Mechanistic study on a novel pseudo-five-component synthesis of 4H-thiopyrans

Article abstract of DOI:10.1080/10426507.2016.1268138

The use of carbon disulfide provides a novel and efficient route for the synthesis of thiopyrans. Herein we describe a study on the pseudo-five-component preparation of 4H-thiopyran derivatives by condensation of aldehydes, malononitrile, carbon disulfide, and primary amines in the presence of triethylamine. Separation and identification of the reaction intermediates and products, additional starting materials designing, repeating of the reaction, and determining of the products, NMR, and GC-mass analysis of the reaction mixtures, were used to evaluate and confirm the reaction pathway.

Full text of DOI:10.1080/10426507.2016.1268138

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Mechanistic study on a novel pseudo-five-component synthesis of 4H-thiopyrans
Sajad Asadbegi, Akbar Mobinikhaledi and Mohammad Ali Bodaghifard*
Department of Chemistry, Faculty of Science, Arak University, 38156-88349 Arak, Iran
*Corresponding author. E-mail: mbodaghi2007@yahoo.com; m-bodaghifard@araku.ac.ir
Abstract
The use of carbon disulfide provides a novel and efficient route for the synthesis of thiopyrans.
Herein we describe a study on the pseudo-five-component preparation of 4H-thiopyran
derivatives by condensation of aldehydes, malononitrile, carbon disulfide, and primary amines in
the presence of trimethylamine. Separation and identification of the reaction intermediates and
products, additional starting materials designing, repeating of the reaction, and determining of
the products, NMR and GC-mass analysis of the reaction mixtures, were used to evaluate and
confirm the reaction pathway.
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Keywords
Mechanistic study, Multicomponent reaction, Thiopyrans, Carbon disulfide, Isothiocyanate
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Introduction
A reaction mechanism consists in the series of actual events that occur as reactant molecules are
stepwise transformed into products. All facts available must fit into a suggested mechanism. The
usual approach is, at first, the recognition of outstanding features of the mechanism and then,
secondly, paying attention to finer details.1-3 Albeit with a good degree of confidence,
mechanisms can be written for most chemical reactions nowadays. However, mechanism
frequently were not definitely and thoroughly identified. For the reason that there are numerous
variables, the problems involved are laborious. For several reactions, there are various suggested
mechanism that will fit the data equally well. On the other hand, certain reactions are recognized
where diverse mechanisms are observed under different conditions.4-6 There are a number of
commonly used methods for determining mechanisms: Separation and identification of the
reaction products, additional starting materials designing, various aspects of the mechanism
testing, the reaction repeating and the determining of products are the preliminary methods for
mechanism determination. Study of the kinetic evidence, catalysis, stereochemical evidence,
solvents and isotopic effects are other methods for validating of mechanisms. In most reactions,
one method is not sufficient, and the problem is usually approached from numerous directions.4,7
Sulfur-containing heterocyclic compounds have gained pointedly increased attention,
since a broad range of biological activities related with the scaffold have been recognized.8
Thiopyrans are attractive heterocyclic compounds that are interesting for their pharmacological
activities, which include anti-hyperplasia,9 anti-bacterial,10 anti-psychotic,11 analgesic, anti-
inflammatory,12 and anticancer activity.13,14 Over the past few years, several methods with use of
2-cyanothioacetamide as the sulfur source for the synthesis of thiopyran derivatives have been
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developed.15-22 There are several drawbacks of these synthetic methods such as the cost of
reagents, need of multiple reaction steps, long reaction times and low yields. Therefore, the
improvement of methods for the synthesis of thiopyrans continues to be an exciting goal in both
medicinal and synthetic chemistry.
Recently, we reported results on the reaction of aldehydes (1) with malononitrile (2),
carbon disulfide (3), and primary amines (4) the in presence of triethylamine as a catalyst at
room temperature that produced 4H-thiopyrans (Scheme 1).23,24 Since the use of carbon disulfide
is a novel and efficient route in this area, a detailed mechanistic study is described here.
Results and discussion
Mechanistic investigation
A probable mechanism for the formation of 2,6-diamino-4-phenyl-4H-thiopyran-3,5-
dicarbonitrile is proposed in Scheme 2. Initially, a standard Knoevenagel condensation of
benzaldehyde 1 with malononitrile 2 in the presence of triethylamine takes place to form 2-
benzylidenemalononitrile A as an intermediate. Then adduct B furnished via a Michael addition
of 2 to intermediate A. Then intermediate C (benzylcarbamodithioic acid) is formed via the
reaction of benzylamine 4 with carbon disulfide 3. Subsequently a nucleophilic attack of C on a
B cyanide group affords the adduct D. A hydrogen transfer and carbon-sulfur bond disconnection
leads to formation of benzyl isothiocyanate 5 and intermediate E. Another H-shift, followed by
attack on C≡N of E and cyclization leads to F. Finally the H-shift (tautomerization) in F gives
product 6.
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We found that the primary amine is essential for enabling the reaction. If it is left out, no
formation of the desired product occurs. It is notable that no product was formed when secondary
or tertiary amines instead of primary amines were used in this reaction.
NMR and GC-mass study of the reaction mixture
The GC-mass spectrum of the reaction mixture proved the releasing of benzyl isothiocyanate as a
byproduct in the reaction. This can be taken as evidence for the proposed mechanism. A concise
literature survey indicates four distinct references that 2-cyanothioacetamide is produced only
via the reaction of hydrogen sulfide with malononitrile.25-28 The in-situ formation of 2-
cyanothioacetamide in our reaction is only possible via the interaction of benzylamine, carbon
disulfide and malononitrile. For the examination and consolidation of the proposed mechanism, a
control test on the probability of the production of 2-cyanothioacetamide was carried out. The
reaction of benzylamine, carbon disulfide and 1 equivalent of malononitrile under similar
conditions did not lead to 2-cyanothioacetamide (Scheme 3).
NMR analysis of the reaction mixture and comparison with authentic samples were
performed. The result is shown in Fig. S1 and S2 (Supplemental materials). A CH2 singlet peak
due to malononitrile appears at 3.60 ppm in the 1H NMR spectrum. Two further peaks appear at
8.7 and 109.2 ppm for malononitrile carbons while the CH2 singlet of the 2-cyanothioacetamide
appears at 3.98 ppm. Three peaks at 33.9, 116.5 and 194.5 ppm are due to its carbons.29 1H NMR
and 13C NMR analysis of the reaction mixture after 5 and 20 minutes shows distinguished peaks
of malononitrile and implicate that 2-cyanothiacetamide under this condition cannot be formed.
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The GC-mass spectrum of the reaction mixture after 2 minutes demonstrated the presence
of malononitrile, benzylamine, triethylamine and benzyl isothiocyanate (maybe formed in the
mass spectrometer from benzylcarbamodithioic acid). It is obvious that no peak appeared for 2-
cyanothioacetamide (m/z = 100.0). GC-mass spectra of the reaction mixture after 15 minutes
indicate no remarkable changes in the products distribution (see Fig. S3, Supplemental
materials).
There are many references related to the reaction of malononitrile and the isothiocyanate
group in organic syntheses.30-32 If the production of benzyl isothiocyanate takes place in the
reaction mixture, it can be reacted with malononitrile as well as the released H2S can convert the
malononitrile to 2-cyanothioacetamide. As mentioned above, the NMR analysis shows that the
malononitrile maintenance in the reaction mixture after 20 minutes and 2-cyanothioacetamide
was not made. Thus, benzyl isothiocyanate appeared in the mass spectrum which can be
attributed to the elimination of hydrogen sulfide (H2S) from benzylcarbamodithioic acid under
mass spectroscopy conditions.
For further corroboration of the mechanism, we performed the reaction of benzylamine
with carbon disulfide under similar conditions. The GC-MS of the reaction mixture after 5 hours
shows the same product formation (Scheme 3 products) in the absence of malononitrile (Figure
S4).
Formation of the intermediate B and its kinetic study was reported in the literature.33
Moreover, we synthesized the benzylidenemalononitrile (intermediate A) and
benzylcarbamodithioic acid (intermediate C) and performed the reaction shown in Scheme 4.
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This reaction resulted in the formation of 2,6-diamino-4-phenyl-4H-thiopyran-3,5-dicarbonitrile
6 and confirmed the presence of the proposed intermediates during the reaction process.
Experimental
General Information
Synthesis grade reagents were commercially available and were used without further
purification. All solvents were dried by standard procedures before use. Melting points were
measured on an Electrothermal 9100 apparatus in open capillaries without correction. IR spectra
were recorded on a Unicom Galaxy Series FT-IR 5000 spectrophotometer using KBr pellets and
1
are expressed in cm1. H and 13C NMR spectra were recorded in the indicated deuterated
solvents with a Bruker Avance 400 MHz spectrometer at 400 MHz (1H) and 100 MHz (13C),
respectively. Mass spectra were recorded with an Agilent-5975 C inert XL MSD mass
spectrometer operating at an ionization potential of 70 eV. Elemental analyses were performed
by Vario EL equipment at Arak University. The progress of the reaction was monitored by TLC
(EtOAc-hexane). The Supplemental Materials contains sample NMR and GC-MS spectra of the
products and characterization data (Figures S 1 – S 4).
General procedure
To a magnetically stirred mixture of aldehyde (1 mmol), malononitrile (2 mmol) and a catalytic
amount of triethylamine in 5 mL dichloromethane, primary amines (1 mmol) and carbon
disulfide (1.2 mmol) were added. The reaction mixture was stirred at room temperature and the
progress of the reaction was monitored by TLC. After the reaction was complete, solid products
were filtered off, washed with EtOH, and dried. The reaction of benzaldehyde, malononitrile,
benzylamine and carbon disulfide was selected for the mechanism determination.
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Benzyl isothiocyanate (5)
IR: 3065, 3030, 2174, 2091, 1465, 1436, 1344, 1332, 1026, 734, 697, 677. EI-MS (m/z): 149
(M+, 23), 91 (100), 65 (18).
2,6-Diamino-4-phenyl-4H-thiopyran-3,5-dicarbonitrile (6)
1
Orange powder; m.p. 186-188 °C; H NMR (DMSO-d6): δ 4.26 (s, 1H, CH), 6.95 (br s, 4H, 2
13
NH2), 7.28-7.23 (m, 3H, Ar-H), 7.38-7.34 (m, 2H, Ar-H); C NMR (DMSO-d6): δ 43.3, 71.9,
118.8, 128.7, 127.1, 126.6, 143.5, 151.2; Anal. Calcd. for C13H10N4S (254.31): C, 61.40; H, 3.96;
N, 22.03; S, 12.61%, found: C, 61.38; H, 3.99; N, 21.97; S, 12.70 %. IR: 3433, 3396, 3317,
3198, 3024, 2183, 1633, 1599, 1448, 1367, 1263, 1151, 887, 713, 599.
Conclusions
We describe a successful strategy for the synthesis of 4H-thiopyran using aldehydes,
malononitrile, carbon disulfide and primary amine in the presence of triethylamine as a catalyst
at ambient temperature. Use of carbon disulfide is a novel and efficient method in this area.
Furthermore, a method for the consolidation of the proposed reaction mechanism is described.
Separation and identification of the reaction products and intermediates, designing of the starting
materials, various aspects of the mechanism testing, the reaction repeating and the determining
of products or intermediates, NMR and GC-mass analysis of reaction mixtures were used to
evaluate and confirm the reaction pathway.
Acknowledgments
We gratefully acknowledge the financial support of this work by the research council of Arak
University.
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Scheme 1. Pseudo-five-component synthesis of 4H-thiopyran derivatives
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Scheme 2. Proposed reaction mechanism for the thiopyran ring formation.
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Scheme 3. Control test for probability of 2-cyanothioacetamide production.
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Scheme 4. 2,6-diamino-4-phenyl-4H-thiopyran-3,5-dicarbonitrile synthesis via prepared
intermediates.
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