ZnCl2-catalyzed synthesis of α-dithiocarbamato-alkyl-β-naphthols via the Betti reaction under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2020.152270

The synthesis of α-dithiocarbamato-alkyl-β-naphthols is reported via the Betti reaction of naphthols, aldehydes and ammonia-based dithiocarbamates in the presence of ZnCl₂ under solvent-free conditions. High to excellent yields and simple reaction conditions are the main advantages of this reaction.

Full text of DOI:10.1016/j.tetlet.2020.152270

Journal Pre-proofs
ZnCl2-catalyzed synthesis of α-dithiocarbamato-alkyl-β-naphthols via the bet‐
ti reaction under solvent-free conditions
Maryam Khalili Foumeshi, Azim Ziyaei Halimehjani, Hossein Paghandeh,
Petr Beier
PII:
S0040-4039(20)30737-1
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Reference:
https://doi.org/10.1016/j.tetlet.2020.152270
TETL 152270
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Tetrahedron Letters
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1 June 2020
11 July 2020
17 July 2020
Please cite this article as: Foumeshi, M.K., Ziyaei Halimehjani, A., Paghandeh, H., Beier, P., ZnCl2-catalyzed
synthesis of α-dithiocarbamato-alkyl-β-naphthols via the betti reaction under solvent-free conditions,
Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152270
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ZnCl2-catalyzed synthesis of α-dithiocarbamato-alkyl-β-naphthols
via the Betti reaction under solvent-free conditions
Maryam Khalili Foumeshi,a,b Azim Ziyaei Halimehjani,a,* Hossein Paghandeh,a Petr Beier,b,*
a Faculty of Chemistry, Kharazmi University, P. O. Box 15719-14911, 49 Mofateh St., Tehran,
Iran. E-mail: ziyaei@khu.ac.ir
b Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences,
Flemingovo nám. 2, 166 10 Prague 6, Czech Republic. E-mail: beier@uochb.cas.cz
Abstract
The synthesis of α-dithiocarbamato-alkyl-β-naphthols is reported via the Betti reaction of
naphthols, aldehydes and ammonia-based dithiocarbamates in the presence of ZnCl2 under
solvent-free conditions. High to excellent yields and simple reaction conditions are the main
advantages of this reaction.
Keywords: Multicomponent reaction, Dithiocarbamate, Naphthol, Betti reaction, Solvent-free
One-pot multicomponent reactions (MCRs) are an efficient alternative to the step-wise
synthesis of organic compounds, especially for the sustainable and diversity-oriented synthesis of
biologically active compounds.1 The development of novel MCRs has attracted significant
attention from various branches of science, such as drug discovery, synthetic organic chemistry
and materials science. In addition, assembling consecutive MCRs has attracted interest due to the
fact that they enable more step- and time-economic conversions of simple starting materials into
complex targets.2
1

Among the various MCRs, the Betti reaction is used for the synthesis of aminoalkyl
naphthols from simple and commercially available starting materials such as naphthols,
aldehydes and an amine source.3 A wide diversity of amine sources such as ammonia, primary
and secondary amines, amides, thioamides, nitriles and carbamates have been utilized for the
synthesis of aminoalkyl/(thio)amidoalkyl/carbamatoalkyl naphthols (Scheme 1A).4-17 To the best
of our knowledge, the application of dithiocarbamates as an amine precursor has not been
reported in this reaction. Although the synthesis of Betti bases with primary and secondary
amines can be carried out under catalyst-free conditions,4 for amine precursors with poor
nucleophilicity such as nitriles, amides, thioamides and carbamates, the application of a catalyst
is required. Various catalysts such as HClO4-SiO2,5 SiO2-NaHSO4,6 FeCl3.SiO2,7 Fe(HSO4)3,8
silica-supported Preyssler nano particles,9 ZnO,10 organocatalysts,11 nano Fe3O4,12 Fe(HSO4)3
16
doped on a carbon source,13 heteropolyacids,14 H3PO4/Al2O3,15 Ce(SO4)2 and iodine17 have
been reported.
2

Scheme 1. Previously reported and proposed methods for the synthesis of 1,3-aminooxygenated
compounds based on naphthols.
Chiral Betti bases are valuable ligands for transition metals in asymmetric synthesis18 and
intermediates in the synthesis of heterocycles.19 Furthermore, dithiocarbamates are important
intermediates for the synthesis of various functional groups and heterocycles.20 These
observations encouraged us to develop a novel route for the synthesis of a new family of
compounds containing dithiocarbamate and naphthol moieties via consecutive MCRs as outlined
in Scheme 1B.
In continuation of our research on the synthesis of novel dithiocarbamates and their
application in organic synthesis,21 herein we report an efficient and novel procedure for the
synthesis of α-dithiocarbamato-alkyl-β-naphthols via two consecutive MCRs. The first MCR is
3

the synthesis of alkyl dithiocarbamates via a one-pot, three-component reaction of ammonia, CS2
and an electrophile such as alkyl halides or α,β-unsaturated carbonyl compounds.22 The second
MCR is the condensation of the prepared alkyl dithiocarbamates with aldehydes and naphthols
(Scheme 1B). We started by examining the model reaction at 60 °C (at this temperature all the
stating materials melted and the reaction mixture forms a liquid phase) for 1 hour under solvent-
and catalyst-free conditions. The corresponding product, benzyl [(2-hydroxynaphthalen-1-
yl)(phenyl)methyl]carbamodithioate 4a, was obtained in 6% isolated yield (Table 1, entry 1).
Using 20 mol% of ZnCl2 and heating for 1 hour, the yield was improved to 21% (Table 1, entry
2). Prolonging the reaction time to 3 hours and 8 hours afforded 4a in 31% and 92% yield,
respectively (Table 1, entries 3-4). No improvement in the yield was observed upon prolonging
the reaction time to 10 hours (Table 1, entry 5). Performing the model reaction in organic
solvents afforded lower yields, except for toluene (Table 1, entries 6-11). Although other Lewis
acids such as AlBr3, SbCl3, CdCl2 and CrCl3 afforded similar yields under neat conditions (Table
1, entries 12-15), ZnCl2 was considered as the catalyst of choice for this reaction because of its
safety and price. The reaction of an equimolar amount of an aldehyde and naphthol with 1.1
equivalents of a dithiocarbamate in the presence of 20 mol% ZnCl2 at 60 °C for 8 hours without
solvent was selected as the optimal conditions.
Table 1. Optimization of the reaction conditions.a
Entry
1
Solvent
solvent-free
Catalyst Time (h) Yield 4a (%)b
-
1
6
4

2
3
4
5
6
solvent-free
solvent-free
solvent-free
solvent-free
toluene
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
1
2
8
10
8
22
31
92
92
92
7
8
THF
DMF
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
8
8
8
8
8
43
trace
10
9
CHCl3
EtOH
MeCN
10
11
85
10
12
13
14
15
solvent-free
solvent-free
solvent-free
solvent-free
SbCl3
AlBr3
CdCl2
CrCl3
8
8
8
8
83
91
92
92
a
Reagents and conditions: benzaldehyde (1 mmol), benzyl
dithiocarbamate (1.1 equiv.), 2-naphthol (1 equiv.), solvent (2 mL),
catalyst (20 mol%), 60 °C. b Isolated yield.
After optimization of the reaction conditions, the scope of this methodology was
investigated using various dithiocarbamates, aldehydes and naphthol derivatives (Table 2).
Structurally diverse dithiocarbamates with different substituents on the sulfur atom afforded the
corresponding products in high to excellent yields. Both aromatic and aliphatic aldehydes are
suitable substrates in this reaction as well as naphthol derivatives such as 2-naphthol, 6-bromo-2-
naphthol, 6-methoxy-2-naphthol and 2,7-dihydroxynaphthalene. An excellent yield was obtained
in the large scale synthesis (90%, 15 mmol scale) of 4a. An attempt to perform the reaction using
2,3-dihydroxynaphthalene was not successful. Furthermore, primary amine-based
dithiocarbamates are not suitable substrates in this protocol. This may be due to the higher steric
hindrance and lower nucleophilic character of the nitrogen in these structures. In addition, by
using indole instead of 2-naphthol in this reaction, the corresponding bis(indolyl)methane 5 was
obtained in 63% yield.
5

Table 1. Diversity in the multicomponent synthesis of dithiocarbamates from naphthols.a
a Isolated yield (1 mmol scale). b Large scale synthesis (15 mmol scale). c Reaction was carried
out at 90 °C.
6

The proposed mechanism for this reaction is depicted in Scheme 2. The reaction of 2-
naphthol with the ZnCl2-activated aldehyde affords the corresponding o-naphthoquinone methide
A, and subsequent nucleophilic attack by the nitrogen of dithiocarbamate 1 provides the desired
product after proton transfer. Two control experiments were carried out to support the proposed
mechanism. No imine was formed between benzaldehyde and benzyl dithiocarbamate in the
presence of 20 mol% ZnCl2 at 60 °C (Scheme 2, reaction 2). This finding is inconsistent with
the Mannich or Betti reaction mechanism. Furthermore, in the absence of dithiocarbamate, the
formation of 1,1'-(phenylmethylene)bis(naphthalen-2-ol) (6) was observed. Compound 6 is
presumably formed via intermediate A.6-7 According to our previous findings, ammonia-based
dithiocarbamates are potential bis-nucleophiles due to their sulfur and nitrogen atoms and the
initial attack usually occurs with the sulfur atom of the thiocarbonyl group.22-23 However, in this
case the intermediate A is attacked by the nitrogen atom of 1 to form the product 4.
7

Scheme 2. Proposed reaction mechanism (i) and control experiments (ii, iii).
Conclusion
The ZnCl2 catalyzed synthesis of 1-dithiocarbamatoalkyl-2-naphthols via a one-pot,
three-component Betti reaction of aldehydes, dithiocarbamates and 2-naphthol derivatives under
solvent-free conditions is reported. This new MCR provides a simple access to a new family of
compounds containing the dithiocarbamate and naphthol moieties in a single structure. In
addition, Betti bases with sulfur atoms in the structure which increase the chelating character of
these compounds as a bidentate ligand for transition metals and may find application in
coordination chemistry.
8

Acknowledgment
We are grateful to the Faculty of Chemistry of Kharazmi University for supporting this work
(Grant number 4/8575 and D/2056). This work was also supported by the Academy of Sciences
of the Czech Republic (RVO: 61388963).
Supporting Information
General experimental procedures, characterization data and copies of NMR spectra for all
compounds.
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ZnCl2-catalyzed synthesis of α-dithiocarbamato-alkyl-β-naphthols
via the Betti reaction under solvent-free conditions
Maryam Khalili Foumeshi, Azim Ziyaei Halimehjani,* Hossein Paghandeh, Petr Beier*
13

α-dithiocarbamato-alkyl-β-naphthols is prepared► the Betti reaction of naphthols, aldehydes and
ammonia-based dithiocarbamates is investigated► ZnCl2 catalyzed the reaction under solvent-
free conditions►High to excellent yields and simple reaction conditions are the main advantages
of this reaction
14

Declaration of interests
 ☐ The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
15