Next Article in Journal
Influence of Er- and Al-Doped ZnO on Mixed-Matrix Membranes of Chitosan Derivatives in Bioelectrochemical Systems
Previous Article in Journal
Electronic Structures and Photodetachment of TeO2−, TeO3−, and HTeO4− Anions: A Cryogenic Photoelectron Spectroscopic Study
Previous Article in Special Issue
Synthesis of Monothiacalix[4]arene Using the Fragment Condensation Approach
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 30
Issue 18
10.3390/molecules30183758
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

2-(Methoxycarbonyl)thiophen-3-yl-diazonium Salts: Efficient Precursors for the Formation of C–C Bonds in Thiophene-Containing Heterocyclic Systems

by
Yurii V. Ostapiuk
1,*,
Oksana V. Barabash
1,
Mary Y. Ostapiuk
1,
Mykola Kravets
2,
Andreas Schmidt
3,* and
Mykola D. Obushak
1
1
Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya Str. 6, 79005 Lviv, Ukraine
2
Institute of Physical Chemistry of the Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
3
Institute of Organic Chemistry, Clausthal University of Technology, Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany
*
Authors to whom correspondence should be addressed.
Molecules 2025, 30(18), 3758; https://doi.org/10.3390/molecules30183758
Submission received: 2 September 2025 / Revised: 14 September 2025 / Accepted: 15 September 2025 / Published: 16 September 2025
(This article belongs to the Special Issue Organosulfur and Organoselenium Chemistry II)
Browse Figures
Versions Notes

Abstract

A first application of 2-(methoxycarbonyl)thiophen-3-diazonium salts in the halothienylation of α,β-unsaturated functionalized compounds under Meerwein reaction conditions is presented. This process provides thiophene-containing building blocks that can then undergo cyclization reactions with bisnucleophiles to synthesize thiophene-3-yl-containing heterocyclic systems. In this way, substituted 2,3′-bithiophene compounds and thiophene-3-yl derivatives of 2-aminothiazole, 2-aminoselenazole, thiazolidine, and selenazolidine can be efficiently prepared.

Graphical Abstract

1. Introduction

Substituted thiophene compounds are an important class of heterocyclic compounds due to their versatile applications. The thiophene core is an important scaffold for a variety of therapeutics and drugs covering the spectrum from antitumor, antibacterial, anti-inflammatory, antifungal, antihelminthic, antihypertensive, antiviral, antipsychotic agents to local anesthetics and SIRT2 inhibitors for the treatment of myocardial fibrosis [1,2,3,4,5,6]. Concerning materials chemistry, thiophene derivatives are also used as chemosensors [7], photovoltaic materials [8], dyes, and fluorophores [9,10,11]. It is striking that the derivatives substituted at positions 2 and 5 of the thiophene ring are the best studied which is due to the ease with which thiophene compounds can be modified at these positions. The introduction of substituents and the formation of C–C bonds at positions 3 and 4 can be difficult, especially if positions 2 and 5 of the thiophene ring are to remain unsubstituted. Nevertheless, the further development of the chemistry of 3-substituted thiophene compounds opens up new and interesting perspectives, and they are playing an increasingly important role in pharmaceutical research [5,6,12,13,14].
Thiophenes with a C–C bond in the 3-position have mostly been synthesized by modifying the existing thiophene core, often starting from 3-thienylboronic acids I for Suzuki-Miyaura cross-couplings [15,16,17,18] or 3-halothiophene compounds II for Sonogashira reactions or Suzuki couplings with boronic acids as coupling partners (Figure 1) [12,19]. In addition, 3-halothiophenes serve as starting materials for the preparation of organolithium compounds and organostannanes as intermediates for the introduction of substituents into the 3-position of the thiophene ring III [20,21,22]. 3-Halothiophene can be obtained by direct halogenation of thiophenes with an electron-withdrawing group in the 5-position or with substituted 2- and 5-positions [19,23,24]. However, the use of 3-aminothiophenes in the Sandmeyer reaction is often much more practical [13,14]. In some cases, the use of suitable acyclic precursors allows the construction of derivatives with a carbon substituent in the 3-position of a thiophene ring. Examples of this are the reaction of 3-oxobutanethioamides IV with α-halogen ketones [25,26], the cyclocondensation of 1,3-dicarbonyl compounds or their synthetic equivalents V with mercaptanes [27,28], and Baylis–Hillman adducts VI with mercaptanes [29]. Despite the synthetic convenience of these approaches, however, they generally only allow the introduction of a limited number of non-functionalized substituents. Only a few examples of intramolecular cyclization of 2-substituted thiophenes VII [30,31,32], ring opening/annulation of cyclopropane derivatives VIII [33,34], and Rh-catalyzed C-H alkylation of the thiophene core IX are known [35].
The literature provides evidence that thiophene-3-yldiazonium salts obtained from the corresponding 3-aminothiophenes X can be valuable intermediates in thiophene chemistry. For example, Sandmeyer reactions [13,14,36,37,38], substitution of the diazo group by a carbonyl fragment [39], azo couplings [40], arylations of heterarenes [41,42,43], Heck-Matsuda couplings [44,45,46,47], photoinduced Ir (ppy)3-catalyzed alkyl sulfonations [48], arylation of arenes [49,50], gold-catalyzed cross-coupling with silanes, alkynes or boronic acids [51,52,53], and the synthesis of aryltriazenes have been investigated [54].
However, these numerous methods have serious disadvantages. First, they are limited to suitable and readily available precursors or expensive catalysts (Pd, Ir, or Rh complexes). Second, these methods are not suitable for introducing polyfunctional substituents into position 3 of the thiophene core, which are useful for the further construction of other heterocycles.
As part of a current project, we investigated whether the Meerwein reaction can overcome these difficulties. In principle, it enables the production of arenic building blocks that are suitable as starting materials for the construction of various heterocycles [55,56], as we have shown in previous work [57,58,59,60,61] with the aim of synthesizing antitumor active substances [62,63]. In the present work, the title compounds, which were prepared from methyl-3-aminothiophene-2-carboxylate as a precursor, enable the production of thiophene-3-yl-containing bifunctional compounds that are suitable for use in heterocyclization reactions. We show that the application potential of this starting material extends beyond C–H arylation, arylations, and oxyarylations of certain alkenes [64,65,66,67,68,69] and can be applied to the addition reaction of a thiophene-3-yl fragment and a halogen atom to the C=C bond of functionalized alkenes in a Meerwein-type reaction. Here, we report the preparation of thiophen-3-yl derivatives of thiazole, selenazole, and thiophene, which can be obtained in two steps from functionalized α,β-unsaturated compounds and 2-(methoxycarbonyl)thiophen-3-yldiazonium salts. We present first examples of Meerwein reactions with thiophen-3-yldiazonium salts here.

2. Results and Discussion

The reaction of 2-(methoxycarbonyl)thiophene-3-diazonium bromide with methyl vinyl ketone was selected as a model transformation and was carried out in the presence of CuBr2 as a catalyst. This diazonium salt was easily produced from 3-amino-2-(methoxycarbonyl)thiophene 1 by treating it with aqueous HBr, followed by diazotization with NaNO2 at −5 °C (Scheme 1). After 5 min at −5 to 0 °C, the solution of resulting 2-(methoxycarbonyl)thiophen-3-yl-diazonium bromide 2a was used directly in a reaction with methyl vinyl ketone 3a in acetone in the presence of CuBr2 (0.45 mol%). The mixture was stirred until the evolution of N2 ceased. The resulting ketone 4a was extracted from the reaction mixture with CH2Cl2 and purified by distillation under reduced pressure (0.2 Torr). The targeted methyl 3-(2-bromo-3-oxobutyl)thiophene-2-carboxylate 4a was obtained in a 78% yield.
The bromothienylations of other functionalized ethenes 3b–e (methyl acrylate, acrylonitrile, 2-chloroacrylonitryl, methyl 3-chloroacrylate) with the diazonium bromide 2a were carried out under analogous conditions. The resulting compounds 5a–8a were purified by distillation under reduced pressure (0.2–0.5 torr). Distillations under slightly higher pressures (~2–5 torr) resulted in partial decomposition of the product and the formation of a resinous residue. However, the interaction of diazonium bromide 2a with styrene 3f leads to the formation of methyl 3-styrylthiophene-2-carboxylate 9, and no product of the addition of a thiophene fragment and a bromine atom to the C=C bond was detected. 3-Styrylthiophene-2-carboxylate 9 has been previously synthesized by other methods, and the NMR data are in accordance with that reported in the literature [70,71].
An attempt to bromothienylate acrolein 3g was unsuccessful and resulted in the formation of resinous substances of unknown structure. In contrast, the chlorothienylation of acrolein proceeds efficiently and leads to the formation of chloraldehyde 11 in a yield of 78%. We also performed chlorothienylation of methyl vinyl ketone, methyl acrylate, methyl methacrylate, and methyl 3-chloroacrylate. This reaction of diazonium chloride 2b with the corresponding α,β-unsaturated functionalized compound 3 was carried out in acetone in the presence of CuCl2 × 2 H2O (29 mol%). The required 2-(methoxycarbonyl)thiophene-3-diazonium chloride 2b was synthesized in situ from 3-amino-2-(methoxycarbonyl)thiophene, hydrochloric acid, and sodium nitrite in the temperature range of −5 to 0 °C. The compounds 4b–12 obtained were purified by distillation under reduced pressure (0.2–0.5 Torr). The structure of the synthesized compounds and their yields are shown in Scheme 1.
The presence of an ortho-methoxycarbonyl group in diazonium bromide 2a opens up the possibility of forming dihydrothieno [2,3-c]pyranones 10 in the bromothiophene reaction of α,β-unsaturated functionalized compounds, although this was not achieved in all cases [66,67,68,69,72,73]. Since thieno [2,3-c]pyranones were not formed in the halothiophene reaction, we attempted to obtain them by treating the products 5a, 6a, and 8a with a KOH solution while varying the reaction conditions [72,73]. Despite varying the solvents (methanol, alcohol, alcohol-water mixtures, aqueous dioxane, THF) and the reaction temperature (from 0 °C to reflux), only HBr cleavage was observed from compounds 5a and 8a, yielding derivatives of 3-(thiophen-3-yl)acrylic acids 13 and 15 (Scheme 2). Although the literature states that compound 13 is synthesized [74], the Supporting Information describes the diester (methyl (E)-3-(3-methoxy-3-oxoprop-1-en-1-yl)thiophene-2-carboxylate).
In the case of nitrile 6a, treatment with KOH solution led to the formation of acid 14a (this compound has been previously described [75]), while carrying out the reaction at 0 °C led to the isolation of ester 14b (this compound has been previously described [76]). This indicates the extreme ease of HBr cleavage with the formation of a conjugated system. According to the 1H NMR data of 13–14b, the elimination of hydrogen bromide mainly leads to the formation of the E isomer.
In all cases, the reaction with the base is exothermic and proceeds rapidly with the elimination of hydrogen bromide, probably due to the formation of a thermodynamically favorable conjugated system in thienylacrylic acid derivatives.
Chlorinated ester 5b reacted with a KOH solution under reflux to form a C=C bond in compound 13 with elimination of HCl. On the other hand, the reaction of ester 5b with KOH at 0 °C led to 7-oxo-4,7-dihydro-5H-thieno [2,3-c]pyran-5-carboxylic acid 16 (Scheme 3). As the reaction is exothermic, the reaction mixture must be cooled intensively and stirred vigorously to prevent the elimination of hydrogen chloride and the formation of thienylacrylic acid. Under the same conditions, ester 8b was converted to 3-(2,2-dichloro-3-methoxy-3-oxopropyl)thiophene-2-carboxylic acid 17, and 7b was converted to 3-(2-carboxy-2-hydroxypropyl)thiophene-2-carboxylic acid 18. It should be noted that compound 18 is highly soluble in water. The interaction of compounds 4b and 11b with KOH solution led to the formation of resinous substances of unknown structure.
It appears that the type of halogen atom in halothienylation products is decisive for the course of either the elimination or substitution reaction. Substitution products 16 and 18 have been obtained from chlorothienylation products only.
We then investigated the synthetic potential of the products of halothienylation for the construction of more complex heterocyclic systems. Although halocarbonyl compounds 4 and 11 proved to be labile to strong bases, they are undoubtedly suitable as bifunctional precursors for constructing a thiazole cycle. Thus, bromoketone 4a and chloroaldehyde 11 reacted smoothly with thiourea in an alcoholic medium to form aminothiazoles 19a and 19b, respectively (Scheme 4). Conversely, chloroketone 4b did not interact with thiourea, even when the reaction mixture was refluxed for an extended period. However, in the presence of KI (10 mol%) the target aminothiazole is nevertheless formed, but with a low yield (42%). The reaction of bromoketone 4a with selenourea proceeded smoothly with the formation of aminoselenazole 20a. However, chloroaldehyde 11 only interacted with selenourea when catalytic amounts of KI (10 mol%) were added.
We also obtained in a similar way thiazolidines and selenazolidines, by the reaction of α-bromoester 5a and α-bromonitrile 6a with thiourea or selenourea, respectively. Thus, we obtained compounds 21–24 as hydrobromides, which crystallized from the reaction mixture when cooled (Scheme 5).
It should be noted that the structure of many practically useful compounds contains a combination of thiophene and other heterocyclic rings. For example, substances whose molecules contain thiophene and thiazole rings are being studied as photoswitches [77], photovoltaic materials [78], angiotensin AT2 receptor ligands [79], and exhibit anticancer activity [80,81]. Compounds containing 3-thienyl and thiazolone fragments are antitumor [82] and anti-neuroinflammatory agents [83].
Since propionitrile 7a and propanoate 8a are synthetic equivalents of the 3C synthon, which are suitable for building a thiophene ring and thus for the synthesis of bithiophenes, we carried out further reactions. This was also driven by the fact that substituted 2,3′-bithiophene compounds have been developed as antibacterial [84] and antitumor compounds [85], pan-ERR agonists [86], and protein tyrosine phosphatase 1B inhibitors [87]. These are mainly derivatives of 4-amino- and 4-hydroxy-2,3′-bithiophene compounds [85,87]. 2,3′-Bithiophene derivatives are usually obtained using halothiophene and thienylboronic acids in the Suzuki reaction [84,86,87]. Acrylonitrile derivatives obtained from acetylthiophene are only used occasionally [85]. This severely limits the range of available functionalized 2,3′-bithiophenes. Therefore, the search for new substrates for the construction of such compounds remains an important task.
For the compounds 7a and 8a, the reaction with methylthioglycolate 25a, mercaptoacetanilide 25b or mercaptoacetone 25c in methanol in the presence of sodium methylate as a base provided access to substituted 4-amino-2,3′-bithiophenes 26 and 4-hydroxy-2,3′-bithiophenes 27 (Scheme 6). In all cases, the reaction proceeded smoothly within two hours and yielded the corresponding 2,3′-bithiophenes. However, when nitrile 7 interacted with mercaptoacetanilide 25b, only acid 26b was obtained as a result of the hydrolysis of the target ester during separation from the reaction mixture. Amine 26c did not crystallize when separated from the reaction mixture, so we obtained it as a hydrochloride. Therefore, the 2,3′-bithiophenes 26–27 were prepared as stable compounds in moderate to good yields, differing in their substituents at the C-5 position and bearing a methoxycarbonyl group at the C-2′ position of the 2,3′-bithiophene core.
In summary, we describe the first general method for using 2-(methoxycarbonyl)thiophene-3-diazonium salts in the Meerwein reaction for the synthesis of bifunctional compounds that are suitable building blocks for the development of thiophene-containing compounds. A wide range of starting materials, including unsaturated compounds and binucleophiles, allowed us to achieve structural diversity in the 3-position of the thiophene ring that had previously been difficult to achieve by other routes. Thus, our method provides a smooth and straightforward route to 5-(thiophen-3-yl)methylene-substituted 2-aminothiazoles, 2-aminoselenazoles, thiazolidines and selenazolidines, as well as derivatives of thiophene-3-ylacrylic acids, thieno [2,3-c]pyrane, 4-amino- and 4-hydroxy-2,3′-bithiophenes.

3. Materials and Methods

Commercially available reagents and solvents were obtained from TCI (TCI, Haven 1063, 2070 Zwijndrecht, Belgium), J&K (J&K, Marbach, Germany), and Aldrich (Merck KGaA, Darmstadt, Germany) and used without further purification unless otherwise specified.
Reported yields are isolated and have not been optimized. Melting points were determined using a Büchi apparatus (Büchi, Uster, Switzerland) and are reported uncorrected.
Thin-layer chromatography (TLC) was carried out on Merck (Merck KGaA, Darmstadt, Germany) silica gel 60 F254 aluminum plates, with visualization under UV light.
1H and 13C NMR spectra were obtained on a Bruker 170 Avance 500 spectrometer (at 500 MHz for 1H, 126 MHz for 13C), and a Bruker Avance 400 MHz spectrometer (at 400 MHz for 1H, 101 MHz for 13C) (Bruker, Bremen, Germany). Chemical shifts (δ) are reported in parts per million (ppm) relative to internal standard or solvent signal. Signal multiplicities are denoted as follows: s = singlet, br.s = broad singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, m = multiplet. Signal orientations in DEPT experiments are indicated as: o = no signal; + = positive (CH, CH3); − = negative (CH2).
Electrospray ionization mass spectra (ESI-MS) were recorded on a Bruker Impact II mass spectrometer using MeCN as the solvent.
ATR-IR spectra were recorded on a Shimadzu IRSpirit-T spectrometer (Shimadzu, Kyoto, Japan) over the range of 400–4000 cm−1.
General Procedure for the Preparation of the Methyl 3-(2-bromo- 3-oxobutyl)thiophene-2-carboxylate 4a, Methyl 3-(2-bromo-3-methoxy-3-oxopropyl)-thiophene-2-carboxylate 5a, Methyl 3-(2-bromo-2-cyanoethyl)thiophene-2-carboxylate 6a, Methyl 3-(2-bromo-2-chloro-2-cyanoethyl)thiophene-2-carboxylate 7a, Methyl 3-(2-bromo-2-chloro-3-methoxy-3-oxopropyl)thiophene-2-carboxylate 8a, and Methyl (E)-3-styrylthiophene-2-carboxylate 9.
The methyl 3-aminothiophene-2-carboxylate 1 (3.14 g, 20 mmol, 1.0 equiv.) was added to 46% aqueous hydrobromic acid (5.1 mL, 42 mmol, 1.1 equiv.). The resulting mixture was cooled to −5 °C, followed by the dropwise addition of a saturated solution of sodium nitrite (1.45 g, 21 mmol, 1.05 equiv.), ensuring that the temperature remained below 5 °C throughout the addition. The freshly obtained cold diazonium salt solution 2a was then added dropwise to a solution containing the corresponding functionalized alkene 3 (20 mmol, 1.0 equiv.) and CuBr2 (20 mg, 0.09 mmol) in acetone (20 mL) under vigorous stirring throughout. The reaction mixture was stirred at room temperature (20 °C) until the evolution of nitrogen gas ceased to evolve. Subsequently, 100 mL of water was added, and the organic layer was separated. The aqueous phase was extracted with CH2Cl2 (5 × 10 mL), and the combined organic extracts were dried over anhydrous MgSO4. The solvent was then removed under reduced pressure, and the product was purified by distillation under vacuum.
Methyl 3-(2-bromo-3-oxobutyl)thiophene-2-carboxylate 4a.
Yield 4.543 g (78%), colorless oil or white solid, bp 138–141 °C/0.25 torr, mp 52–53 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 7.83 (d, J = 5.1 Hz, 1H, H-thiophene), 7.17 (d, J = 5.1 Hz, 1H, H-thiophene), 4.96 (dd, J = 8.6, 6.1 Hz, 1H, CH), 3.81 (s, 3H, CH3), 3.64 (dd, J = 14.7, 6.1 Hz, 1H, CH2), 3.57 (dd, J = 14.7, 8.6 Hz, 1H, CH2), 2.32 (s, 3H, CH3).
13C NMR (101 MHz, [D6]DMSO): δ = 201.3, 162.1, 145.3, 131.7, 131.3, 127.2, 53.0, 52.0, 32.2, 26.7.
MS (ESI): m/z = 291.0 [M + H]+.
IR (ATR) νmax = 1718 (C=O), 1701 (C=O) cm−1.
Anal. Calcd for C10H11BrO3S: C, 41.25; H, 3.81. Found: C, 41.14; H, 3.73.
Methyl 3-(2-bromo-3-methoxy-3-oxopropyl)thiophene-2-carboxylate 5a.
Yield 4.670 g (76%), light-yellow oil, bp 143–146 °C/0.5 torr.
1H NMR (400 MHz, [D6]DMSO): δ = 7.83 (d, J = 5.1 Hz, 1H, H-thiophene), 7.16 (d, J = 5.1 Hz, 1H, H-thiophene), 4.81 (t, J = 7.6 Hz, 1H, CH), 3.81 (s, 3H, CH3), 3.84–3.78 (m, 1H, CH2), 3.69 (s, 3H, CH3), 3.67 (d, J = 7.6 Hz, 1H, CH2).
1H NMR (500 MHz, CDCl3): δ = 7.42 (d, J = 5.0 Hz, 1H, H-thiophene), 7.00 (d, J = 5.0 Hz, 1H, H-thiophene), 4.62 (t, J = 7.6 Hz, 1H, CH), 3.87 (s, 3H, CH3), 3.79–3.74 (m, 1H, CH2), 3.73 (s, 3H, CH3), 3.63 (dd, J = 13.8, 7.6 Hz, 1H, CH2).
13C NMR (101 MHz, [D6]DMSO): δ = 169.4, 162.0, 144.6, 131.8, 131.2, 127.5, 52.9, 52.1, 44.5, 33.8.
13C NMR (126 MHz, CDCl3): δ = 170.1, 162.7, 144.8, 131.8, 130.6, 128.5, 53.0, 52.2, 43.8, 34.9.
MS (ESI): m/z = 307.0 [M + H]+.
IR (ATR) νmax = 1737 (C=O), 1702 (C=O) cm−1.
Anal. Calcd for C10H11BrO4S: C, 39.10; H, 3.61. Found: C, 39.01; H, 3.55.
Methyl 3-(2-bromo-2-cyanoethyl)thiophene-2-carboxylate 6a.
Yield 4.659 g (85%), light-yellow crystalline solid, bp 149–151 °C/0.5 torr, mp 51–52 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 7.90 (d, J = 5.1 Hz, 1H, H-thiophene), 7.27 (d, J = 5.1 Hz, 1H, H-thiophene), 5.31 (dd, J = 8.1, 7.1 Hz, 1H, CH), 3.84 (dd, J = 13.9, 8.1 Hz, 1H, CH2), 3.82 (s, 3H, CH3), 3.77 (dd, J = 13.9, 7.1 Hz, 1H, CH2).
13C NMR (101 MHz, [D6]DMSO): δ = 162.0, 142.7, 132.2, 131.2, 128.5, 117.9, 52.2, 34.7, 26.9.
MS (ESI): m/z = 274.0 [M + H]+.
IR (ATR) νmax = 2243 (CN), 1687 (C=O) cm−1.
Anal. Calcd for C9H8BrNO2S: C, 39.43; H, 2.94. Found: C, 39.35; H, 2.85.
Methyl 3-(2-bromo-2-chloro-2-cyanoethyl)thiophene-2-carboxylate 7a.
Yield 4.451 g (72%), white crystalline solid, bp 128–130 °C/0.2 torr, mp 74–75 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 7.96 (d, J = 5.1 Hz, 1H, H-thiophene), 7.35 (d, J = 5.1 Hz, 1H, H-thiophene), 4.53 (d, J = 14.3 Hz, 1H, CH2), 4.46 (d, J = 14.3 Hz, 1H, CH2), 3.83 (s, 3H, CH3).
1H NMR (400 MHz, MeOD): δ = 7.74 (d, J = 5.2 Hz, 1H, H-thiophene), 7.35 (d, J = 5.1 Hz, 1H, H-thiophene), 4.53 (d, J = 14.3 Hz, 1H, CH2), 4.45 (d, J = 14.3 Hz, 1H, CH2), 3.88 (s, 3H, CH3).
13C NMR (101 MHz, [D6]DMSO): δ = 162.0, 139.4, 132.1, 131.6, 130.3, 116.2, 52.3, 49.3, 44.5.
13C NMR (101 MHz, MeOD): δ = 163.9 (o), 140.6 (o), 132.6 (+), 132.3 (o), 132.2 (+), 117.2 (o), 52.7 (+), 50.9 (o), 46.7 (+).
MS (ESI): m/z = 307.9 [M + H]+.
IR (ATR) νmax = 2229 (CN), 1702 (C=O) cm−1.
Anal. Calcd for C9H7BrClNO2S: C, 35.03; H, 2.29; N, 4.54. Found: C, 34.92; H, 2.23; N, 4.50.
Methyl 3-(2-bromo-2-chloro-3-methoxy-3-oxopropyl)thiophene-2-carboxylate 8a.
Yield 5.260 g (77%), light-yellow oil, bp 150–153 °C/0.2 torr.
1H NMR (400 MHz, [D6]DMSO): δ = 7.87 (d, J = 5.1 Hz, 1H, H-thiophene), 7.18 (d, J = 5.1 Hz, 1H, H-thiophene), 4.50 (d, J = 14.7 Hz, 1H, CH2), 4.26 (d, J = 14.7 Hz, 1H, CH2), 3.87 (s, 3H, CH3), 3.81 (s, 3H, CH3).
13C NMR (126 MHz, [D6]DMSO): δ = 166.2, 162.1, 140.9, 131.5, 130.9, 129.8, 70.7, 54.8, 52.1, 42.5.
MS (ESI): m/z = 340.9 [M + H]+.
IR (ATR) νmax = 1741 (C=O), 1708 (C=O) cm−1.
Anal. Calcd for C10H10BrClO4S: C, 35.16; H, 2.95. Found: C, 35.05; H, 2.88.
Methyl (E)-3-styrylthiophene-2-carboxylate 9.
Yield 3.524g (72%), white crystalline solid, bp 145–149 °C/0.25 torr, mp 85–86 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 8.02 (d, J = 16.6 Hz, 1H, CH=), 7.87 (dd, J = 5.3, 0.5 Hz, 1H, 4H-thiophene), 7.72 (d, J = 5.3 Hz, 1H, 5H-thiophene), 7.58 (d, J = 7.3 Hz, 2H, C6H5), 7.44–7.35 (m, 3H, C6H5, CH=), 7.37–7.27 (m, 1H, C6H5), 3.85 (s, 3H, CH3).
13C NMR (101 MHz, [D6]DMSO): δ = 162.3, 145.1, 136.6, 133.3, 132.0, 128.9, 128.4, 126.7, 125.5, 121.2, 52.1.
MS (ESI): m/z = 245.1 [M + H]+.
IR (ATR) νmax = 1722 (C=O) cm−1.
NMR data are in accordance with that reported in the literature [70,71].
General Procedure for the Preparation of Methyl 3-(2-chloro-3-oxobutyl)thiophene-2-carboxylate 4b, Methyl 3-(2-chloro-3-methoxy-3-oxopropyl)thiophene-2-carboxylate 5b, Methyl 3-(2,2-dichloro-3-methoxy-3-oxopropyl)thiophene-2-carboxylate 8b, Methyl 3-(2-chloro-3-oxopropyl)thiophene-2-carboxylate 11, and Methyl 3-(2-chloro-3-methoxy-2-methyl-3-oxopropyl)thiophene-2-carboxylate 12.
The methyl 3-aminothiophene-2-carboxylate 1 (3.14 g, 20 mmol, 1.0 equiv.) was added to 37% aqueous hydrochloric acid (3.54 mL, 42 mmol, 2.1 equiv.). The resulting mixture was cooled to −5 °C, followed by the dropwise addition of a saturated solution of sodium nitrite (1.45 g, 21 mmol, 1.05 equiv.), ensuring that the temperature remained below 5 °C throughout the addition. The freshly obtained cold diazonium salt solution 2a was then added dropwise to a solution containing the corresponding functionalized alkene 3 (20 mmol, 1.0 equiv.) and CuCl2×2H2O (1.00 g, 5.8 mmol) in acetone (20 mL) under vigorous stirring throughout. The reaction mixture was stirred at room temperature (20 °C) until the evolution of nitrogen gas ceased to evolve. Subsequently, 100 mL of water was added, and the organic layer was separated. The aqueous phase was extracted with CH2Cl2 (5 × 10 mL), and the combined organic extracts were dried over anhydrous MgSO4. The solvent was then removed under reduced pressure, and the product was purified by distillation under reduced pressure.
Methyl 3-(2-chloro-3-oxobutyl)thiophene-2-carboxylate 4b.
Yield 2.830 g (57%), light-yellow oil, bp 137–140 °C/0.5 torr.
1H NMR (400 MHz, [D6]DMSO): δ = 7.82 (d, J = 5.1 Hz, 1H, H-thiophene), 7.17 (d, J = 5.1 Hz, 1H, H-thiophene), 4.89 (dd, J = 9.2, 5.2 Hz, 1H, CH), 3.81 (s, 3H, OCH3), 3.64 (dd, J = 14.4, 5.2 Hz, 1H, CH2), 3.43 (dd, J = 14.4, 9.2 Hz, 1H, CH2), 2.31 (s, 3H, CH3).
13C NMR (101 MHz, [D6]DMSO): δ = 201.8, 162.1, 144.7, 131.7, 131.6, 127.3, 62.9, 52.0, 32.4, 26.6.
MS (ESI): m/z = 247.0 [M + H]+.
IR (ATR) νmax = 1704 (C=O) cm−1.
Anal. Calcd for C10H11ClO3S: C, 48.69; H, 4.49. Found: C, 48.60; H, 4.39.
Methyl 3-(2-chloro-3-methoxy-3-oxopropyl)thiophene-2-carboxylate 5b.
Yield 3.261 g (62%), colorless oil or crystalline solid, bp 130–133 °C/0.5 torr, mp 32–33 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 7.84 (d, J = 5.1 Hz, 1H, H-thiophene), 7.17 (d, J = 5.1 Hz, 1H, H-thiophene), 4.87 (dd, J = 8.4, 6.3 Hz, 1H, CH), 3.81 (s, 3H, CH3), 3.70 (s, 3H, CH3), 3.69–3.65 (m, 1H, CH2), 3.61 (dd, J = 10.9, 7.3 Hz, 1H, CH2).
13C NMR (101 MHz, [D6]DMSO): δ = 169.1 (o), 162.1 (o), 143.8 (o), 131.8 (+), 131.4 (+), 127.6 (o), 56.1 (+), 52.9 (+), 52.1 (+), 33.7 (−).
MS (ESI): m/z = 263.0 [M + H]+.
IR (ATR) νmax = 1742 (C=O), 1702 (C=O) cm−1.
Anal. Calcd for C10H11ClO4S: C, 45.72; H, 4.22. Found: C, 45.63; H, 4.13.
Methyl 3-(2,2-dichloro-3-methoxy-3-oxopropyl)thiophene-2-carboxylate 8b.
Yield 3.030 g (51%), colorless oil or crystalline solid, bp 139–142 °C/ 0.5 torr, mp 34–35 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 7.86 (d, J = 5.1 Hz, 1H, H-thiophene), 7.19 (d, J = 5.2 Hz, 1H, H-thiophene), 4.29 (s, 2H, CH2), 3.87 (s, 3H, CH3), 3.80 (s, 3H, CH3).
13C NMR (126 MHz, [D6]DMSO): δ = 165.7, 162.2, 140.1, 131.5, 131.4, 129.9, 83.5, 54.9, 52.2, 41.8.
MS (ESI): m/z = 297.0 [M + H]+.
IR (ATR) νmax = 1755 (C=O), 1707 (C=O) cm−1.
Anal. Calcd for C10H10Cl2O4S: C, 40.42; H, 3.39. Found: C, 40.34; H, 3.31.
Methyl 3-(2-chloro-3-oxopropyl)thiophene-2-carboxylate 11.
Yield 3.640 g (78%), light-yellow oil, bp 119–124 °C/0.25 torr.
1H NMR (400 MHz, CDCl3): δ = 9.52 (d, J = 1.7, 1H, CHO), 7.44 (d, J = 5.0 Hz, H-thiophene), 7.01 (d, J = 5.0 Hz, H-thiophene), 4.61–4.49 (m, 1H, CH), 3.87–3.75 (m, 4H, OCH3, CH2), 3.33 (dd, J = 14.1, 8.5 Hz, 1H, CH2).
13C NMR (101 MHz, CDCl3): δ = 193.7, 162.7, 143.7, 131.7, 130.8, 127.8, 62.7, 52.1, 32.0.
MS (ESI): m/z = 233.0 [M + H]+.
IR (ATR) νmax = 1698 (C=O) cm−1.
Anal. Calcd for C9H9ClO3S: C, 46.46; H, 3.90. Found: C, 46.38; H, 3.80.
Methyl 3-(2-chloro-3-methoxy-2-methyl-3-oxopropyl)thiophene-2-carboxylate 12.
Yield 3.485 g (63%), light-yellow oil or crystalline solid, bp 130–134 °C/0.25 torr, mp 38–39 °C.
1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 5.1 Hz, 1H, H-thiophene), 7.09 (d, J = 5.1 Hz, 1H, H-thiophene), 3.95 (d, J = 14.1 Hz, 1H, CH2), 3.86 (s, 3H, CH3), 3.82 (d, J = 14.1 Hz, 1H, CH2), 3.80 (s, 3H, CH3), 1.68 (s, 3H, CH3).
13C NMR (101 MHz, CDCl3): δ = 171.6 (o), 162.9 (o), 143.1 (o), 131.8 (+), 130.2 (+), 129.6 (o), 68.3 (o), 53.4 (+), 52.1 (+), 39.4 (−), 26.7 (+).
MS (ESI): m/z = 277.0 [M + H]+.
IR (ATR) νmax = 1738 (C=O), 1701 (C=O) cm−1.
Anal. Calcd for C11H13ClO4S: C, 47.74; H, 4.74. Found: C, 47.66; H, 4.67.
General Procedure for the Preparation of (E)-3-(2-carboxyvinyl)thiophene- 2-carboxylic acid 13, Methyl (E)-3-(2-cyanovinyl)thiophene-2-carboxylate 14b, and 3-(2-Carboxy-2-chlorovinyl)thiophene-2-carboxylic acid 15
The solution of the corresponding methyl 3-(2-bromo-3-methoxy-3-oxopropyl)thiophene-2-carboxylate 5a, or methyl 3-(2-bromo-2-cyanoethyl)thiophene-2-carboxylate 6a, or methyl 3-(2-bromo-2-chloro-3-methoxy-3-oxopropyl)thiophene-2-carboxylate 8a (5 mmol, 1.0 equiv.) in 5 mL methanol was added dropwise under vigorous stirring to the mixture of KOH (0.98 g, 17.5 mmol, 3.5 equiv.), methanol (5 mL), and water (10 mL) at 0 °C. Then the mixture was stirred 1.5 h. After that, the reaction mixture was cooled and poured into a mixture of 10 mL of 37% HCl and 20 g of ice. The product was filtered off and recrystallized from methanol or methanol-H2O.
(E)-3-(2-Carboxyvinyl)thiophene-2-carboxylic acid 13.
Yield 0.945 g (95%), white crystalline solid, mp > 300 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 13.30–12.75 (m, 2H, 2COOH), 8.39 (d, J = 16.1 Hz, 1H, =CH), 7.83 (dd, J = 5.3, 0.6 Hz, 1H, 4H-thiophene), 7.69 (d, J = 5.3 Hz, 1H, 5H-thiophene), 6.54 (d, J = 16.1 Hz, 1H, =CH).
13C NMR (101 MHz, [D6]DMSO): δ = 167.7 (o), 162.9 (o), 141.1 (o), 135.9 (+), 132.2 (o), 131.7 (+), 127.5 (+), 122.7 (+).
MS (ESI): m/z = 199.0 [M + H]+.
IR (ATR) νmax = 1685 (C=O), 1648 (C=O) cm−1.
Anal. Calcd for C8H6O4S: C, 48.48; H, 3.05. Found: C, 48.43; H, 2.95.
Although the literature states that compound 13 is synthesized, the Supporting Information describes the diester (methyl (E)-3-(3-methoxy-3-oxoprop-1-en-1-yl)thiophene-2-carboxylate) [73].
Methyl (E)-3-(2-cyanovinyl)thiophene-2-carboxylate 14b.
Yield 0.781 g (81%), white crystalline solid, mp 126–127 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 8.14 (d, J = 16.8 Hz, 1H, =CH), 7.94 (d, J = 4.9 Hz, 1H, H-thiophene), 7.66 (d, J = 4.8 Hz, 1H, H-thiophene), 6.55 (d, J = 16.8 Hz, 1H, =CH), 3.84 (s, 3H, CH3).
13C NMR (101 MHz, [D6]DMSO): δ = 161.6, 141.7, 140.6, 132.8, 130.6, 126.8, 118.4, 101.0, 52.5.
MS (ESI): m/z = 194.0 [M + H]+.
IR (ATR) νmax = 2217 (CN), 1697 (C=O) cm−1.
Anal. Calcd for C9H7NO2S: C, 55.95; H, 3.65; N, 7.25. Found: C, 55.88; H, 3.61; N, 7.15.
Melting point and NMR data are in accordance with that reported in the literature [75].
3-(2-Carboxy-2-chlorovinyl)thiophene-2-carboxylic acid 15.
Yield 1.060 g (91%), white crystalline solid, mp 240–241 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 14.00–12.94 (m, 2H, 2COOH), 8.73 (s, 1H, =CH), 7.92 (d, J = 5.3 Hz, 1H, H-thiophene), 7.90 (d, J = 5.3 Hz, 1H, H-thiophene).
13C NMR (101 MHz, [D6]DMSO): δ = 163.9, 162.7, 138.0, 134.2, 131.6, 129.7, 129.0, 124.0.
MS (ESI): m/z = 233.0 [M + H]+.
IR (ATR) νmax = 1674 (C=O) cm−1.
Anal. Calcd for C8H5ClO4S: C, 41.30; H, 2.17. Found: C, 41.23; H, 2.13.
Procedure for the Preparation of (E)-3-(2-Cyanovinyl)thiophene-2-carboxylic acid 14a
The solution of methyl 3-(2-bromo-2-cyanoethyl)thiophene-2-carboxylate 6a (0.548 g, 2 mmol, 1.0 equiv.) in 3 mL of methanol was added dropwise under vigorous stirring to the mixture of KOH (0.39 g, 7 mmol, 3.5 equiv.), methanole (2 mL), and water (5 mL) at 60 °C. Then the mixture was stirred under reflux 1 h. After that, the reaction mixture was cooled and poured into a mixture of 4 mL of 37% HCl and 20 g of ice. The product was filtered off and recrystallized from methanol.
(E)-3-(2-Cyanovinyl)thiophene-2-carboxylic acid 14a.
Yield 0.325 g (90%), white crystalline solid, mp 200–201 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 14.29–12.93 (br.s, 1H, COOH), 8.22 (d, J = 16.7 Hz, 1H, =CH), 7.87 (d, J = 4.4 Hz, 1H, H-thiophene), 7.63 (d, J = 4.5 Hz, 1H, H-thiophene), 6.50 (d, J = 16.8 Hz, 1H, =CH).
13C NMR (101 MHz, [D6]DMSO): δ = 162.7, 142.2, 140.0, 132.8, 132.1, 126.7, 118.6, 100.3.
MS (ESI): m/z = 180.0 [M + H]+.
IR (ATR) νmax = 2216 (CN), 1655 (C=O) cm−1.
Anal. Calcd for C8H5NO2S: C, 53.62; H, 2.81; N, 7.82. Found: C, 53.55; H, 2.78; N, 7.76.
NMR data are in accordance with that reported in the literature [75].
General Procedure for the Preparation of 7-Oxo-4,7-dihydro- 5H-thieno [2,3-c]pyran-5-carboxylic acid 16, 2,2-Dichloro-3-(2-(methoxy- carbonyl)thiophen-3-yl)propanoic acid 17, and 3-(2-Carboxy-2-hydroxypropyl)-thiophene- 2-carboxylic acid 18.
The solution of the corresponding methyl 3-(2-chloro-3-methoxy-3-oxopropyl)thiophene-2-carboxylate 5b, methyl 3-(2,2-dichloro-3-methoxy-3-oxopropyl)thiophene-2-carboxylate 8b, or methyl 3-(2-chloro-3-methoxy-2-methyl-3-oxopropyl)thiophene-2-carboxylate 12 (5 mmol, 1.0 equiv.) in 5 mL of methanol was added dropwise under vigorous stirring to the mixture of KOH (0.98 g, 17.5 mmol, 3.5 equiv.), methanol (5 mL), and water (10 mL) at 0 °C. Then the mixture was stirred 1.5 h. After that, the reaction mixture was cooled and poured into a mixture of 10 mL of 37% HCl and 20 g of ice. The product was filtered off and recrystallized from methanol or methanol-DMF.
In the case of the reaction of methyl 3-(2-chloro-3-methoxy-2-methyl-3-oxopropyl)thiophene-2-carboxylate 12, after acidification the water was evaporated under reduced pressure from the reaction mixture. The resulting precipitate was extracted with dichloromethane (5 × 10 mL). The combined organic extracts were dried over MgSO4, evaporated, and the residue was recrystallized from hexane to obtain 18.
7-Oxo-4,7-dihydro-5H-thieno [2,3-c]pyran-5-carboxylic acid 16.
Yield 0.915 g (92%), white solid, mp 190–191 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 13.96–12.96 (br.s, 1H, COOH), 8.03 (d, J = 5.0 Hz, 1H, H-thiophene), 7.18 (d, J = 5.0 Hz, 1H, H-thiophene), 5.39 (dd, J = 6.1, 4.2 Hz, 1H, CH), 3.39 (dd, J = 17.3, 6.1 Hz, 1H, CH2), 3.28 (dd, J = 17.3, 4.2 Hz, 1H, CH2).
13C NMR (101 MHz, [D6]DMSO): δ = 170.9 (o), 159.5 (o), 145.8 (+), 135.6 (+), 127.6 (+), 125.6 (o), 75.6 (+), 27.1 (−).
MS (ESI): m/z = 199.0 [M + H]+.
IR (ATR) νmax = 1715 (C=O) cm−1.
Anal. Calcd for C8H6O4S: C, 48.48; H, 3.05. Found: C, 48.40; H, 2.97.
3-(2,2-Dichloro-3-methoxy-3-oxopropyl)thiophene-2-carboxylic acid 17.
Yield 1.067 g (75%), white crystalline solid, mp 97–98 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 7.85 (d, J = 5.1 Hz, 1H, H-thiophene), 7.22 (d, J = 5.2 Hz, 1H, H-thiophene), 4.25 (s, 2H, CH2), 3.80 (s, 3H, CH3).
13C NMR (101 MHz, [D6]DMSO): δ = 166.6, 162.2, 140.7, 131.3, 131.3, 129.9, 84.6, 52.2, 41.8.
MS (ESI): m/z = 283.0 [M + H]+.
IR (ATR) νmax = 1737 (C=O), 1698 (C=O) cm−1.
Anal. Calcd for C9H8Cl2O4S: C, 38.18; H, 2.85. Found: C, 38.07; H, 2.80.
3-(2-Carboxy-2-hydroxypropyl)thiophene-2-carboxylic acid 18.
Yield 0.911 g (79%), white crystalline solid, mp 195–196 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 12.95–12.50 (m, 2H, 2COOH), 7.67 (d, J = 5.0 Hz, 1H, H-thiophene), 7.15 (d, J = 5.0 Hz, 1H, H-thiophene), 5.50–4.90 (br.s, 1H, OH), 3.55 (d, J = 13.8 Hz, 1H, CH2), 3.21 (d, J = 13.8 Hz, 1H, CH2), 1.17 (s, 3H, CH3).
13C NMR (101 MHz, [D6]DMSO): δ = 177.3, 163.7, 144.4, 132.3, 129.7, 129.3, 73.7, 37.6, 24.6.
MS (ESI): m/z = 231.0 [M + H]+.
IR (ATR) νmax = 3404 (OH), 1708 (C=O), 1672 (C=O) cm−1.
Anal. Calcd for C9H10O5S: C, 46.95; H, 4.38. Found: C, 46.86; H, 4.31.
General Procedure for the Preparation of Methyl 3-((2-amino-4-methylthiazol-5-yl)methyl)thiophene-2-carboxylate 19a, Methyl 3-((2-aminothiazol-5-yl)methyl)thiophene-2-carboxylate 19b, and Methyl 3-((2-amino-4-methyl-1,3-selenazol-5-yl)methyl)thiophene-2-carboxylate 20a
Method A. A mixture of the corresponding methyl 3-(2-bromo-3-oxobutyl)thiophene-2-carboxylate 4a or methyl 3-(2-chloro-3-oxopropyl)thiophene-2-carboxylate 11 (3 mmol, 1.0 equiv.), thiourea (0.228 g, 3 mmol, 1.0 equiv.) or selenourea (0.369 g, 3 mmol, 1.0 equiv.) and 5 mL of methanol was stirred under reflux temperature over a period of 2 h. Then 40 mL of hot water was added to the mixture, the aqueous layer was separated and alkalified by a 20% solution of NH3 to pH ≈ 11. The mixture was allowed to cool to 20 °C whereupon a precipitate formed which was filtered off, dried on air and recrystallized from hexane–toluene.
Methyl 3-((2-amino-4-methylthiazol-5-yl)methyl)thiophene-2-carboxylate 19a.
Yield 0.648 g (80%), light-yellow solid, mp 178–179 °C.
1H NMR (400 MHz, CDCl3): δ = 7.38 (d, J = 5.1 Hz, 1H, H-thiophene), 6.89 (d, J = 5.1 Hz, 1H, H-thiophene), 5.14–4.59 (m, 2H, NH2), 4.29 (s, 2H, CH2), 3.88 (s, 3H, CH3), 2.17 (s, 3H, CH3).
1H NMR (500 MHz, [D6]DMSO): δ = 7.78 (d, J = 5.0 Hz, 1H, H-thiophene), 7.00 (d, J = 5.0 Hz, 1H, H-thiophene), 6.57 (s, 2H, NH2), 4.21 (s, 2H, CH2), 3.82 (s, 3H, CH3), 2.06 (s, 3H, CH3).
13C NMR (101 MHz, CDCl3): δ = 165.1 (o), 163.1 (o), 148.4 (o), 143.8 (o), 130.8 (+), 130.4 (+), 126.5 (o), 118.7 (o), 52.1 (+), 26.2 (−), 14.9 (+).
MS (ESI): m/z = 269.0 [M + H]+.
IR (ATR) νmax = 3441 (NH), 3267 (NH), 1694 (C=O) cm−1.
Anal. Calcd for C11H12N2O2S2: C, 49.23; H, 4.51; N, 10.44. Found: C, 49.14; H, 4.45; N, 10.36.
Methyl 3-((2-aminothiazol-5-yl)methyl)thiophene-2-carboxylate 19b.
Yield 0.545 g (71%), light-yellow solid, mp 130–131 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 7.80 (d, J = 5.1 Hz, 1H, H-thiophene), 7.07 (d, J = 5.1 Hz, 1H, H-thiophene), 6.70 (s, 1H, H-thiazole), 6.73–6.67 (br.s, 2H, NH2), 4.25 (s, 2H, CH2), 3.81 (s, 3H, CH3).
13C NMR (101 MHz, [D6]DMSO): δ = 168.1 (o), 162.2 (o), 148.6 (o), 135.7 (+), 132.1 (+), 131.1 (+), 125.6 (o), 123.0 (o), 51.9 (+), 26.2 (−).
MS (ESI): m/z = 255.0 [M + H]+.
IR (ATR) νmax = 3407 (NH), 3295 (NH), 1633 (C=O) cm−1.
Anal. Calcd for C10H10N2O2S2: C, 47.23; H, 3.96; N, 11.02. Found: C, 47.16; H, 3.91; N, 10.93.
Methyl 3-((2-amino-4-methyl-1,3-selenazol-5-yl)methyl)thiophene-2-carboxylate 20a.
Yield 0.803 g (85%), light-yellow solid, mp 199–200 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 7.78 (d, J = 5.1 Hz, 1H, H-thiophene), 7.03 (d, J = 5.1 Hz, 1H, H-thiophene), 6.87 (s, 2H, NH2), 4.23 (s, 2H, CH2), 3.81 (s, 3H, CH3), 2.04 (s, 3H, CH3).
13C NMR (101 MHz, [D6]DMSO): δ = 166.8 (o), 162.3 (o), 149.6 (o), 143.5 (o), 132.0 (+), 130.8 (+), 125.2 (o), 120.5 (o), 51.9 (+), 27.5 (−), 15.2 (+).
77Se NMR (76 MHz, [D6]DMSO): δ = 571.1.
MS (ESI): m/z = 317.0 [M + H]+.
IR (ATR) νmax = 3435 (NH), 3263 (NH), 1690 (C=O) cm−1.
Anal. Calcd for C11H12N2O2SSe: C, 41.91; H, 3.84; N, 8.89. Found: C, 41.88; H, 3.76; N, 8.81.
Procedure for the Preparation of Methyl 3-((2-amino-1,3-selenazol-5-yl)methyl)thiophene-2-carboxylate 20b
Method B. A mixture of the methyl 3-(2-chloro-3-oxopropyl)thiophene-2-carboxylate 11 (0.699 g, 3 mmol, 1.0 equiv.), selenourea (0.369 g, 3 mmol, 1.0 equiv.), KI (48 mg, 0.3 mmol, 0.1 equiv.) and 5 mL of methanol was stirred under reflux temperature over a period of 2 h. Then 50 mL of hot water was added to the mixture, the aqueous layer was separated and alkalified by a 20% solution of NH3 to pH ≈ 11. The mixture was allowed to cool to 20 °C whereupon a precipitate formed which was filtered off, dried on air and recrystallized from hexane–toluene.
Methyl 3-((2-amino-1,3-selenazol-5-yl)methyl)thiophene-2-carboxylate 20b.
Yield 0.637 g (70%), light-yellow solid, mp 110–112 °C (decomp.).
1H NMR (400 MHz, [D6]DMSO): δ = 7.77 (d, J = 5.0 Hz, 1H, H-thiophene), 7.09 (d, J = 5.0 Hz, 1H, H-thiophene), 6.98–6.94 (br.s, 2H, NH2), 4.28 (s, 2H, CH2), 3.81 (s, 3H, CH3).
13C NMR (101 MHz, [D6]DMSO): δ = 170.4, 162.3, 149.3, 136.6, 132.0, 131.1, 128.4, 125.5, 52.0, 26.4.
MS (ESI): m/z = 303.0 [M + H]+.
IR (ATR) νmax = 3103 (NH), 2949 (NH), 1698 (C=O) cm−1.
Anal. Calcd for C10H10N2O2SSe: C, 39.87; H, 3.35; N, 9.30. Found: C, 39.77; H, 3.30; N, 9.21.
General Procedure for the Preparation of the Hydrobromides of Methyl 3-((2-imino-4-oxothiazolidin-5-yl)methyl)thiophene-2-carboxylate 21, Methyl 3-((2,4-diiminothiazolidin-5-yl)methyl)thiophene-2-carboxylate 22, Methyl 3-((2-imino-4-oxo-1,3-selenazolidin-5-yl)methyl)thiophene-2-carboxylate 23, and Methyl 3-((2,4-diimino-1,3-selenazolidin-5-yl)methyl)thiophene-2-carboxylate 24.
A mixture of the corresponding methyl 3-(2-bromo-3-methoxy-3-oxopropyl)thiophene-2-carboxylate 5a or methyl 3-(2-bromo-2-cyanoethyl)thiophene-2-carboxylate 6a (3 mmol, 1.0 equiv.), thiourea (0.228 g, 3 mmol, 1.0 equiv.) or selenourea (0.369 g, 3 mmol, 1.0 equiv.) and 3 mL of methanol was stirred under reflux temperature over a period of 3 h. The mixture was allowed to cool to 20 °C whereupon a precipitate of product was formed which was filtered off and recrystallized from methanol-MTBE.
Methyl 3-((2-imino-4-oxothiazolidin-5-yl)methyl)thiophene-2-carboxylate hydrobromide 21.
Yield 0.846 g (80%), white crystalline solid, mp 162–163 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 9.31–9.02 (m, 2H, NH), 7.81 (d, J = 5.1 Hz, 1H, H-thiophene), 7.08 (d, J = 5.1 Hz, 1H, H-thiophene), 4.69 (dd, J = 8.8, 5.0 Hz, 1H, CH), 3.80–3.73 (m, 4H, CH3, CH2), 3.35 (dd, J = 14.1, 8.9 Hz, 1H, CH2).
13C NMR (101 MHz, [D6]DMSO): δ = 186.5, 180.2, 162.3, 145.9, 132.1, 130.9, 127.4, 55.5, 52.1, 31.7.
MS (ESI): m/z = 271.0 [M + H]+.
IR (ATR) νmax = 3368 (C=O), 3266 (C=O), 1604 (C=O) cm−1.
Anal. Calcd for C10H11BrN2O3S2: C, 34.20; H, 3.16; N, 7.98. Found: C, 34.11; H, 3.07; N, 7.91.
Methyl 3-((2,4-diiminothiazolidin-5-yl)methyl)thiophene-2-carboxylate hydrobromide 22.
Yield 0.749 g (71%), white crystalline solid, mp 245–246 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 10.41–10.19 (br.s, 2H, NH), 10.16–10.04 (br.s, 1H, NH), 10.01–9.83 (br.s, 1H, NH), 7.91 (d, J = 5.0 Hz, 1H, H-thiophene), 7.18 (d, J = 5.0 Hz, 1H, H-thiophene), 5.59 (dd, J = 8.9, 4.5 Hz, 1H, CH), 3.92 (dd, J = 14.4, 4.3 Hz, 1H, CH2), 3.80 (s, 3H, CH3), 3.70 (dd, J = 14.3, 9.3 Hz, 2H, CH2).
13C NMR (101 MHz, [D6]DMSO): δ = 184.2, 162.1, 143.9, 132.6, 130.2, 127.9, 56.6, 52.2, 31.9.
MS (ESI): m/z = 270.0 [M + H]+.
IR (ATR) νmax = 3198 (NH), 2989 (NH), 1641 (C=O) cm−1.
Anal. Calcd for C10H12BrN3O2S2: C, 34.29; H, 3.45; N, 12.00. Found: C, 34.18; H, 3.40; N, 11.91.
Methyl 3-((2-imino-4-oxo-1,3-selenazolidin-5-yl)methyl)thiophene-2-carboxylate hydrobromide 23.
Yield 1.015 g (85%), white crystalline solid, mp 212–213 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 9.13–8.83 (m, 2H, NH), 7.81 (d, J = 5.1 Hz, 1H, H-thiophene), 7.10 (d, J = 5.1 Hz, 1H, H-thiophene), 4.95 (dd, J = 9.2, 4.9 Hz, 1H, CH), 3.87 (dd, J = 14.3, 5.0 Hz, 1H, CH2), 3.79 (s, 3H, CH3), 3.45 (dd, J = 14.3, 9.2 Hz, 1H, CH2).
13C NMR (101 MHz, [D6]DMSO): δ = 188.9, 175.7, 162.2, 147.2, 132.0, 130.6, 126.9, 55.3, 52.0, 32.3.
MS (ESI): m/z = 319.0 [M + H]+.
IR (ATR) νmax = 3293 (NH), 2928 (NH), 1701 (C=O), 1648 (C=O) cm−1.
Anal. Calcd for C10H11BrN2O3SSe: C, 30.17; H, 2.78; N, 7.04. Found: C, 30.08; H, 2.75; N, 6.93.
Methyl 3-((2,4-diimino-1,3-selenazolidin-5-yl)methyl)thiophene-2-carboxylate hydrobromide 24.
Yield 0.695 g (73%), white crystalline solid, mp 246–247 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 10.37–9.88 (br.s, 4H), 7.89 (d, J = 5.1 Hz, 1H, H-thiophene), 7.17 (d, J = 5.1 Hz, 1H, H-thiophene), 5.69 (dd, J = 9.3, 4.7 Hz, 1H, CH), 3.97 (dd, J = 14.6, 4.8 Hz, 1H, CH2), 3.80 (s, 3H, CH3), 3.8–3.73 (m, 1H, CH2).
13C NMR (101 MHz, [D6]DMSO): δ = 185.1, 182.0, 162.2, 145.2, 132.6, 130.1, 127.7, 54.1, 52.2, 32.8.
MS (ESI): m/z = 318.0 [M + H]+.
IR (ATR) νmax = 3200 (NH), 1710 (C=O)cm−1.
Anal. Calcd for C10H12BrN3O2SSe: C, 30.24; H, 3.05; N, 10.58. Found: C, 30.15; H, 2.97; N, 10.51.
General Procedure for the Preparation of Dimethyl 4-amino-[2,3′-bithiophene]-2′,5-dicarboxylate 26a and Methyl 4-amino-5-(phenylcarbamoyl)-[2,3′-bithiophene]-2′-carboxylate 26b.
A solution of methyl 3-(2-bromo-2-chloro-2-cyanoethyl)thiophene-2-carboxylate 7a (3 mmol, 1.0 equiv.) in methanol (5 mL) was added dropwise under stirring to a mixture of the appropriate thiol 25 (methyl thioglycolate 25a, mercaptoacetanilide 25b, or mercaptoacetone 25c) (3.03 mmol, 1.01 equiv.) with a solution of MeONa (9 mL, 1M) in methanol at ambient temperature. The resulting mixture was stirred for 2 h at ambient temperature, then under reflux over 1 h. The solvent was evaporated under reduced pressure. Acetic acid (20 mL, ω = 2%) was added to residue. The product was filtered off and recrystallized from methanol.
In the case of the reaction with mercaptoacetone 25c, the reaction mixture was extracted after acidification with MTBE (3 × 5 mL). The organic phase was separated, dried over Na2SO4, and then 37% aqueous HCl (0.25 mL, 3 mmol, 1 equiv.) was added. The resulting precipitate of 26c was filtered off and recrystallized from methanol-MTBE.
Dimethyl 4-amino-[2,3′-bithiophene]-2′,5-dicarboxylate 26a.
Yield 0.670 g (75%), white solid, mp 128–129 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 7.94 (d, J = 5.2 Hz, 1H, H-thiophene’), 7.35 (d, J = 5.2 Hz, 1H, H-thiophene’), 7.12 (s, 1H, 4H-thiophene), 6.58 (s, 2H, NH2), 3.80 (s, 3H, CH3), 3.73 (s, 3H, CH3).
13C NMR (101 MHz, [D6]DMSO): δ = 163.9, 161.4, 154.6, 139.9, 138.4, 132.4, 130.8, 126.9, 121.6, 98.0, 52.3, 51.0.
MS (ESI): m/z = 298.0 [M + H]+.
IR (ATR) νmax = 1670 (C=O) cm−1.
Anal. Calcd for C12H11NO4S2: C, 48.47; H, 3.73; N, 4.71. Found: C, 48.42; H, 3.65; N, 4.62.
Methyl 4-amino-5-(phenylcarbamoyl)-[2,3′-bithiophene]-2′-carboxylate 26b.
Yield 0.736 g (71%), white solid, mp 218–219 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 13.65–12.84 (m, 1H, COOH), 9.32 (s, 1H, NH), 7.89 (d, J = 5.2 Hz, 1H, H-thiophene’), 7.67 (dd, J = 8.6, 1.0 Hz, 2H, C6H5), 7.31 (d, J = 5.2 Hz, 1H, H-thiophene’), 7.32–7.27 (m, 2H, C6H5), 7.15 (s, 1H, H-thiophene), 7.03 (t, J = 7.4 Hz, 1H, C6H5), 6.76–6.57 (m, 2H, NH2).
13C NMR (101 MHz, [D6]DMSO): δ = 163.1, 162.5, 154.1, 139.2, 137.8, 137.4, 131.6, 130.7, 129.0, 128.4, 123.0, 122.2, 120.8, 101.4.
MS (ESI): m/z = 359.0 [M + H]+.
IR (ATR) νmax = 3484 (NH), 3440 (NH), 1667 (C=O), 1648 (C=O) cm−1.
Anal. Calcd for C17H14N2O3S2: C, 56.97; H, 3.94; N, 7.82. Found: C, 56.89; H, 3.90; N, 7.73.
Methyl 5-acetyl-4-amino-[2,3′-bithiophene]-2′-carboxylate hydrochloride 26c.
Yield 0.660 g (69%), white crystalline solid, mp 115–116 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 7.96 (d, J = 5.2 Hz, 1H, H-thiophene), 7.36 (d, J = 5.2 Hz, 1H, H-thiophene), 7.11 (s, 1H, H-thiophene’), 4.07–3.67 (br.s, 3H, NH3), 3.80 (s, 3H, CH3), 2.27 (s, 3H, CH3).
13C NMR (101 MHz, [D6]DMSO): δ = 189.6, 161.5, 154.5, 140.1, 138.3, 132.6, 130.9, 127.3, 121.8, 109.7, 52.4, 28.4.
MS (ESI): m/z = 282.0 [M + H]+.
IR (ATR) νmax = 3437 (NH), 3344 (NH), 1727(C=O) cm−1.
Anal. Calcd for C12H12ClNO3S2: C, 45.35; H, 3.81; N, 4.41. Found: C, 45.24; H, 3.77; N, 4.33.
General Procedure for the Preparation of Dimethyl 4-hydroxy-[2,3′-bithiophene]-2′,5-dicarboxylate 27a, Methyl 4-hydroxy-5-(phenyl- carbamoyl)-[2,3′-bithiophene]-2′-carboxylate 27b, and Methyl 5-acetyl-4-hydroxy- [2,3′-bithiophene]-2′-carboxylate 27c.
A solution of methyl 3-(2-bromo-2-chloro-3-methoxy-3-oxopropyl)thiophene-2-carboxylate 8a (3 mmol, 1.0 equiv.) in methanol (5 mL) was added dropwise under stirring to a mixture of appropriate thiol 25 (methyl thioglycolate 25a, mercaptoacetanilide 25b, or mercaptoacetone 25c) (3.03 mmol, 1.01 equiv.) with a solution of MeONa (9 mL, 1 M) in methanol at ambient temperature. The resulting mixture was stirred for 2 h at ambient temperature, then under reflux over 1 h. The solvent was then evaporated under reduced pressure. Acetic acid (20 mL, ω = 2%) was added to the residue. The product was filtered off and recrystallized from methanol.
Dimethyl 4-hydroxy-[2,3′-bithiophene]-2′,5-dicarboxylate 27a.
Yield 0.670 g (74%), white crystalline solid, mp 113–114 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 10.65–10.17 (br.s, 1H, OH), 7.96 (d, J = 5.1 Hz, 1H, H-thiophene’), 7.42 (d, J = 5.2 Hz, 1H, H-thiophene’), 7.30 (s, 1H, 3H-thiophene), 3.80 (s, 3H, CH3), 3.77 (s, 3H, CH3).
13C NMR (101 MHz, [D6]DMSO): δ = 162.7, 161.4, 160.1, 139.3, 138.0, 132.5, 130.7, 126.9, 122.0, 105.7, 52.4, 51.5.
MS (ESI): m/z = 299.0 [M + H]+.
IR (ATR) νmax = 3331 (OH), 1715 (C=O), 1675 (C=O) cm−1.
Anal. Calcd for C12H10O5S2: C, 48.31; H, 3.38. Found: C, 48.21; H, 3.36.
Methyl 4-hydroxy-5-(phenylcarbamoyl)-[2,3′-bithiophene]-2′-carboxylate 27b.
Yield 0.862 g (80%), white solid, mp 213–214 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 12.40–11.80 (br.s, 1H, OH), 9.55 (s, 1H, NH), 7.97 (d, J = 5.0 Hz, 1H, H-thiophene’), 7.66 (d, J = 7.4 Hz, 2H), 7.44–7.33 (m, 4H), 7.10 (t, J = 7.4 Hz, 1H, C6H5), 3.82 (s, 3H, CH3).
13C NMR (101 MHz, [D6]DMSO): δ = 161.5, 160.2, 155.7, 138.4, 138.3, 137.8, 132.6, 130.7, 128.9, 126.5, 123.6, 121.6, 119.8, 113.1, 52.4.
MS (ESI): m/z = 360.0 [M + H]+.
IR (ATR) νmax = 3315 (NH), 1711 (C=O), 1640 (C=O) cm−1.
Anal. Calcd for C17H13NO4S2: C, 56.81; H, 3.65; N, 3.90. Found: C, 56.74; H, 3.60; N, 3.81.
Methyl 5-acetyl-4-hydroxy-[2,3′-bithiophene]-2′-carboxylate 27c.
Yield 0.716 g (84%), white crystalline solid, mp 122–123 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 11.82–11.18 (m, 1H, OH), 7.96 (d, J = 5.0 Hz, 1H, H-thiophene), 7.39 (d, J = 4.9 Hz, 1H, H-thiophene), 7.33 (s, 1H, 1H, H-thiophene’), 3.81 (s, 3H, CH3), 2.47 (s, 3H, CH3).
13C NMR (101 MHz, [D6]DMSO): δ = 190.3, 161.4, 159.2, 140.7, 138.2, 132.6, 130.7, 127.1, 122.2, 119.4, 52.4, 28.7.
MS (ESI): m/z = 283.0 [M + H]+.
IR (ATR) νmax = 3104 (OH), 1710 (C=O), 1614 (C=O) cm−1.
Anal. Calcd for C12H10O4S2: C, 51.05; H, 3.57. Found: C, 50.94; H, 3.51.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules30183758/s1; Figure S1: 1H-NMR spectrum of 4a; Figure S2: 13C-NMR spectrum of 4a; Figure S3: 1H-NMR spectrum of 5a; Figure S4: 1H-NMR spectrum of 5a; Figure S5: 13C-NMR spectrum of 5a; Figure S6: 13C-NMR spectrum of 5a; Figure S7: 1H-NMR spectrum of 6a; Figure S8: 13C-NMR spectrum of 6a; Figure S9: 1H-NMR spectrum of 7a; Figure S10: 1H-NMR spectrum of 7a; Figure S11: 13C-NMR spectrum of 7a; Figure S12: 13C-NMR spectrum of 7a; Figure S13: 1H-NMR spectrum of 8a; Figure S14: 13C-NMR spectrum of 8a; Figure S15: 1H-NMR spectrum of 9; Figure S16: 13C-NMR spectrum of 9; Figure S17: 1H-NMR spectrum of 4b; Figure S18: 13C-NMR spectrum of 4b; Figure S19: 1H-NMR spectrum of 5b; Figure S20: 13C-NMR spectrum of 5b; Figure S21: 1H-NMR spectrum of 8b; Figure S22: 13C-NMR spectrum of 8b; Figure S23: 1H-NMR spectrum of 11; Figure S24: 13C-NMR spectrum of 11; Figure S25: 1H-NMR spectrum of 12; Figure S26: 13C-NMR spectrum of 12; Figure S27: 1H-NMR spectrum of 13; Figure S28: 13C-NMR spectrum of 13; Figure S29: 1H-NMR spectrum of 14a; Figure S30: 13C-NMR spectrum of 14a; Figure S31: 1H-NMR spectrum of 14b; Figure S32: 13C-NMR spectrum of 14b; Figure S33: 1H-NMR spectrum of 15; Figure S34: 13C-NMR spectrum of 15; Figure S35: 1H-NMR spectrum of 16; Figure S36: 13C-NMR spectrum of 16; Figure S37: 1H-NMR spectrum of 17; Figure S38: 13C-NMR spectrum of 17; Figure S39: 1H-NMR spectrum of 18; Figure S40: 13C-NMR spectrum of 18; Figure S41: 1H-NMR spectrum of 19a; Figure S42: 1H-NMR spectrum of 19a; Figure S43: 13C-NMR spectrum of 19a; Figure S44: 1H-NMR spectrum of 19b; Figure S45: 13C-NMR spectrum of 19b; Figure S46: 1H-NMR spectrum of 20a; Figure S47: 13C-NMR spectrum of 20a; Figure S48: 77Se-NMR spectrum of 20a; Figure S49: 1H-NMR spectrum of 20b; Figure S50: 13C-NMR spectrum of 20b; Figure S51: 1H-NMR spectrum of 21; Figure S52: 13C-NMR spectrum of 21; Figure S53: 1H-NMR spectrum of 22; Figure S54: 13C-NMR spectrum of 22; Figure S55: 1H-NMR spectrum of 23; Figure S56: 13C-NMR spectrum of 23; Figure S57: 1H-NMR spectrum of 24; Figure S58: 13C-NMR spectrum of 24; Figure S59: 1H-NMR spectrum of 26a; Figure S60: 13C-NMR spectrum of 26a; Figure S61: 1H-NMR spectrum of 26b; Figure S62: 13C-NMR spectrum of 26b; Figure S63: 1H-NMR spectrum of 26c; Figure S64: 13C-NMR spectrum of 26c; Figure S65: 1H-NMR spectrum of 27a; Figure S66: 13C-NMR spectrum of 27a; Figure S67: 1H-NMR spectrum of 27b; Figure S68: 13C-NMR spectrum of 27b; Figure S69: 1H-NMR spectrum of 27c; Figure S70: 13C-NMR spectrum of 27c.

Author Contributions

Conceptualization, Y.V.O.; methodology, Y.V.O., A.S. and M.D.O.; software, Y.V.O. and M.K.; validation, Y.V.O., O.V.B., M.Y.O., M.K., A.S. and M.D.O.; formal analysis, Y.V.O., O.V.B., M.Y.O., M.K., A.S. and M.D.O.; investigation, Y.V.O., O.V.B., M.Y.O., M.K.; resources, Y.V.O., A.S. and M.D.O.; data curation, Y.V.O., A.S. and M.K.; writing—original draft preparation, Y.V.O., A.S. and M.D.O.; writing—review and editing, Y.V.O., A.S. and M.D.O.; visualization, Y.V.O., A.S. and M.K.; supervision, Y.V.O. All authors have read and agreed to the published version of the manuscript.

Funding

This research was partially funded by the Simons Foundation (Award Number: SFI-PD-Ukraine-00014574) and by the Ministry of Education and Science of Ukraine.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data are contained within the article; further inquiries can be directed to the corresponding authors.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Thakur, S.; Kumar, D.; Jaiswal, S.; Goel, K.K.; Rawat, P.; Srivastava, V.; Dhiman, S.; Jadhav, H.R.; Dwivedi, A.R. Medicinal chemistry-based perspectives on thiophene and its derivatives: Exploring structural insights to discover plausible druggable leads. RSC Med. Chem. 2025, 16, 481–510. [Google Scholar] [CrossRef] [PubMed]
  2. Shah, R.; Verma, P.K. Therapeutic importance of synthetic thiophene. Chem. Cent. J. 2018, 12, 137. [Google Scholar] [CrossRef] [PubMed]
  3. Hamad, H. The anti-cancer effectiveness of some heterocyclic compounds containing sulfur atom. Results Chem. 2025, 15, 102182. [Google Scholar] [CrossRef]
  4. da Cruz, R.M.D.; Mendonça-Junior, F.J.B.; de Mélo, N.B.; Scotti, L.; de Araújo, R.S.A.; de Almeida, R.N.; de Moura, R.O. Thiophene-Based Compounds with Potential Anti-Inflammatory Activity. Pharmaceuticals 2021, 14, 692. [Google Scholar] [CrossRef]
  5. Keddis, P.M.; My Tu, T.K.; Scherer, H.; Kany, A.M.; Hafez, D.E.; Darwish, S.S.; Abadi, A.H.; Hirsch, A.K.H.; Engel, M.; Hamed, M.M. From Dyrk1A inhibitors to a novel class of antiviral agents: Targeting Enterovirus EV-A71 with 2-aryl-substituted thiophene scaffolds. Eur. J. Med. Chem. 2025, 287, 117348. [Google Scholar] [CrossRef]
  6. Zhang, Z.; Ma, C.; Gao, X.; Wang, C.; Li, Y.; Yang, C.; Ma, E.; Cheng, M. Design, synthesis, and biological evaluation of novel 3-naphthylthiophene derivatives as potent SIRT2 inhibitors for the treatment of myocardial fibrosis. Bioorg. Chem. 2025, 154, 108033. [Google Scholar] [CrossRef]
  7. Fernandes, R.S.; Shetty, N.S.; Mahesha, P.; Gaonkar, S.L. A Comprehensive Review on Thiophene Based Chemosensors. J. Fluoresc. 2022, 32, 19–56. [Google Scholar] [CrossRef]
  8. Yang, N.; Zhang, S.; Cui, Y.; Wang, J.; Cheng, S.; Hou, J. Molecular design for low-cost organic photovoltaic materials. Nat. Rev. Mater. 2025, 10, 404–424. [Google Scholar] [CrossRef]
  9. Anan, J.; Fosu, E.A.; Obuah, C.; Ainooson, M.K.; Aniagyei, A.; Hamenu, L.; Oppong, A.; Muller, A. A DFT and TD-DFT studies of the photosensitizing capabilities of thiophene-based dyes. Comput. Theor. Chem. 2024, 1237, 114633. [Google Scholar] [CrossRef]
  10. Sharma, S.J.; Sekar, N. The role of secondary donor in thiophene-based azo dyes for dye-sensitized solar cells and non-linear optics. J. Photochem. Photobiol. A Chem. 2024, 455, 115770. [Google Scholar] [CrossRef]
  11. Zhu, C.; Han, J.; Liang, F.; Zhu, M.; Zhang, G.; James, T.D.; Wang, Z. Advances in multi-target fluorescent probes for imaging and analyzing biomarkers in Alzheimer’s disease. Coord. Chem. Rev. 2024, 517, 216002. [Google Scholar] [CrossRef]
  12. Bonafoux, D.; Bonar, S.; Christine, L.; Clare, M.; Donnelly, A.; Guzova, J.; Kishore, N.; Lennon, P.; Libby, A.; Mathialagan, S. Inhibition of IKK-2 by 2-[(aminocarbonyl)amino]-5-acetylenyl-3-thiophenecarboxamides. Bioorg. Med. Chem. Lett. 2005, 15, 2870–2875. [Google Scholar] [CrossRef] [PubMed]
  13. Zhang, D.; Liu, L.; Li, M.; Hu, X.; Zhang, X.; Xia, W.; Wang, Z.; Song, X.; Huang, Y.; Dong, Z. Development of 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors showing potent antileukemia activities. Eur. J. Med. Chem. 2025, 289, 117444. [Google Scholar] [CrossRef] [PubMed]
  14. Sinha, N.; Karche, N.P.; Verma, M.K.; Walunj, S.S.; Nigade, P.B.; Jana, G.; Kurhade, S.P.; Hajare, A.K.; Tilekar, A.R.; Jadhav, G.R. Discovery of Novel, Potent, Brain-Permeable, and Orally Efficacious Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptor [4-(5-(4-Chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide]: Structure–Activity Relationship and Preclinical Characterization. J. Med. Chem. 2020, 63, 944–960. [Google Scholar] [CrossRef]
  15. Liu, H.; El-Salfiti, M.; Lautens, M. Expeditious Synthesis of Tetrasubstituted Helical Alkenes by a Cascade of Palladium-Catalyzed C–H Activations. Angew. Chem. Int. Ed. 2012, 51, 9846–9850. [Google Scholar] [CrossRef]
  16. Kumar, P.; Panhotra, S.; Muskan; Changotra, A.; Lata, S.; Mehta, A.; Maitra, T.; Gupta, P. Palladium immobilized on functionalized halloysite: A robust catalyst for ligand free Suzuki–Miyaura cross coupling and synthesis of pyrano [2,3-c]pyrazole motifs via four component cascade reaction and their in-silico antitubercular screening. Appl. Catal. A 2025, 689, 120003. [Google Scholar] [CrossRef]
  17. Qiu, J.; Wang, C.; Zhou, L.; Lou, Y.; Yang, K.; Song, Q. Ni-Catalyzed Radical-Promoted Defluoroalkylborylation of Trifluoromethyl Alkenes To Access gem-Difluorohomoallylic Boronates. Org. Lett. 2022, 24, 2446–2451. [Google Scholar] [CrossRef]
  18. Dutta, S.; Maity, A.; Yang, S.; Mallick, R.K.; Gogoi, M.P.; Gandon, V.; Sahoo, A.K. Synthetic Strategy for Unsymmetrical α-Fluoro-α′-aryl Ketones. Org. Lett. 2025, 27, 808–813. [Google Scholar] [CrossRef]
  19. Fredrich, S.; Bonasera, A.; Valderrey, V.; Hecht, S. Sensitive Assays by Nucleophile-Induced Rearrangement of Photoactivated Diarylethenes. J. Am. Chem. Soc. 2018, 140, 6432–6440. [Google Scholar] [CrossRef]
  20. Luo, N.; Liu, L.; Luo, J.; Zhou, Z.; Sun, C.L.; Hua, X.; Luo, L.; Wang, J.; Geng, H.; Shao, X. Alternating Donor-Acceptor Ladder-Type Heteroarene for Efficient Photothermal Conversion via Boosting Non-Radiative Decay. Angew. Chem. Int. Ed. 2025, 64, e202418047. [Google Scholar] [CrossRef]
  21. Barale, M.; Turcas, I.; Gousseau, V.; Escadeillas, M.; Caytan, E.; Taupier, G.; Molard, Y.; Fihey, A.; Boixel, J. Photo-modulation of the two-photon excited fluorescence of dithienylethene bis-(1-pyrenyl) compounds: An experimental and theoretical study. Dyes Pigm. 2025, 232, 112473. [Google Scholar] [CrossRef]
  22. Conboy, G.; Taylor, R.G.D.; Findlay, N.J.; Kanibolotsky, A.L.; Inigo, A.R.; Ghosh, S.S.; Ebenhoch, B.; Jagadamma, L.K.; Thalluri, G.K.V.V.; Sajjad, M.T. Novel 4,8-benzobisthiazole copolymers and their field-effect transistor and photovoltaic applications. J. Mater. Chem. C 2017, 5, 11927–11936. [Google Scholar] [CrossRef]
  23. Malamas, M.S.; Erdei, J.; Gunawan, I.; Barnes, K.; Hui, Y.; Johnson, M.; Robichaud, A.; Zhou, P.; Yan, Y.; Solvibile, W. New pyrazolyl and thienyl aminohydantoins as potent BACE1 inhibitors: Exploring the S2′ region. Bioorg. Med. Chem. Lett. 2011, 21, 5164–5170. [Google Scholar] [CrossRef] [PubMed]
  24. Salamoun, J.M.; McQueeney, K.E.; Patil, K.; Geib, S.J.; Sharlow, E.R.; Lazo, J.S.; Wipf, P. Photooxygenation of an amino-thienopyridone yields a more potent PTP4A3 inhibitor. Org. Biomol. Chem. 2016, 14, 6398–6402. [Google Scholar] [CrossRef] [PubMed]
  25. Alharbi, A.; Alqahtani, A.M.; Mojally, M.; Qarah, A.F.; Alessa, A.H.; Alatawi, O.M.; Attar, R.M.S.; El-Metwaly, N.M. Synthesis of new methylthiourea-thiophene, -thiazole, and -pyrazole conjugates: Molecular modelling and docking studies as antimicrobial agents. J. Mol. Struct. 2024, 1305, 137833. [Google Scholar] [CrossRef]
  26. Alalawy, A.I.; Alatawi, K.; Alenazi, N.A.; Qarah, A.F.; Alatawi, O.M.; Alnoman, R.B.; Alharbi, A.; El-Metwaly, N.M. Synthesis, molecular modeling, and anticancer activity of new thiophene and thiophene-pyrazole analogues incorporating benzene-sulfonamide moiety as carbonic anhydrase isozymes (CA-IX and CA-XII). J. Mol. Struct. 2024, 1295, 136609. [Google Scholar] [CrossRef]
  27. Bolli, M.H.; Velker, J.; Müller, C.; Mathys, B.; Birker, M.; Bravo, R.; Bur, D.; de Kanter, R.; Hess, P.; Kohl, C. Novel S1P1 Receptor Agonists—Part 2: From Bicyclo [3.1.0]hexane-Fused Thiophenes to Isobutyl Substituted Thiophenes. J. Med. Chem. 2014, 57, 78–97. [Google Scholar] [CrossRef]
  28. Bolli, M.H.; Müller, C.; Mathys, B.; Abele, S.; Birker, M.; Bravo, R.; Bur, D.; Hess, P.; Kohl, C.; Lehmann, D. Novel S1P1 Receptor Agonists—Part 1: From Pyrazoles to Thiophenes. J. Med. Chem. 2013, 56, 9737–9755. [Google Scholar] [CrossRef]
  29. Lee, H.S.; Kim, S.H.; Kim, J.N. Regioselective synthesis of poly-substituted thiophenes from Baylis–Hillman adducts. Tetrahedron Lett. 2009, 50, 6480–6483. [Google Scholar] [CrossRef]
  30. Fraňová, P.; Šafář, P.; Moncoľ, J.; Žídeková, I.; Daïch, A.; Marchalín, Š. Diastereoselective Entry to Novel Aminoindolizidines with Fused Furan, Thiophene, and Pyrrole Ring Starting from L-Glutamic Acid. Eur. J. Org. Chem. 2025, 28, e202401219. [Google Scholar] [CrossRef]
  31. Chen, F.; Lai, S.-Q.; Zhu, F.-F.; Meng, Q.; Jiang, Y.; Yu, W.; Han, B. Cu-Catalyzed Radical Cascade Annulations of Alkyne-Tethered N-Alkoxyamides with Air: Facile Access to Isoxazolidine/1,2-Oxazinane-Fused Isoquinolin-1(2H)-ones. ACS Catal. 2018, 8, 8925–8931. [Google Scholar] [CrossRef]
  32. Jones, S.A.; Botello, J.A.; Singh, J.; Damstedt, G.L.; Payne, J.C.; Griffin, E.D.; Osayawe, O.J.; Castle, S.L. Microwave-Promoted Synthesis of 1-Tetralones via Iminyl Radical-Mediated 1,5-Hydrogen Atom Transfer. J. Org. Chem. 2025, 90, 2547–2552. [Google Scholar] [CrossRef] [PubMed]
  33. Wang, T.; An, Z.; Qi, Z.; Zhuang, D.; Chang, A.; Yang, Y.; Yan, R. Ring-opening/annulation reaction of cyclopropyl ethanols: Concise access to thiophene aldehydes via C–S bond formation. Org. Chem. Front. 2019, 6, 3705–3709. [Google Scholar] [CrossRef]
  34. Sathishkannan, G.; Srinivasan, K. [3+3] Annulation of donor–acceptor cyclopropanes with mercaptoacetaldehyde: Application to the synthesis of tetrasubstituted thiophenes. Chem. Commun. 2014, 50, 4062–4064. [Google Scholar] [CrossRef]
  35. Chen, D.; Wan, J.-P.; Liu, Y. Rh-Catalyzed and Self-Directed Aromatic C–H Activation of Enaminones to Divergent Alkenylated and Annulated Compounds. Org. Lett. 2025, 27, 2371–2376. [Google Scholar] [CrossRef]
  36. Filipski, K.J.; Martinez-Alsina, L.A.; Reese, M.R.; Evrard, E.; Buzon, L.M.; Cameron, K.O.; Zhang, Y.; Coffman, K.J.; Bradow, J.; Kormos, B.L. Discovery of First Branched-Chain Ketoacid Dehydrogenase Kinase (BDK) Inhibitor Clinical Candidate PF-07328948. J. Med. Chem. 2025, 68, 2466–2482. [Google Scholar] [CrossRef]
  37. Kim, J.; Jung, Y.K.; Kim, C.; Shin, J.S.; Scheers, E.; Lee, J.-Y.; Han, S.B.; Lee, C.-K.; Neyts, J.; Ha, J.-D. A Novel Series of Highly Potent Small Molecule Inhibitors of Rhinovirus Replication. J. Med. Chem. 2017, 60, 5472–5492. [Google Scholar] [CrossRef]
  38. Mukhopadhyay, S.; Batra, S. Direct Transformation of Arylamines to Aryl Halides via Sodium Nitrite and N-Halosuccinimide. Chemistry 2018, 24, 14622–14626. [Google Scholar] [CrossRef]
  39. Stuhr, R.; Jacobi von Wangelin, A. Organic Photoredox Carbonylation of Arenediazonium under Mild Conditions. Synlett 2024, 35, 1889–1892. [Google Scholar] [CrossRef]
  40. Song, S.; Peng, M.; Zhang, Z.; Hu, H.; Wei, Y.; Yan, S.J.; Wang, Y.; Yu, F. Divergent Synthesis of 2-Chromonyl-3-hydrazono-chromones and 2-Alkoxy-3-hydrazono-chromones through Switchable Annulation Reactions of o-Hydroxyphenylenaminones with Aryldiazonium Salts. Org. Lett. 2024, 26, 4980–4985. [Google Scholar] [CrossRef]
  41. Liu, Q.-H.; Kang, S.-L.; Cui, Z.-S.; Liu, Y.-H.; Zhang, M.; Zhang, Z.-H. Visible light-driven C–H arylation of heteroarenes with aryl diazonium salts in water catalyzed by a Z-scheme CuInS2/K-C3N4 heterojunction. Green Chem. 2024, 26, 4803–4810. [Google Scholar] [CrossRef]
  42. Hari, D.P.; Schroll, P.; König, B. Metal-Free, Visible-Light-Mediated Direct C–H Arylation of Heteroarenes with Aryl Diazonium Salts. J. Am. Chem. Soc. 2012, 134, 2958–2961. [Google Scholar] [CrossRef] [PubMed]
  43. Wang, P.; Yang, Z.; Wang, Z.; Xu, C.; Huang, L.; Wang, S.; Zhang, H.; Lei, A. Electrochemical Arylation of Electron-Deficient Arenes through Reductive Activation. Angew. Chem. Int. Ed. 2019, 58, 15747–15751. [Google Scholar] [CrossRef]
  44. Melchior de Oliveira Leão, L.P.; de Oliveira, V.C.; Duarte Chorro, T.H.; Gorbatov, S.A.; Duarte Correia, C.R. Second-Generation One-Pot Enantioselective Heck-Matsuda Arylations of Unactivated Olefins Directly from Anilines and Nitroarenes. Adv. Synth. Catal. 2025, 367, e202500024. [Google Scholar] [CrossRef]
  45. Herrera, C.L.; Oliveira, R.L.; Silva, R.C.; Correia, C.R.D.; Pastre, J.C. Enantioselective Heterogeneous Heck–Matsuda Reaction with Polymer-Supported PyOx Ligands. Synlett 2024, 35, 1135–1140. [Google Scholar] [CrossRef]
  46. Krause, A.; Sperlich, E.; Schmidt, B. Matsuda–Heck arylation of itaconates: A versatile approach to heterocycles from a renewable resource. Org. Biomol. Chem. 2021, 19, 4292–4302. [Google Scholar] [CrossRef]
  47. Barbero, M.; Dughera, S. Gold catalyzed Heck-coupling of arenediazonium o-benzenedisulfonimides. Org. Biomol. Chem. 2018, 16, 295–301. [Google Scholar] [CrossRef]
  48. Huang, J.; Wang, C.; Wang, X.; Yuan, H.; Li, H.; Zhu, M.; Hu, Z.; Han, Q.-S.; Shi, M. Photoinduced radical sulfur dioxide insertion with asymmetric cyclization of alkenes: Accessing β-chiral sulfones bearing S-stereocentric cyclic sulfinamides. Sci. China Chem. 2025, 68, 257–263. [Google Scholar] [CrossRef]
  49. Antenucci, A.; Barbero, M.; Dughera, S.; Ghigo, G. Copper catalysed Gomberg-Bachmann-Hey reactions of arenediazonium tetrafluoroborates and heteroarenediazonium o-benzenedisulfonimides. Synthetic and mechanistic aspects. Tetrahedron 2020, 76, 131632. [Google Scholar] [CrossRef]
  50. Fu, Y.; Guo, L.-L.; Chen, X.; Chen, H.; Liu, J.-J.; Li, F.-R.; Xiao, C.-Q.; Du, Z. Pd/Cu Co-Catalyzed ortho-Arylation of Aryl Iodides via Radical Intermediates with Aryl Diazonium Salts. Adv. Synth. Catal. 2023, 365, 4248–4255. [Google Scholar] [CrossRef]
  51. Li, J.; Song, B.; Cai, M. Photosensitizer-free, visible light-mediated heterogeneous gold-catalyzed cross-coupling of aryldiazonium salts with allyltrimethylsilane. Synth. Commun. 2024, 54, 478–490. [Google Scholar] [CrossRef]
  52. Song, B.; Li, J.; Hao, W.; Cai, M. External oxidant-free, ligand-assisted heterogeneous gold-catalyzed C(sp2)–C(sp) cross-coupling of aryldiazonium salts with terminal alkynes. Catal. Sci. Technol. 2024, 14, 4354–4365. [Google Scholar] [CrossRef]
  53. Li, J.; Chen, J.; Zhu, H.; Cai, M. Photosensitizer-free, visible light-mediated recyclable gold-catalyzed cross-coupling of aryldiazonium salts and alkynyltrimethylsilanes. New J. Chem. 2023, 47, 14894–14905. [Google Scholar] [CrossRef]
  54. Gao, G.; Han, C.-J.; Liu, Q.-H.; Mo, L.-P.; Zhang, Z.-H. Photocatalytic synthesis of aryltriazenes by CulnS2/K-C3N4 heterojunctions. Mol. Catal. 2025, 572, 114764. [Google Scholar] [CrossRef]
  55. Kindt, S.; Heinrich, M.R. Recent Advances in Meerwein Arylation Chemistry. Synthesis 2016, 48, 1597–1606. [Google Scholar] [CrossRef]
  56. Mo, F.; Qiu, D.; Zhang, L.; Wang, J. Recent Development of Aryl Diazonium Chemistry for the Derivatization of Aromatic Compounds. Chem. Rev. 2021, 121, 5741–5829. [Google Scholar] [CrossRef] [PubMed]
  57. Ostapiuk, Y.V.; Barabash, O.V.; Ostapiuk, M.Y.; Goreshnik, E.; Obushak, M.D.; Schmidt, A. Thiocyanatoarylation of Methyl Vinyl Ketone under Meerwein Conditions for the Synthesis of 2-Aminothiazole-Based Heterocyclic Systems. Org. Lett. 2022, 24, 4575–4579. [Google Scholar] [CrossRef]
  58. Barabash, O.V.; Ostapiuk, M.Y.; Kravets, M.; Obushak, M.D.; Schmidt, A.; Ostapiuk, Y.V. Pyrazol-3-yldiazonium Salts as Key Reagents for C–C Bond Formation and Pyrazole-Containing Heterocycle Synthesis. Synthesis 2025, 57, 2351–2362. [Google Scholar] [CrossRef]
  59. Barabash, O.V.; Ostapiuk, Y.V.; Ostapiuk, M.Y.; Herzberger, C.; Kravets, M.; Schmidt, A. Pyrazolyldiazonium Salts in the Synthesis of 4-Amino-1,3′-bipyrazoles. Eur. J. Org. Chem. 2024, 27, e202301049. [Google Scholar] [CrossRef]
  60. Batsyts, S.; Shehedyn, M.; Goreshnik, E.A.; Obushak, M.D.; Schmidt, A.; Ostapiuk, Y.V. 2-Bromo-2-chloro-3-arylpropanenitriles as C-3 Synthons for the Synthesis of Functionalized 3-Aminothiophenes. Eur. J. Org. Chem. 2019, 48, 7842. [Google Scholar] [CrossRef]
  61. Ostapiuk, Y.V.; Shehedyn, M.; Barabash, O.V.; Demydchuk, B.; Batsyts, S.; Herzberger, C.; Schmidt, A. Bromoarylation of Methyl 2-Chloroacrylate under Meerwein Conditions for the Synthesis of Substituted 3-Hydroxythiophenes. Synthesis 2022, 54, 732–740. [Google Scholar] [CrossRef]
  62. Hreniukh, V.P.; Finiuk, N.S.; Shalai, Y.R.; Manko, B.O.; Manko, B.V.; Ostapiuk, Y.V.; Kulachkovskyy, O.R.; Obushak, M.D.; Stoika, R.S.; Babsky, A.M. Effects of thiazole derivatives on intracellular structure and functions in murine lymphoma cells. Ukr. Biochem. J. 2020, 92, 121–130. [Google Scholar] [CrossRef]
  63. Finiuk, N.S.; Ivasechko, I.I.; Klyuchivska, O.Y.; Ostapiuk, Y.V.; Hreniukh, V.P.; Shalai, Y.R.; Matiychuk, V.S.; Obushak, M.D.; Babsky, A.M.; Stoika, R.S. Apoptosis induction in human leukemia cells by novel 2-amino-5-benzylthiazole derivatives. Ukr. Biochem. J. 2019, 91, 29–39. [Google Scholar] [CrossRef]
  64. Wang, Q.; Yang, X.; Wu, P.; Yu, Z. Photoredox-Catalyzed C–H Arylation of Internal Alkenes to Tetrasubstituted Alkenes: Synthesis of Tamoxifen. Org. Lett. 2017, 19, 6248–6251. [Google Scholar] [CrossRef]
  65. Felipe-Blanco, D.; Gonzalez-Gomez, J.C. Salicylic Acid-Catalyzed Arylation of Enol Acetates with Anilines. Adv. Synth. Catal. 2018, 360, 2773–2778. [Google Scholar] [CrossRef]
  66. Shyyka, O.Y.; Martyak, R.L.; Tupychak, M.A.; Pokhodylo, N.T.; Obushak, M.D. Facile synthetic route to benzo[c]chromenones and thieno [2,3-c]chromenones. Synth. Commun. 2017, 48, 2399–2405. [Google Scholar] [CrossRef]
  67. Felipe-Blanco, D.; Gonzalez-Gomez, J.C. Metal-Free Arylation-Lactonization Sequence of γ-Alkenoic Acids Using Anilines as Aryl Radical Precursors. Eur. J. Org. Chem. 2019, 2019, 7735–7744. [Google Scholar] [CrossRef]
  68. Yao, C.-J.; Sun, Q.; Rastogi, N.; König, B. Intermolecular Formyloxyarylation of Alkenes by Photoredox Meerwein Reaction. ACS Catal. 2015, 5, 2935–2938. [Google Scholar] [CrossRef]
  69. Khan, R.K.M.; Zhao, Y.; Scully, T.D.; Buchwald, S.L. Catalytic Arylhydroxylation of Dehydroalanine in Continuous Flow for Simple Access to Unnatural Amino Acid. Chemistry 2018, 24, 15215–15218. [Google Scholar] [CrossRef]
  70. Raduán, M.; Padrosa, J.; Pla-Quintana, A.; Parella, T.; Roglans, A. Functionalization of the 3-Position of Thiophene and Benzo[b]thiophene Moieties by Palladium-Catalyzed C–C Bond Forming Reactions using Diazonium Salts. Adv. Synth. Catal. 2011, 353, 2003–2012. [Google Scholar] [CrossRef]
  71. Hu, Z.; Belitz, F.; Zhang, G.; Papp, F.; Gooßen, L.J. Ru-Catalyzed (E)-Specific ortho-C–H Alkenylation of Arenecarboxylic Acids by Coupling with Alkenyl Bromides. Org. Lett. 2021, 23, 3541–3545. [Google Scholar] [CrossRef] [PubMed]
  72. Obushak, M.D.; Matiychuk, V.S.; Turytsya, V.V. A new approach to the synthesis of 3,4-dihydroisocoumarin derivatives. Tetrahedron Lett. 2009, 50, 6112–6115. [Google Scholar] [CrossRef]
  73. Turytsya, V.V.; Ostapiuk, Y.V.; Matiychuk, V.V.; Obushak, M.D. Synthesis of 3-Aryl/methoxycarbonyl-3,4-dihydroisocoumarin-6-carboxylic Acid Derivatives. J. Heterocycl. Chem. 2014, 51, 1898–1901. [Google Scholar] [CrossRef]
  74. Mandal, A.; Bera, R.; Baidya, M. Regioselective C–H Alkenylation and Unsymmetrical Bis-olefination of Heteroarene Carboxylic Acids with Ruthenium Catalysis in Water. J. Org. Chem. 2021, 86, 62–73. [Google Scholar] [CrossRef]
  75. González-Gallardo, N.; Saavedra, B.; Guillena, G.; Ramón, D.J. A jackpot C–H activation protocol using simple ruthenium catalyst in deep eutectic solvents. Green Chem. 2022, 24, 4941–4951. [Google Scholar] [CrossRef]
  76. Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Ruthenium-Catalyzed Oxidative Vinylation of Heteroarene Carboxylic Acids with Alkenes via Regioselective C−H Bond Cleavage. Org. Lett. 2011, 13, 706–708. [Google Scholar] [CrossRef]
  77. Suganuma, M.; Kitagawa, D.; Hamatani, S.; Kobatake, S. Effect of substitution position of aryl groups on the thermal back reactivity of aza-diarylethene photoswitches and prediction by density functional theory. Beilstein J. Org. Chem. 2025, 21, 242–252. [Google Scholar] [CrossRef]
  78. Liu, H.; Zhang, H.; Li, M.; Wu, D.; Tang, H.; Zhang, X.; Huang, M.; Zhao, B. Tuning molecular aggregation to enhance photovoltaic performance of polymers by isomerizing benzodithiophene moiety. Synth. Met. 2025, 310, 117783. [Google Scholar] [CrossRef]
  79. Wannberg, J.; Gising, J.; Henriksson, M.; Duy Vo, D.; Sävmarker, J.; Sallander, J.; Gutiérrez-de-Terán, H.; Larsson, J.; Hamid, S.; Ablahad, H. N-(Heteroaryl)thiophene sulfonamides as angiotensin AT2 receptor ligands. Eur. J. Med. Chem. 2024, 265, 116122. [Google Scholar] [CrossRef]
  80. Hampton, C.S.; Sitaula, S.; Billon, C.; Haynes, K.; Avdagic, A.; Wanninayake, U.; Adeyemi, C.M.; Chatterjee, A.; Griffett, K.; Banerjee, S. Rational design of bioorthogonally activatable PROTAC for tumor-targeted protein degradation. J. Med. Chem. 2023, 66, 14843–14852. [Google Scholar] [CrossRef]
  81. Fan, H.; Zhou, Z.; Yu, D.; Sun, J.; Wang, L.; Jia, Y.; Tian, J.; Mi, W.; Sun, H. Selective degradation of BRD4 suppresses lung cancer cell proliferation using GSH-responsive PROTAC precursors. Bioorg. Chem. 2023, 140, 106793. [Google Scholar] [CrossRef]
  82. Karnik, K.S.; Sarkate, A.P.; Lokwani, D.K.; Tiwari, S.V.; Azad, R.; Wakte, P.S. Molecular dynamic simulations based discovery and development of thiazolidin-4-one derivatives as EGFR inhibitors targeting resistance in non-small cell lung cancer (NSCLC). J. Biomol. Struct. Dyn. 2022, 41, 4696–4710. [Google Scholar] [CrossRef] [PubMed]
  83. Xu, S.; Fang, L.; Cai, J.; Fang, S.; Zhu, H.; Lin, F.; Cai, X. Design and discovery of novel heteroaryl substituted pregnenolone derivatives as potent anti-neuroinflammatory agents targeting LPS-stimulated BV-2 microglial cells. Steroids 2025, 216, 109588. [Google Scholar] [CrossRef] [PubMed]
  84. Nazeer, W.; Qamar, M.U.; Rasool, N.; Taibi, M.; Salamatullah, A.M. Synthesis of 2-Ethylhexyl 5-Bromothiophene-2-Carboxylates; Antibacterial Activities against Salmonella Typhi, Validation via Docking Studies, Pharmacokinetics, and Structural Features Determination through DFT. Molecules 2024, 29, 3005. [Google Scholar] [CrossRef] [PubMed]
  85. Romagnoli, R.; Baraldi, P.G.; Remusat, V.; Carrion, M.D.; Cara, C.L.; Preti, D.; Fruttarolo, F.; Pavani, M.G.; Tabrizi, M.A.; Tolomeo, M. Synthesis and Biological Evaluation of 2-(3‘,4‘,5‘-Trimethoxybenzoyl)-3-Amino 5-Aryl Thiophenes as a New Class of Tubulin Inhibitors. J. Med. Chem. 2006, 49, 6425–6428. [Google Scholar] [CrossRef]
  86. Hampton, C.S.; Sitaula, S.; Billon, C.; Haynes, K.; Avdagic, A.; Wanninayake, U.; Adeyemi, C.M.; Chatterjee, A.; Griffett, K.; Banerjee, S. Development and pharmacological evaluation of a new chemical series of potent pan-ERR agonists, identification of SLU-PP-915. Eur. J. Med. Chem. 2023, 258, 115582. [Google Scholar] [CrossRef]
  87. Wan, Z.K.; Lee, J.; Xu, W.; Erbe, D.V.; Joseph-McCarthy, D.; Follows, B.C.; Zhang, Y.L. Monocyclic thiophenes as protein tyrosine phosphatase 1B inhibitors: Capturing interactions with Asp48. Bioorg. Med. Chem. Lett. 2006, 16, 4941–4945. [Google Scholar] [CrossRef]
Molecules 30 03758 g001
Figure 1. Methods for C–C bond formations in position 3 of thiophenes (above). Synthetic potential of the title compounds (below).
Figure 1. Methods for C–C bond formations in position 3 of thiophenes (above). Synthetic potential of the title compounds (below).
Molecules 30 03758 g001
Molecules 30 03758 sch001
Scheme 1. Gram-scale Meerwein halothienylation of unsaturated compounds 3a-h with thiophen-3-yldiazonium salts 2.
Scheme 1. Gram-scale Meerwein halothienylation of unsaturated compounds 3a-h with thiophen-3-yldiazonium salts 2.
Molecules 30 03758 sch001
Molecules 30 03758 sch002
Scheme 2. Synthesis of derivatives of (thiophen-3-yl)acrylic acids.
Scheme 2. Synthesis of derivatives of (thiophen-3-yl)acrylic acids.
Molecules 30 03758 sch002
Molecules 30 03758 sch003
Scheme 3. Hydrolysis of α-chloroesters 5b, 8b, and 12 at 0 °C.
Scheme 3. Hydrolysis of α-chloroesters 5b, 8b, and 12 at 0 °C.
Molecules 30 03758 sch003
Molecules 30 03758 sch004
Scheme 4. Syntheses of 3-thienyl containing derivatives of 2-aminothia(selena)zoles.
Scheme 4. Syntheses of 3-thienyl containing derivatives of 2-aminothia(selena)zoles.
Molecules 30 03758 sch004
Molecules 30 03758 sch005
Scheme 5. Syntheses of 3-thienyl derived thia(selena)zolidines.
Scheme 5. Syntheses of 3-thienyl derived thia(selena)zolidines.
Molecules 30 03758 sch005
Molecules 30 03758 sch006
Scheme 6. Syntheses of 4-amino- and 4-hydroxy-2,3′-bithiophenes.
Scheme 6. Syntheses of 4-amino- and 4-hydroxy-2,3′-bithiophenes.
Molecules 30 03758 sch006
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Ostapiuk, Y.V.; Barabash, O.V.; Ostapiuk, M.Y.; Kravets, M.; Schmidt, A.; Obushak, M.D. 2-(Methoxycarbonyl)thiophen-3-yl-diazonium Salts: Efficient Precursors for the Formation of C–C Bonds in Thiophene-Containing Heterocyclic Systems. Molecules 2025, 30, 3758. https://doi.org/10.3390/molecules30183758

AMA Style

Ostapiuk YV, Barabash OV, Ostapiuk MY, Kravets M, Schmidt A, Obushak MD. 2-(Methoxycarbonyl)thiophen-3-yl-diazonium Salts: Efficient Precursors for the Formation of C–C Bonds in Thiophene-Containing Heterocyclic Systems. Molecules. 2025; 30(18):3758. https://doi.org/10.3390/molecules30183758

Chicago/Turabian Style

Ostapiuk, Yurii V., Oksana V. Barabash, Mary Y. Ostapiuk, Mykola Kravets, Andreas Schmidt, and Mykola D. Obushak. 2025. "2-(Methoxycarbonyl)thiophen-3-yl-diazonium Salts: Efficient Precursors for the Formation of C–C Bonds in Thiophene-Containing Heterocyclic Systems" Molecules 30, no. 18: 3758. https://doi.org/10.3390/molecules30183758

APA Style

Ostapiuk, Y. V., Barabash, O. V., Ostapiuk, M. Y., Kravets, M., Schmidt, A., & Obushak, M. D. (2025). 2-(Methoxycarbonyl)thiophen-3-yl-diazonium Salts: Efficient Precursors for the Formation of C–C Bonds in Thiophene-Containing Heterocyclic Systems. Molecules, 30(18), 3758. https://doi.org/10.3390/molecules30183758

Article Metrics

Back to TopTop