)-H-functionalization of thiosemicarbazones of aromatic
and heteroaromatic aldehydes with acrylonitrile to afford the corresponding cyanoethyl
derivatives in up to 74% yield has been developed. The reaction opens a straightforward
access to hitherto unknown families of functionalized thiosemicarbazones, promising
6

synthetic building blocks and precursors for drug design. Fundamentally, the reaction
essentially contributes to a better understanding of thiosemicarbazone chemistry.
EXPERIMENTAL
1Н, 13С and 15N NMR spectra of the studied compounds were recorded on a Bruker DPX-
400 and Bruker AV-400 spectrometers (400.13, 100.62 and 40.56 MHz, respectively) in
DMSO-d6 at rt, and referred to HMDSO (1Н, 13С) or nitromethane (15N). NMR signals
were assigned using 2D NMR techniques (HSQC or HMBC 1H-13C and HMBC 1H-15N).
IR spectra were measured on a Bruker Vertex-70 in KВr pellets. X-ray diffractions study
of crystal was carried out on a Bruker D8 VENTURE PHOTON 100 CMOS
diffractometer with MoKα radiation (λ = 0.71073) at 100(2) K. Elemental analyses were
performed on a FLASH 2000. All melting points were taken on a Kofler micro hot stage.
The reaction was controlled by TLC on SiO2 (acetone/n-hexane, 1:1, 5:2 v/v, as eluent).
Thiosemicarbazide, aromatic and heteroaromatic aldehydes, SiO2 (0.063-0.200 nm) are
commercial products purchased from Merck.
General Procedure For The Preparation Of The Compounds 1a-E
Thiosemicarbazide (25 mmol) was dissolved in 20 mL of dry ethanol upon stirring and
warming at 40 oC for 1 h. To the warm thiosemicarbazide a solution of aldehyde (25
mmol) in 5 mL of anhydrous ethanol was added and the mixture was stirred and refluxed
for 6-13 h. The mixture was cooled down to room temperature. The resulting precipitate
was collected by filtration and sequentially washed with EtOH and Et2O, dried in vacuum
to give compounds 1a-e. The structures of the products were confirmed by elemental
7

analysis, IR, 1H, 13C, 15N NMR, and comparison with authentic samples prepared
according to literature methods.[21,22,41,46,47]
2-[(E)-(Phenylmethylidene]-1-hydrazinecarbothioamide (1a):[46] 72% yield, white
powder, mp 160-161 oC; IR (KBr): 3414, 3401, 3234, 3146, 3062, 3022, 2989, 2801,
1602, 1587, 1531, 1494, 1469, 1449, 1371, 1285, 1227, 1175, 1100, 1058, 1028, 948,
870, 819, 759, 712 cm-1; 1H NMR /ppm: 11.42 (s, 1H, NH), 8.18, 7.99 (brs, 2H, NH2),
8.05 (s, 1Н, HC=N), 7.79-7.77 (m, 2Н, Н-2, H-6), 7.40-7.38 (m, 3H, H-3, H-4, H-5); 13C
NMR /ppm: 178.15 (С=S), 142.38 (HC=N), 134.20 (C-1), 129.83 (C-4), 128.66 (C-3,
5), 127.29 (C-2, 6); 15N NMR /ppm: -269.7 (NH2), -207.9 (NH), -59.7 (HC=N); Anal.
Calcd for C8H9N3S: C, 53.61; H, 5.06; N, 23.44; S, 17.89. Found: C, 53.83; H, 4.84; N,
23.29; S, 17.76.13e
General Procedure For The Preparation Of The Compounds 3а-Е
To a suspension of compound 1a-e (10 mmol) in acetone (3-6 mL) was added
sequentially under vigorous stirring a solution of KОН∙0.5H2O (1.4 mmol) in H2O (1
mL) and a solution of acrylonitrile (10-30 mmol) in acetone (1 mL). The reaction mixture
was stirred vigorously at 35 оС for 6-21 h. The mixture was cooled down to room
temperature and neutralized with 0.1 M HCl. Mixtures with compounds 3b and 3e left
overnight at room temperature. The resulting precipitate was collected by filtration and
sequentially washed with H2O, EtOH and Et2O, dried in vacuum and to give compound
3a-e (37-74%, Table 1, 2).
8

1-(2-Cyanoethyl)-2-[(E)-phenylmethylidene]-1-hydrazinecarbothioamide (3a): 67%
yield, white powder, mp 172-174 °C (mp 184-186 °C[59]); IR (KBr): 3421, 3252, 3133,
3025, 2949, 2917, 2249, 1588, 1456, 1423, 1386, 1360, 1297, 1248, 1219, 1145, 1106,
1074, 988, 948, 908, 873, 763 cm-1; 1H NMR /ppm: 8.58, 8.33 (brs, 2H, NH2), 8.11 (s,
1Н, HC=N), 7.96-7.94 (m, 2Н, Н-2, H-6), 7.43-7.42 (m, 3Н, Н-3, H-4, H-5), 4.80 (t, J =
6.9 Hz, 2Н, NCH2), 2.89 (t, J = 6.9 Hz, 2H, СН2CN): 13C NMR /ppm: 180.30 (С=S),
141.82 (HC=N), 134.26 (C-1), 130.06 (C-4), 128.59 (C-3, 5), 128.03 (C-2, 6), 118.47
(CN), 39.29 (NCH2), 14.57 (CH2CN); 15N NMR /ppm: -264.9 (NH2), -211.2 (NNC=S),
-129.7 (CN), 66.3 (HC=NN); Anal. Calcd for C11H12N4S: C, 56.87; H, 5.21; N, 24.12; S,
13.80. Found: C, 56.97; H, 4.93; N, 24.41; S, 13.52.
General Procedure For The Preparation Of The Compounds 4а-Е
A suspension of compound 3a-e (1 mmol) and KOH∙0.5Н2О (0.3-1.0 mmol) in ethanol
(6-12 mL) was stirred at 50-52 oC for 3-11 h. The mixture was cooled down to room
temperature. The resulting precipitate was collected by filtration and sequentially washed
with Et2O and H2O, dried in vacuum to give compounds 4a,e and 1a,e (from 3a and 3e);
of compounds 4b and 3b (conversion 97%) (1Н NMR) from 3b. Compounds 1a,b,e and
4a,b,e were isolated by column chromatography on silica gel (acetone-n-hexane, 5:2 v/v)
to give compounds 4a (rf = 0.60-0.62), 1a (rf = 0.80-0.82); (aceton-n-hexane, 1:1v/v) to
give compounds 4b (rf = 0.21-0.22), 3b (rf = 0.72-0.74) and 4e (rf = 0.21-0.22), 1e (rf =
0.71-0.73). The ethanol was removed in vacuo from the reaction mixture containing
compounds 4c,d. The residue was dissolved in H2O (10 ml) and 0.1 M HCl was added to
reach a pH of 5-6. The resulting precipitate was collected by filtration, washed with H2O,
9

dried in vacuum and sequentially washed with CHCl3 and Et2O to give compounds 4c,d.
Yield of the compounds 4а-е was 46.5-60 % (Table 3).
3-{1-(Aminocarbothioyl)-2-[(E)-phenylmethylidene]hydrazine}propanamide (4a):
yield 47%, light-yellow powder; mp 167-169 °C; IR (KBr): 3488, 3420, 3399, 3265,
3202, 3139, 2959, 2926, 2856, 1664, 1588, 1462, 1447, 1400, 1383, 1359, 1341, 1309,
1295, 1231, 1201, 1165, 1127, 1088, 988, 938, 921, 870, 751 cm-1; 1H NMR /ppm: 8.32,
8.17 (brs, 2H, NH2), 7.98 (s, 1Н, HC=N), 7.92-7.90 (m, 2Н, Н-2, H-6), 7.41, 6.88 (brs,
2H, NH2), 7.44-7.40 (m, 3Н, Н-3, H-4, H-5), 4.66 (t, J = 7.8 Hz, 2Н, NCH2), 2.42 (t, J =
7.8 Hz, 2H, СН2CO(NH2)); 13C NMR /ppm: 180.32 (С=S), 172.08 (С=O), 140.84
(HC=N), 134.45 (C-1), 129.92 (C-4), 128.63 (C-3, 5), 127.87 (C-2, 6), 40.49 (NCH2),
31.22 (СН2CO(NH2)); 15N NMR /ppm: -268.7 (CO(NH2)), -266.8 (NH2), -208.2
(NNC=S), -65.9 (HC=N); Anal. Calcd for C11H14N4SO: C, 52.78; H, 5.64; N, 22.38; S,
12.81. Found: C, 52.97; H, 5.90; N, 22.41; S, 12.53.
Synthesis Of The 4-{[(E)-2-(Aminocarbothioyl)-2-(2-
Cyanoethyl)Hydrazono]Methyl}Pyridinium Chloride (5)
To a suspension of 1-(2-cyanoethyl)-2-[(E)-4-pyridinylmethylidene]-1-
hydrazinecarbothioamide (3e) (1.150 g, 4.93 mmol) in dry diethyl ether (15 mL) was
added a solution of HCl in anhydrous diethyl ether (5 mmol, 3 mL) at room temperature.
The reaction mixture was stirred for 4 h. The diethyl ether was removed. The residue was
dried in vacuum and to give 1.330 g (~100%) 4-{[(E)-2-(aminocarbothioyl)-2-(2-
cyanoethyl)hydrazono]methyl}pyridinium chloride (5); yellow powder; mp 210-214 °C
10

(decomp.); IR (KBr): 3390, 3242, 3040, 2250, 2080, 1638, 1596, 1564, 1504, 1447,
1377, 1343, 1319, 1293, 1248, 1192, 1105, 991, 917, 885, 814, 769, 724 cm-1; 1H NMR
/ppm: 9.00, 8.76 (brs, 2 H, NH2), 8.87 (d, J = 6.0 Hz, 2Н, Н-2, H-6), 8.44 (d, J = 6.0 Hz,
2Н, Н-3, H-5), 8.26 (s, 1H, HC=N), 4.84 (t, J = 7.1 Hz, 2Н, NСН2), 2.94 (t, J = 7.1 Hz,
2H, CH2CN); 13C NMR /ppm: 181.09 (C=S), 148.49 (C-4), 143.54 (C-2), 136.98
(HC=N), 123.99 (C-3), 118.33 (CN), 39.95 (NCH2), 14.28 (CH2CN); 15N NMR /ppm: -
205.4 (NNC=S], -147.7 (HN+(Pyr)), -47.4 (HC=N); Anal. Calcd for C10H12ClN5S: C,
44.52; H, 4.48; Cl, 13.14; N, 25.94; S, 11.89. Found: C, 44.35; H, 4.70; Cl, 13.25; N,
25.63; S, 11.54.
ACKNOWLEDGEMENTS
This work was supported by the President of the Russian Federation (programs for the
support of leading scientific schools, grant NSh-7145.2016.3). The main results were
obtained using the equipment of Baikal analytical center of collective using SB RAS.
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16

Table 1. Optimization of base-catalyzed nucleophilic addition of the 2-[(E)-4-
pyridinylmethylidene]-1-hydrazinecarbothioamide (1e) to acrylonitrile 2
Entry Ratio
1ea:2
Baseb
Solvent
(mL)
H2O
Т
Time
Isolated Yield
(mol%)
(mL)
(оС) (h)
of 3e (%)
(mol)
1
1:30
NaOH (22) -
0.1
35-
40
50
40
50-
55
30
3
10.0c
2
3
4
1:3
KOH (1.4)
KOH (1.4)
KOH (30)
-
-
-
0.5
0.5
5.0
8
7
6
3.0
1:7.6
1:15
6.0
15.0d
5
6
7
8
9
1:3
1:3
1:15
1:3
1:8
KOH (14) Acetone,
1.0
1.0
-
7
8
1
4
6
60.0
64.0
12.0e
33.0
20.0
2.0
KOH (14) Acetone,
4.0
35
50
50
50
t-BuOK
(18)
-
t-BuOK
(8)
MeCN,
5.0
-
t-BuOK
(80)
MeCN,
5.0
-
17

10
11
12
1:1.4
1:1.4
1:2
t-BuOK
(1.4)
-
DMSO,
4.0
-
-
-
50
50
70
6
-
-
-
DMSO,
4.0
3
Piperi-dine DMF, 5.0
(30)
12
a Thiosemicarbazone 1e (5 mmol).
b Relative to thiosemicarbazone 1e.
c Based on the reacted 1e (79% conversion).
d Based on the reacted 1e (83% conversion).
e Based on the reacted 1e (50% conversion).
18

Table 2. Conditions of N(2)-H-functionalization of thiosemicarbazones 1a-e with
acrylonitrile 2a
Starting
Ratio of 1a-
e:2 (mol)
1:2
Acetone
(mL)
5.0
Time
(h)
19
9
Product
3a-e
3a
Isolated yield of
compound 1a-e
3a-e (%)
67
74
37
60
64
1a
1b
1c
1d
1e
1:2
5.0
3b
1:2
7.0
21
6
3c
1:1
6.0
3d
1:3
4.0
8
3e
a Reaction conditions: 14 mol% of KOH relative to thiosemicarbazone 1a-e (10 mmol),
H2O (1 mL), 35 оС.
19

Table 3. Transformation of thiosemicarbazones 3а-е to amides 4a-e.
Thiosemi-
KOH
Ethanol
(mL)
12
Time Amide 4a-e
Isolated yield
of 4a-e (%)
47.0
carbazone 3a-ea (mol%)
(h)
11
30
100
50
30
30
3a
3b
3c
3d
3e
12
6
5
46.5b
49.0
60.0
60.0
6
12
6
11
3
a Thiosemicarbazone 3a-e (1 mmol).
b Based on the reacted 3e (97% conversion).
20

Scheme 1. Preparation of 4-{[(E)-2-(aminocarbothioyl)-2-(2-
cyanoethyl)hydrazono]methyl}-pyridinium chloride (5)
21

Figure 1. Medicines derived from thiosemicarbazide
22

Figure 2. Synthesis of thiosemicarbazones.
23