Direct synthesis of piperazines containing dithiocarbamate derivatives via DABCO bond cleavage

Article abstract of DOI:10.1016/j.tetlet.2020.152610

DABCO bond cleavage with dithiocarbamic acid salts was applied as a direct synthetic route for the preparation of a novel category of piperazines containing dithiocarbamate functional group. This metal-free and operationally simple approach can be applied

Full text of DOI:10.1016/j.tetlet.2020.152610

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Direct synthesis of piperazines containing dithiocarbamate derivatives via
DABCO bond cleavage
Farzane Jafari Asar, Farinaz Soleymani, Seyyed Emad Hooshmand, Azim
Ziyaei Halimehjani
PII:
S0040-4039(20)31109-6
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152610
TETL 152610
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
28 August 2020
17 October 2020
27 October 2020
Please cite this article as: Jafari Asar, F., Soleymani, F., Emad Hooshmand, S., Ziyaei Halimehjani, A., Direct
synthesis of piperazines containing dithiocarbamate derivatives via DABCO bond cleavage, Tetrahedron Letters
(2020), doi: https://doi.org/10.1016/j.tetlet.2020.152610
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Direct synthesis of piperazines containing
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bond cleavage
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Farzane Jafari Asar, Farinaz Soleymani, Seyyed Emad Hooshmand, Azim Ziyaei Halimehjani

1
Tetrahedron Letters
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Direct synthesis of piperazines containing dithiocarbamate derivatives via DABCO
bond cleavage
Farzane Jafari Asar,a Farinaz Soleymani,a Seyyed Emad Hooshmand,*b Azim Ziyaei Halimehjani*a
aFaculty of Chemistry, Kharazmi University, 49 Mofateh St., 15719-14911, Tehran, Iran. E-mail: ziyaei@khu.ac.ir
b Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran. E-mail:
emad.hooshmand@yahoo.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
DABCO bond cleavage with dithiocarbamic acid salts was applied as a direct synthetic route for
the preparation of a novel category of piperazines containing dithiocarbamate functional group.
This metal-free and operationally simple approach can be applied with good to excellent yields
and high selectivity. Besides, substituted bis-piperazines and piperidines containing
dithiocarbamate groups were successfully prepared via the same protocol using quaternized
quinuclidine and bis-quaternized DABCO.
Available online
Keywords:
Dithiocarbamate
Piperazines
2020 Elsevier Ltd. All rights reserved.
C-N bond cleavage
DABCO ring-opening
piperidines
To meet the challenges encountered in organic synthesis
accompanied by total synthesis implementation, in recent years,
organic chemists have constantly tried to introduce efficient
synthetic route via a various range of new substrates. Within the
organic transformation, several neoteric synthetic approaches
such as re-engineering method,1 pot, atom, step economy (PASE)
method and also alternative reactants for common reactions have
gained widespread attention.2 The most prominent trends in this
scientific area during the past decade are abridged including
using thiols and phenols instead of acid in Ugi-multicomponent
reactions,3,4 amides and ammonium salts rather than alkyl
halides,5,6 nitroalkenes instead of phenylacetylenes in Huisgen
click reaction.7 These state-of-the-art synthetic strategies not only
enable chemists and pharmacists to tackle the problems in total
N
H
N
Cl
NH
S
N
N
S
N
OH
NH
O
N
N
Cl
N
F
N
O
Geodon
antipsychotic
Sprycel
anticancer drug
F
H
S
RO
O
N
N
N
R1
N
S
S
O
N
Br
N
N
Potent anticancer activity
Bioactive molecule
synthesis, but also provide privilege tools for
a direct,
expeditious and viable synthesis to access more complex
compounds containing several functional groups and heterocyclic
moieties.
Figure 1. Selected piperazine-based drugs and bioactive
molecules
It is true that among the top 25 best-selling
pharmaceuticals in the year 2014, there have been 12 small-
molecule drugs with heterocyclic moieties. In the meanwhile,
nearly 90% of all marketed drugs contain at least one nitrogen
atom as a key structural element in their structure8 and account
for exceeding 50 billion USD in annual revenue.9 Among FDA
approved drugs, one of the most important heterocyclic rings is
piperazine. Additionally, substituted piperazines have found
enormous applications as drugs, intermediates of biologically
active molecules, agrochemicals, and also ligands.10,11
Functionalized piperazine motif is considered as a key structural
scaffold in a variety of marketed drugs such as Geodon™ and
Sprycel™ which have been approved for treatment of
schizophrenia and cancer respectively (Figure 1).12,13
Moreover, dithiocarbamate derivatives are a remarkable
pharmacophore which indicated various biological activities
when incorporated in a particular structure.14 Take, for instance,
thiram which could be used in dermatology as a scabicide.15
Dithiocarbamates also constitute an important class of fungicides,
herbicides, and pesticides and many compounds of this category
namely ferbam, mancozeb, zineb, and ziram have been
commercialized.16 Hence, the combination of these
pharmacophores (piperazine and dithiocarbamate) in a single
scaffold via a synergistic effect is likely to be a potential
candidate for the development of new pharmacologically active
molecules.
In the light of the crucial role of functionalized
piperazines in several medical disciplines, a synthetic route to

2
Tetrahedron Letters
access diversely functionalized derivatives of piperazines have
In the present communication, as part of our studies on
dithiocarbamate chemistry,27–29 we report the synthesis of 1,4-
disubstituted piperazine derivatives 3a-p via the reaction of
quaternized derivatives of DABCO 1 with dithiocarbamate salts
2 in the absence of any catalyst, additive or metals. First of all, to
optimize the reaction conditions, various organic solvents were
applied to the model reaction forming 3h (Table 1).
been highly sought after. In the past, N-alkylated piperazine
scaffolds are commonly achieved by multi-step reactions and
these methods have suffered from several drawbacks. These
synthetic routes typically are based on transition- metal-catalyzed
carbon-nitrogen bond-forming transformation via expensive
metals and ligands.17,18 Costly catalysts and additives, relatively
detrimental metals as well as harsh reaction conditions are
considered as main shortcomings for reported methods. As a
result, designing a direct, straightforward, and step economy
strategy to access piperazines heterocyclic compounds have been
gained widespread attention in recent years. As a result, very
recently, 1,4-diazabicyclo[2.2.2]octane (DABCO) which has
commonly addressed as an organic catalyst19,20 in chemical
progress has been used as a substrate in carbon-nitrogen bond
cleavage reactions for the synthesis of outstanding piperazines
derivatives. Diversities of nucleophiles including thiols,
carboxylic acid salts, phenolates, alkoxides, halides, amines,
azide, and enolates were applied successfully for DABCO bond
cleavage.21–26
Owing to the importance of reaction temperature in
carbon-nitrogen bond cleavage reactions, expectedly no reaction
was occurred at room temperature in THF (Table 1, entry 1).
o
When, reaction temperature was raised to 120 C in THF for 4h,
the yield of 3h improved to 62% (Table 1, entry 2). Prolonging
the reaction time to 8, 16 and 24 hours improved the yields to 70,
75 and 80 %, respectively (Table 1, entries 3-5). No further
improvement in reaction yield was observed by further
prolonging the reaction time. By screening the model reaction in
protic and aprotic organic solvents such as MeOH, EtOH, iPrOH,
MeCN, DMF, DMSO, toluene and dioxane lower yields were
obtained (Table 1, entries 6-13). Using water gave inferior results
in yield (Table 1, entry 14). The use of polyethylene glycol
(PEG) led to the formation of the desired product, whereas the
yield was not satisfactory and work-up is extremely harsh and
time-consuming (Table 1, entries 15-16). In addition, a one-pot
three-component reaction was examined using amine and carbon
disulfide instead of dithiocarbamate salt along with quaternized
derivatives of DABCO, which afforded the corresponding
product in 40% isolated yield (Table 1, entry 17). Finally, using
THF as the reaction medium and heating the reaction mixture to
120 °C for 24 h was considered as optimal conditions for further
synthesis. Evidently, as this temperature is much higher than
THF boiling point, these reactions carried out in sealed tube and
under high pressure.
Table 1. Selected conditions for optimization of the reaction
S
N
S
N
N+
conditions
N
N
S
N
S
Na
+
Br-
2
1
3h
Entry
1
Solvent
THF
Temp. (°C)
25
Time (h) Yield (%)a
24
4
trace
62
70
75
80
65
70
70
56
60
63
15
45
5
The scope of this reaction was examined using various secondary
amines including diethylamine, dimethylamine, and cyclic
amines namely morpholine, pyrrolidine, piperidine and azepane
and the corresponding 1,4-disubstituted piperazines containing
dithiocarbamate 3a-p were obtained in high to excellent yields
(Scheme 1). Interestingly, using cyclic amines in this approach
leads to synthesize novel bis-heterocycle scaffolds containing
dithiocarbamates. A combination of two remarkable heterocyclic
rings in one complex structure must undoubtedly create new
entities with privileged biological properties due to synergistic
effect.30 Moreover, a wide range of quaternized derivatives of
DABCO which prepared via the reaction of DABCO with
primary and secondary alkyl halides were applied in this
synthetic route. Then, quatenized DABCO salts with benzyl,
allyl and 2-oxopropyl groups were used for further investigation.
These reactions have progressed through the SN2 mechanism that
quaternized DABCO undergoes ring opening with the aid of a
dithiocarbamate salt to furnish desired products. To sum up, the
desired carbon-sulfur bond formation proceeded well through a
carbon-nitrogen bond cleavage in DABCO ring. According to the
experimental results, the regioselectivity of the reaction rely on
the type of alkyl group attached to the DABCO salt whereby the
nucleophilic attack on the carbon of bridge or the carbon of the
alkyl group have invariably competed. In the cases of 3o and 3p,
in addition to desired products, alkyl dithiocarbamates as a main
byproduct have been synthesized. On the basis of the previous
reports,24 a plausible mechanism for this reaction is suggested in
Scheme 2. The outcome pertains to the hard-soft properties of the
nucleophiles and electrophiles (HSAB theory) as well as the
steric hindrance of the alkyl halides.31 This mechanism can be
justified by the theory of stable carbocation and transition state
formation for benzyl, allyl, and carbonyl groups as a softer
nucleophilic site through which contributed to reduce yields in
the corresponding products.
2
THF
120
3
THF
120
8
4
THF
120
16
24
24
24
24
24
24
24
24
24
24
24
24
24
5
THF
120
6
MeOH
EtOH
iPrOH
CH3CN
DMF
120
7
120
8
120
9
120
10
11
12
13
14
15
16
17
120
DMSO
120
Toluene
Dioxane
H2O
120
120
120
PEG 1500
PEG 400
THF
120
45
61
40b
120
120
a Isolated yields. b Isolated yield for one-pot three-component
route using diethylamine, CS2 and DABCO salt 1.

3
S
NH
+
N
C
S
+
RX
N
R
S
N
EtOH NaOH
S
THF
N
N
S
3h
N
N+
THF
N
S
Na
or
120 o
C
+
S
C-N bond
cleavage
X-
R
R
2
N
S
1
Scheme 2. Proposed reaction mechanism.
Scheme 1. Diversity in the synthesis of piperazines containing dithiocarbamate motifa
S
S
S
S
S
S
S
S
N
N
N
N
N
N
N
N
N
N
N
N
3a
, 92%
3d
, 65%
3c
, 76%
3b
, 84%
S
N
S
S
S
N
S
N
S
O
N
S
N
N
N
N
N
N
S
N
N
3e
, 54%
3f
, 86%
3g
, 90%
3h
, 80%
S
N
S
N
S
N
S
S
N
N
N
N
N
N
S
N
S
N
N
N
S
N
O
O
3j
, 72%
3i
, 93%
3k
, 85%
3l
, 55%
S
N
N
S
Ph
S
N
N
O
S
N
S
N
S
N
N
N
S
N
S
3p
, 27%
3o
, 31%
3n
, 49%
3m
, 72%
a Isolated yield.
In the next step, we turned to implement bis-ammonium
salt 4 to access N, N′-bis piperazine containing dithiocarbamate
compounds 3q-t, which in all cases, pure products have been
obtained in appropriate yields (Scheme 3). Basically, fungicidal
activity of
a
molecule is depend on the number of
dithiocarbamate moieties in the scaffolds and can be improved by
increasing the number of dithiocarbamate motifs.32
R
S
N
N
R
N
S
Br-
S
N
S
n
N+
R
N
R
N
N+
N
R
S
THF
120 oC
+
N
R
S-K+
n
N
Br-
3q: R:Me, n=3;
3r: R:Me, n=2;
3s: R:Et, n=3;
46%
76%
55%
4
2
3t: R:Pyrrolidine, n=2;
74%
Scheme 3. Diversity in the synthesis of N, N′-bis piperazines containing dithiocarbamate groups
Thereafter, to expand the diversity of the synthetic strategy, aside
from DABCO, quaternized derivatives of quinuclidine have been
S
R
N+
S-K+
THF
120 o
N
R
3 u-v
+
Br-
applied.
Hereupon,
N-alkyl
piperidine
containing
C
dithiocarbamates 3u-v were synthesized with high selectivity
(Scheme 4).
2
1
S
S
N
N
S
S
N
N
3u,
75%
3v,
89%

4
Tetrahedron Letters
14. Francioli, C.; Wang, X.; Parapanov, R.; Abdelnour, E.; Lugrin, J.;
Scheme 4. Synthesis of N-alkyl piperidines containing
Gronchi, F.; Perentes, J.; Eckert, P.; Ris, H.-B.; Piquilloud, L.
PLoS One 2017, 12, e0173916.
dithiocarbamates with quinuclidine salts
15. Bala, V.; Gupta, G.; L Sharma, V. Chemical and Medicinal
Versatility of Dithiocarbamates: An Overview. Mini Rev. Med.
Chem. 2014, 14, 1021–1032.
Conclusion
16. Halimehjani, A. Z.; Hooshmand, S. E.; Shamiri, E. V.
Tetrahedron Lett. 2014, 55, 5454–5457.
17. Gettys, K. E.; Ye, Z.; Dai, M. Recent Advances in Piperazine
Synthesis. Synthesis (Stuttg). 2017, 49 (12), 2589–2604.
18. Boursalian, G. B.; Ham, W. S.; Mazzotti, A. R.; Ritter, T. Nat.
Chem. 2016, 8, 810.
19. Halimehjani, A. Z.; Hooshmand, S. E.; Shamiri, E. V. RSC Adv.
2015, 5, 21772–21777.
20. Ye, S.; Wang, H.; Wu, J. ACS Comb. Sci. 2011, 13, 120–125.
21. Zhu, Q.; Yuan, Q.; Chen, M.; Guo, M.; Huang, H. Angew. Chemie
2017, 129, 5183–5187.
22. Bugaenko, D. I.; Yurovskaya, M. A.; Karchava, A. V. J. Org.
Chem. 2017, 82, 2136–2149.
23. Ross, S. P.; Hoye, T. R. Org. Lett. 2018, 20, 100–103.
24. Halimehjani, A. Z.; Badali, E. RSC Adv. 2019, 9, 36386–36409.
25. Zhu, Q.; Chen, M.; Hu, J.; Yang, L. Chem. Asian J. 2018, 13,
1124–1128.
26. Maraš, N.; Polanc, S.; Kočevar, M. Org. Biomol. Chem. 2012, 10,
1300–1310.
27. Ziyaei Halimehjani, A.; Lotfi Nosood, Y. Org. Lett. 2017, 19,
6748–6751.
In the light of the medicinal properties of piperazine and also
dithiocarbamate motifs, we introduce an initiative procedure to
synthesize piperazines containing dithiocarbamate derivatives via
carbon-nitrogen bond cleavage of DABCO. With this direct and
practical synthetic pathway, a library of piperazines and
piperidines containing dithiocarbamates were easily obtained by
the reaction of a diversified number of quaternized derivatives of
DABCO and quinuclidine accompanied by various
dithiocarbamate salts. Joyfully, despite most of the carbon-
nitrogen bond cleavage reports, our novel desired products were
achieved in the absence of any catalyst, additive, and metals. A
great deal of benefits can be derived from catalyst-free reactions,
take decreasing chemical pollutions and improving the E-factor
as critical parameters in an environmentally benign organic
reaction, for instance.33 Furthermore, metal-free organic
transformations are particularly interesting to the pharmaceutical
industry as they overcome the problem of toxic metal
contaminants being present in the final products. Finally, we
anticipate that these synthetic strategies come up with a solution
to a certain number of barriers to drug design and total synthesis.
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83, 5778–5783.
29. Schlüter, T.; Ziyaei Halimehjani, A.; Wachtendorf, D.;
Schmidtmann, M.; Martens, J. ACS Comb. Sci. 2016, 18, 456–460.
30. Lu, H.-Y.; Barve, I. J.; Selvaraju, M.; Sun, C.-M. ACS Comb. Sci.
2019, 22, 42–48.
Acknowledgment
31. Ho, T.-L. Chem. Rev. 1975, 75, 1–20.
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P.; Ronco, G. J. Agric. Food Chem. 2000, 48, 5283–5287.
33. Sheldon, R. A. Green Chem. 2017, 19, 18–43.
We are grateful to the Faculty of Chemistry of Kharazmi
University for supporting this work.
References and notes
Declaration of interests
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Graphical Abstract

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Direct synthesis of piperazines containing
dithiocarbamate derivatives via DABCO
bond cleavage
Leave this area blank for abstract info.
Farzane Jafari Asar, Farinaz Soleymani, Seyyed Emad Hooshmand, Azim Ziyaei Halimehjani
DABCO bond cleavage with dithiocarbamic acid
salts was nvestigated ► A novel category of
piperazines containing dithiocarbamate functional
group was prepared ► This method provided
piperazines with good to excellent yields and high
selectivity►Substituted
bis-piperazines
and
piperidines were successfully prepared via the same
protocol.