4-Amino-3-pentadecyl-3H-1,2,4-triazole-3-thiones and 3-pentadecyl-1,3,4-oxadiazole-2(3H)-thione for the preparation of dimeric palladium(II) complexes and their applications in Tsuji–Trost and Mizoroki–Heck reactions

Article abstract of DOI:10.1080/00397911.2019.1599954

The synthesis of palladium complexes derived from 4-amino-3-pentadecyl-3H-1,2,4-triazole-3-thiones and 3-pentadecyl-1,3,4-oxadiazole-2(3H)-thiones are reported. They were obtained from palladium acetate and dipotassium tetrachloropalladate(II) and their composition was assigned by elemental analysis (solid state). The resulting metallic entities were also characterized in solution based in mass spectrometry experiments. Their application in organic synthesis as cross-coupling reaction catalysts is described. One example of both conventional Tsuji–Trost and Mizoroki–Heck reactions were efficiently carried out in very high chemical yield.

Full text of DOI:10.1080/00397911.2019.1599954

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
4-Amino-3-pentadecyl-3H-1,2,4-triazole-3-thiones
and 3-pentadecyl-1,3,4-oxadiazole-2(3H)-thione
for the preparation of dimeric palladium(II)
complexes and their applications in Tsuji–Trost
and Mizoroki–Heck reactions
Manel Chehrouri, Adil A. Othman, Samuel Jiménez-Cecilia, Cristina Moreno-
Cabrerizo & José M. Sansano
To cite this article: Manel Chehrouri, Adil A. Othman, Samuel Jiménez-Cecilia, Cristina Moreno-
Cabrerizo & José M. Sansano (2019): 4-Amino-3-pentadecyl-3H-1,2,4-triazole-3-thiones and 3-
pentadecyl-1,3,4-oxadiazole-2(3H)-thione for the preparation of dimeric palladium(II) complexes
and their applications in Tsuji–Trost and Mizoroki–Heck reactions, Synthetic Communications, DOI:
10.1080/00397911.2019.1599954
To link to this article: https://doi.org/10.1080/00397911.2019.1599954
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https://doi.org/10.1080/00397911.2019.1599954
4-Amino-3-pentadecyl-3H-1,2,4-triazole-3-thiones and
3-pentadecyl-1,3,4-oxadiazole-2(3H)-thione for the
preparation of dimeric palladium(II) complexes and their
applications in Tsuji–Trost and Mizoroki–Heck reactions
a
a
b
ꢀ
Manel Chehrouri , Adil A. Othman , Samuel Jimenez-Cecilia ,
b
b
ꢀ
Cristina Moreno-Cabrerizo , and Jose M. Sansano
a
ꢁ
ꢀ
ꢀ
Laboratoire de Synthese Organique Bioactive, Departement de Chimie Organique Industrielle, Faculte
b
ꢀ
de Chimie, Universite des Sciences et de la Technologie d’Oran, Oran, Algeria; Departamento de
Quımica Organica, Facultad de Ciencias, Centro de Innovacion en Quımica Avanzada (ORFEO-CINQA),
Instituto de Sıntesis Organica (ISO), Universidad de Alicante, Alicante, Spain
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ABSTRACT
ARTICLE HISTORY
Received 20 February 2019
The synthesis of palladium complexes derived from 4-amino-
3-pentadecyl-3H-1,2,4-triazole-3-thiones and 3-pentadecyl-1,3,4-oxa-
diazole-2(3H)-thiones are reported. They were obtained from
palladium acetate and dipotassium tetrachloropalladate(II) and their
composition was assigned by elemental analysis (solid state). The
resulting metallic entities were also characterized in solution based
in mass spectrometry experiments. Their application in organic syn-
thesis as cross-coupling reaction catalysts is described. One example
of both conventional Tsuji–Trost and Mizoroki–Heck reactions were
efficiently carried out in very high chemical yield.
KEYWORDS
Mizoroki–Heck; palladium;
palmitic acid; Tsuji–Trost
GRAPHICAL ABSTRACT
H
Ph
OAc
N
Ph
N
Tsuji-Trost
O
O
N
N
N
N
S
S
N
N
( )
14
(
)
Cl
14
NH2
N
Pd
Pd
S
H2
N
NH2
N
H2
N
(
(
)
)
14
14
Pd
Cl
(
)
)
14
S
N
N
N
N
O
(
14
O
N
S
S
Pd
S
Pd
N
N
N
Cl
Pd
S
Cl
N
N
N
N
I
O
(
)
14
O
(
)
14
Mizoroki-Heck
ꢁ ꢀ
Laboratoire de Synthese Organique Bioactive, Departement
de Chimie Organique Industrielle, Faculte de Chimie, Universite des Sciences et de la Technologie d’Oran, Mohamed
CONTACT Adil A.Othman
adelaliothman@gmail.com
ꢀ
ꢀ
ꢀ
Boudiaf-USTO-MB, BP. 1505, El-M’naouer, Oran, 31003, Algeria; Jose M. Sansano
jmsansano@ua.es
Departamento
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
de Quımica Organica, Centro de Innovacion en Quımica Avanzada (ORFEO-CINQA), Instituto de Sıntesis Organica (ISO).
Facultad de Ciencias, Universidad de Alicante, Alicante, 03080, Spain
Supplemental data for this article can be found accessing on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
M. CHEHROURI ET AL.
H
N
H
N
N
S
N
S
N
( )14
O
( )14
NH2
2
1
Figure 1. Fatty acid derivatives 1 and 2.
Introduction
It is very well known that fatty acids possess many crucial functions in the organism.
During the last two decades, the importance of these compounds in the treatment of
cancer,[1] among other degenerative pathologies as, for example, Alzheimer’s disease
and type 2 diabetic dementia,[2] acquired an enormous dimension. In this context, sev-
eral classes of molecules derived from fatty acids have received the same interest. For
example, 4-amino-3-pentadecyl-3H-1,2,4-triazole-3-thione 1 and its corresponding 3H-
(1,3,4)-oxadiazol-2-thione 2 (Fig. 1) have been prepared[3,4] and next their biological
and other interesting properties were evaluated by several groups. These families of
compounds exhibited antidepressant,[5] antitumor,[4,6] antimicrobial and antioxidant
activities,[7] corrosion inhibitors of carbon steel,[8] etc.
In addition, these molecules 1 and 2 demonstrated to be good ligands in the prepar-
ation and characterization of salen-type complexes of cobalt(II), nickel(II) and
copper(II) with Schiff bases derived from substituted salicylaldehydes.[9] However, to
the best of our knowledge, no palladium(II) complexes of these ligands have been
reported yet.[10] So, in this work, the corresponding complexes derived from hetero-
cycles 1 and 2 will be prepared, and immediately their efficiency as catalysts[11] will be
evaluated in two conventional processes such as standard Tsuji–Trost and
Mizoroki–Heck reactions.
Discussion
Initially, the preparation of the heterocyclic ligands 1 and 2 was performed, according
to the literature, starting from palmitic acid[3,4] (Scheme 1). This route consisted in the
preparation of the corresponding hydrazide and further reaction with carbon disulfide
and final acid-mediated cyclization in the presence of hydrazine or in absence of
the latter.[12]
Next step was the preparation of the palladium(II) complexes. For this purpose, the
formation of palladium(II) complexes from heterocyclic-2-thiones was selected as model
employing, palladium(II) acetate or K2PdCl4 as palladium sources.[13–15] After reaction
of heterocycles 1 and 2 with these salts in chloroform, at room temperature, for 24 h
(Scheme 2) the resulting complexes 3a–d were obtained. The tentative structures shown
in Scheme 2 corresponded to the information obtained in solid state and in solution.
No signal of acetate anion was detected by NMR of samples 3a and 3d. Unfortunately,

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SYNTHETIC COMMUNICATIONSV
3
O
CS2, KOH/EtOH
rt
NH
N
1. H2NNH2
NH
NH
S
( )14
KO
N
2. HCl
( )14
1. MeOH
H2SO4
NH2
O
1
S
CO2H
( )14
NH
( )14
2. H2NNH2
EtOH
NH2
NH
N
1. CS2, KOH/EtOH
2. HCl
S
O
( )14
2
Scheme 1. Synthesis of heterocycles 1 and 2.
N
N
S
N
Pd(OAc)2, CHCl3
rt, 1 d
( )14
NH2
Pd
S
H2N
N
( )14
N
N
NH
N
S
N
N
S
N
K2PdCl4, CHCl3
rt, 1 d
3a
( )14
N
Cl
Pd
( )14
Pd
H2N
NH2
N
NH2
Cl
( )14
1
S
N
O
( )14
N
3b
S
Pd(OAc)2, CHCl3
rt, 1 d
N
N
Pd
S
N
N
NH
O
N
( )14
N
S
S
O
K2PdCl4, CHCl3
rt, 1 d
( )14
Pd
N
O
3c
( )14
Cl
Pd
S
Cl
N
O
2
N
( )14
3d
Scheme 2. Synthesis of palladium complexes 3a–d.
NMR did not give very useful information about the real structure present in solution,
possibly several complexes are present in chloroform in such a way that carbonyl group
signals in 13C NMR disappeared. MS was recorded using electrospray ionization (ESI)
in a mixture of water/acetonitrile revealing that palladium complexes 3a and 3b or 3c
and 3d exhibited a mixture of aggregates confirming the existence of dimeric species in
different ratios and also coordinated with molecules of solvents employed during the
analyses (MeCN and water).
After a careful washing of the four palladium complexes, with methanol/water, micro-
analysis was performed. The elemental analysis revealed that, in solid state, it is appro-
priate to draw the structure of 3a and3cfor complexes formed using palladium(II)
acetate. Combustion data of palladium complexes 3b and 3d provided a high content in
chlorine, so it was possible to represent these dimeric bridged structures in the
solid state.
With these four complexes in hand, the study of their catalytic activity in the palla-
dium-promoted carbon–nitrogen and carbon–carbon bond coupling reactions were

4
M. CHEHROURI ET AL.
Pd complex (2 mol%)
PPh3 (4 mol%)
O
OAc
N
+
O
K2CO3 (2 equiv)
solvent (0.2 M), T
N
H
5
6
4
Scheme 3. Synthesis of compound 6 using palladium complexes 3a–d.
Table 1. Synthesis of product 6 through a Tsuji–Trost reactiona.
Entry
Pd complex (mol%)
Base
Solvent
Additive
T (ꢀC)b
T (h)
Yield (%)
__
1
3a (2)
3a (2)
3a (2)
3a (2)
3a (2)
3a (2)
3a (2)
3a (1)
3b (2)
3c (2)
3d (2)
3a (2)
3a (2)
3a (2)
3b (2)
3c (2)
3d (2)
TMG
EtOH
80 (A)
80 (A)
80 (A)
80 (A)
80 (A)
19
19
19
19
19
19
19
19
19
19
19
1
70c
76c
45c
43c
67c
81
93
67
90
61
52
25
35
93
93
91
92
__
2
3
K2CO3
TMG
EtOH
H2O
CTAB
4
5
6
7
8
9
10
11
12
13
14
15
16
17
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
H2O
MeCN
CTAB
__
__
__
__
__
__
__
__
__
__
__
__
__
MeCNdry
MeCNdry
MeCNdry
MeCNdry
MeCNdry
MeCNdry
MeCNdry
MeCNdry
MeCNdry
MeCNdry
MeCNdry
MeCNdry
80 (A)
110 (A)
110 (A)
110 (A)
110 (A)
110 (A)
50 (B)
75 (B)
1
1
1
1
100 (B)
100 (B)
100 (B)
100 (B)
1
aThe corresponding amount of palladium species 3 and PPh3 were mixed for 1 h and then, a solution of 1 mmol of
both 4 and 5, and the additive was added. The resulting mixture was stirred at the temperature and reaction times
indicated. Evaporation of the solvent and flash chromatography of the crude residue afforded pure product 6.
bMethod A: conventional heating in a sealed pressure tube; Method B: 50 W microwave irradiation at different
temperatures.
cVariable proportions of cinnamyl alcohol were also isolated.
surveyed. These palladium species were freshly prepared and immediately employed in
the Tsuji–Trost[16] reaction and in the Mizoroki–Heck[17] transformation.
For the first reaction, we took – as reference – the work of Billamboz et al.[18,19] in
which cinnamyl acetate (4) was allowed to react with morpholine (5) using several con-
ditions (Scheme 3 and Table 1) to afford the substitution product 6. Two calefaction
methods were employed. Method A involved a conventional heating in a sealed pressure
tube, meanwhile Method B represented a 50 W microwave irradiation at different tem-
peratures. Starting with the optimization process using palladium complex 3a, Method
A revealed that ethanol was not an appropriate solvent either with tetramethylguanidine
(TMG) or potassium carbonate because large amounts (>10%) of cinnamyl alcohol
were isolated (Table 1, entries 1 and 2). Using water as solvent (Table 1, entries 3 and
4), an analogous situation was observed but with more than 15% content of cinnamyl
alcohol. With acetonitrile the generation of this alcohol was diminished and with dry
acetonitrile was suppressed (Table 1, entries 5 and 6). The increment of the temperature
to 110 ꢀC afforded a higher yield (93%) being the 2 mol% the optimal catalyst loading
(Table 1, entries 7 and 8). Under this reaction conditions complex 3b afforded similar
chemical yield than that obtained one for complex 3a (Table 1, entry 9). However, pal-
ladium dimers 3c and 3d did not catalyze the Tsuji–Trost reaction so efficiently
(Table 1, entries 10 and 11). Using Method B reaction times were shorter and the

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5
Pd complex (2 mol%)
PPh3 (4 mol%)
I
+
K2CO3 (2 equiv)
refluxing toluene, 1 d
9
7
8
With 3a, 86%
With 3b, 82%
Scheme 4. Study of the Mizoroki–Heck reaction using complexes 3a and 3b.
highest yields were achieved by catalysts 3a and 3b at 100 ꢀC for 1 h (Table 1, entries
12–17) although catalytic complexes 3c and 3d were also effective under these condi-
tions. The presence of the triphenylphosphine was crucial for obtaining high conver-
sions and good chemical yields of the desired product 6.
Once demonstrated the best catalytic performance of palladium complexes 3a and 3b,
they were tested in the same proportion in the Mizoroki–Heck reaction between iodo-
benzene (7) and styrene (8) to give exclusively E-stilbene 9 in 86% and 82% yield,
respectively (Scheme 4).
Conclusions
This new synthesized palladium complexes were prone to form dimeric arrangements as
revealed data in solid state. In solution, this aggregates looked relatively strong and they
preferentially formed dimeric structures too. The efficiency of these robust
palladium(II) complexes was demonstrated in the classical Tsuji–Trost and
Mizoroki–Heck reactions. The long chain (pentadecyl) was introduced with the purpose
of the recovery of these complexes and their use in another catalytic process, but no
results were obtained and more work is currently underway.
Experimental part
General synthetic procedure for the Tsuji-Trost reaction
Method A: Cinnamyl acetate (40 mg, 0.2 mmol), morpholine (35 mg, 0.4 mmol) K2CO3
(55.2 mg, 0.4 mmol), complex 3a or 3b (0.004 mmol, 2 mol%), and PPh3 (2.1 mg,
0.008 mmol, 4 mol%) were suspended in dry MeCN (1 mL, 0.2M) in a pressure tube for
1 h. The mixture was heated at 110 ꢀC in a sand bath for 19 h. Water was added (5 mL)
and it was extracted with ethyl acetate (3 Â 5 mL). The organic solvent was dried, fil-
tered, evaporated and purified by column chromatography.
Method B: Cinnamyl acetate (40 mg, 0.2 mmol), morpholine (35 mg, 0.4 mmol)
K2CO3 (55.2 mg, 0.4 mmol), complex 3a or 3b (0.004 mmol, 2 mol%), and PPh3 (2.1 mg,
0.008 mmol, 4 mol%) were suspended in dry MeCN (1 mL, 0.2M). The mixture was
heated at 100 ꢀC in the microwave oven at 50 W for 1 h. Water was added (5 mL) and it
was extracted with ethyl acetate (3x5 mL). The organic solvent was dried, filtered,
evaporated and purified by column chromatographyfurnishing product 6[15,16] as color-
less oil, 44 mg, 93%.

6
M. CHEHROURI ET AL.
General synthetic procedures for the Mizoroki–Heck reaction
Iodobenzene (41 mg, 0.2 mmol), styrene (21 mg, 0.2 mmol), K2CO3 (55.2 mg, 0.4 mmol),
complex 3a or 3b (0.004 mmol, 2 mol%), and PPh3 (2.1 mg, 0.008 mmol, 4 mol%) were
suspended in toluene (3 mL) in a pressure tube. The mixture was heated at 110 ꢀC in a
sand bath for 24 h. Water was added (5 mL) and it was extracted with ethyl acetate
(3 Â 5 mL). The organic solvent was dried, filtered, evaporated and purified by column
chromatography affording pure 9 (Commercially available compound) as colorless oil,
31 mg 86% or 30 mg 82%.
Supplementary information (SI)
1
Supplementary material includes the characterization data of known compounds 1 and 2 H and
13CNMR spectra of compounds 6, 9, and complexes 3a–d and ESI of complexes 3a–d.
Funding
ꢀ
Financial support was provided by the Spanish Ministerio de Ciencia e Innovacion (MICINN)
(projects CTQ2010-20387, and ConsoliderIngenio 2010, CSD2007-00006), the Spanish Ministerio
ꢀ
de Economıa y Competitividad (MINECO) (projects CTQ2013-43446-P, and CTQ2014-51912-
REDC), FEDER, the GeneralitatValenciana (PROMETEO 2009/039 and PROMETEOII/2014/017)
and the University of Alicante. M.C. thanks USTO-MB for scientific leave.
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