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Proceeding Paper

One-Pot Synthesis of New 4,5,6,7-tetrahydro-3H-[1,2]dithiolo[3,4-b]pyridines Starting from N,N’-Diphenyldithiomalondiamide †

by
Ekaterina A. Varzieva
1,*,
Anna E. Sinotsko
1,
Victor V. Dotsenko
1,2 and
Nicolai A. Aksenov
2
1
Department of Organic Chemistry and Technologies, Kuban State University, 149 Stavropolskaya St., 350040 Krasnodar, Russia
2
Department of Organic Chemistry, North Caucasus Federal University, 1a Pushkin St., 355017 Stavropol, Russia
*
Author to whom correspondence should be addressed.
Presented at the 27th International Electronic Conference on Synthetic Organic Chemistry (ECSOC-27), 15–30 November 2023; Available online: https://ecsoc-27.sciforum.net/.
Chem. Proc. 2023, 14(1), 21; https://doi.org/10.3390/ecsoc-27-16134
Published: 15 November 2023

Abstract

:
Active methylene compounds such as thioamides are widely used in the organic chemistry for the construction of a variety of heterocyclic systems, such as thieno[2,3-b]pyridines, 1,2,4-dithiazoles, isothiazoles, 1,2,3-thiadiazoles, etc. N,N′-Diphenyldithiomalondiamide (dithiomalondianilide) as a compound with methylene active group is also of interest as a starting reagent for the synthesis of new N,S-containing heterocycles with potential pharmacological application. However, the reactions of dithiomalondianilide are poorly studied. In the present study, we report the synthesis of new 4,5,6,7-tetrahydro[1,2]dithiolo[3,4-b]dithiolopyridine-5-carboxamides through the reaction of dithiomalondianilide with 3-aryl-2-cyanoacrylamides. The products were characterized using FTIR and NMR spectroscopy as well as X-ray analysis.

1. Introduction

Active methylene compounds such as thioamides are widely used in organic chemistry for the construction of a variety of heterocyclic systems such as thieno[2,3-b]pyridines [1,2,3,4], 1,2,4-dithiazoles [5], isothiazoles [6], 1,2,3-thiadiazoles [7], etc. N,N’-Diphenyldithiomalondiamide (dithiomalondianilide) as a compound with a methylene active group is also of interest as a starting reagent for the synthesis of new N,S-containing heterocycles with potential pharmacological applications. However, the reactions of dithiomalondianilide are poorly studied. Thus, up to date, only a few reactions with dithiomalondianilide have been reported to give heterocyclic compounds. Recently, we reported a new reaction of dithiomalondianilide 1 with 3-aryl-2-cyanoacrylates 2 that resulted in the formation of new dithiolodihydropyridines [8] (Scheme 1):
We suggested that the reaction is applicable to a wide range of Michael acceptors. Our assumption is that the interaction of thioamide 1 with substituted cyanoacrylamides 3 representing substituted acriylonitrile has to lead to the formation of related dithiolodihydropyridine-5-carboxamides 4, according the Scheme 2:
In general, carboxamides found an application as steel corrosion inhibitors [9], fungicides with a wide antifungal spectrum [10], and antimicrobials, antibacterial and antimalarial drugs [11]. Therefore, the development of new synthetic approaches towards substituted dithiolopyridine-5-carboxamides seems to be an important task.

2. Result and Discussion

We found that dithiomalondianilide 1 reacts with 3-aryl-2-cyanoacrylamides 3 under mild conditions to create dithiolotetrahydropyridine-5-carboxamides 5 in good yields. Presumably, the reaction proceeds as the morpholine-catalyzed Michael addition is followed by oxidative heterocyclization to give 6-imino-4,5,6,7-tetrahydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamides 5 (Scheme 3).
We previously discovered the crucial role of an oxidant in the successful formation of dithiolopyridine core [8], so the synthesis was carried out under air oxygen. Against our expectations, there was no absorption band of amino group in the IR spectra of prepared compounds. Thus, the spectral data indicated the formation of 6-imino-4,5,6,7-tetrahydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamides 5 (Figure 1), but not 6-amino-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamides 4.
The compounds 5b–g were also prepared by one-pot method involving the formation of cyanoacrylamide 3 in situ from aromatic aldehydes and N-substituted cyanoacetamide, followed by treatment with dithiomalondianilide 1 without isolation of any intermediates (Scheme 4):

3. Experimental

3.1. Procedure for the Preparation of 4,5,6,7-tetrahydro-3H-[1,2]dithiolo[3,4-b]pyridine 5a

Cyanoacrylamide 3a (0.9 mmol) and 0.9 mmol of thioamide 1 were suspended in EtOH, and an excess of morpholine (1.5 mmol) was added. The reaction mixture was then refluxed until thioamide 1 was completely consumed. The reaction was monitored by TLC. Yellow crystalline precipitate was filtered off, washed with ethanol to give [1,2]dithiolo[3,4-b]pyridine 5a.

3.2. Procedure for One-Pot Preparation of 4,5,6,7-tetrahydro-3H-[1,2]dithiolo[3,4-b]pyridines 5b–g

An aromatic aldehyde (1.5 mmol) and corresponding N-substituted cyanoacetamide (1.5 mmol) were dissolved in ethanol (10 mL), and an excess of morpholine (10 mmol) was added. The reaction mixture was heated until cyanoacetamide was consumed completely. Then, an equimolar amount of thioamide 1 was added, and the heating was continued until cyanoacrylamide intermediate was exhausted. The crystalline precipitate was filtered off, washed with ethanol and recrystallized from ethylacetate.

4. Conclusions

Here we report the first example of the synthesis of dithiolotetrahydropyridine-5-carboxamides through the reaction of dithiomalondianilide with N-substituted 3-aryl-2-cyanoacrylamides. A series of new dithiolotetrapyridines was prepared in modest yields (17–47%).

Author Contributions

E.A.V.—investigation, writing (original draft); A.E.S.—investigation; V.V.D.—conceptualization, supervision, investigation, data analysis, funding acquisition, writing (review and editing); N.A.A.—data analysis. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Russian Science Foundation, grant number 22-23-00458, https://rscf.ru/en/project/22-23-00458 (accessed on 9 October 2023).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflict of interest.

References

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Scheme 1. The reaction of N,N’-diphenyldithiomalondiamide with 3-aryl-2-cyanoacrylates.
Scheme 1. The reaction of N,N’-diphenyldithiomalondiamide with 3-aryl-2-cyanoacrylates.
Chemproc 14 00021 sch001
Scheme 2. Expected result of the reaction between dithiomalondianilide with N-substituted 2-cyanoacrylamides.
Scheme 2. Expected result of the reaction between dithiomalondianilide with N-substituted 2-cyanoacrylamides.
Chemproc 14 00021 sch002
Scheme 3. Preparation of 6-imino-4,5,6,7-tetrahydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamides 5.
Scheme 3. Preparation of 6-imino-4,5,6,7-tetrahydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamides 5.
Chemproc 14 00021 sch003
Figure 1. Structures and yields of the prepared 6-imino-4,5,6,7-tetrahydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamides 5.
Figure 1. Structures and yields of the prepared 6-imino-4,5,6,7-tetrahydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamides 5.
Chemproc 14 00021 g001
Scheme 4. One-pot synthesis of 6-imino-4,5,6,7-tetrahydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamides 5bg.
Scheme 4. One-pot synthesis of 6-imino-4,5,6,7-tetrahydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamides 5bg.
Chemproc 14 00021 sch004
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MDPI and ACS Style

Varzieva, E.A.; Sinotsko, A.E.; Dotsenko, V.V.; Aksenov, N.A. One-Pot Synthesis of New 4,5,6,7-tetrahydro-3H-[1,2]dithiolo[3,4-b]pyridines Starting from N,N’-Diphenyldithiomalondiamide. Chem. Proc. 2023, 14, 21. https://doi.org/10.3390/ecsoc-27-16134

AMA Style

Varzieva EA, Sinotsko AE, Dotsenko VV, Aksenov NA. One-Pot Synthesis of New 4,5,6,7-tetrahydro-3H-[1,2]dithiolo[3,4-b]pyridines Starting from N,N’-Diphenyldithiomalondiamide. Chemistry Proceedings. 2023; 14(1):21. https://doi.org/10.3390/ecsoc-27-16134

Chicago/Turabian Style

Varzieva, Ekaterina A., Anna E. Sinotsko, Victor V. Dotsenko, and Nicolai A. Aksenov. 2023. "One-Pot Synthesis of New 4,5,6,7-tetrahydro-3H-[1,2]dithiolo[3,4-b]pyridines Starting from N,N’-Diphenyldithiomalondiamide" Chemistry Proceedings 14, no. 1: 21. https://doi.org/10.3390/ecsoc-27-16134

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