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Article

Expedient Synthesis of Substituted Thieno[3,2-b]thiophenes and Selenopheno[3,2-b]selenophenes Through Cascade Cyclization of Alkynyl Diol Derivatives

by
Yingqi Feng
1,
Xuelin Zhang
1,
Ziqing He
1,
Miaoshan Zhao
1,
Lu Chen
1,
Yibiao Li
1,* and
Xiai Luo
2,*
1
Jiangmen Key Laboratory of Synthetic Chemistry and Cleaner Production, School of Environmental & Chemical Engineering, Wuyi University, Jiangmen 529020, China
2
Hunan Province Key Laboratory for Synthetic Biology of Traditional Chinese Medicine, School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua 418000, China
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(23), 5507; https://doi.org/10.3390/molecules29235507
Submission received: 24 October 2024 / Revised: 19 November 2024 / Accepted: 19 November 2024 / Published: 21 November 2024
(This article belongs to the Special Issue Recent Advances in Domino Reactions)
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Abstract

Thieno[3,2-b]thiophenes are used as key components in optoelectronic materials, porous hydrogen-storage hosts, organic solar cells, and polymer semiconductors. A step-efficient synthetic protocol was proposed herein for obtaining multisubstituted thieno[3,2-b]thiophene and selenopheno[3,2-b]selenophenes in moderate to good yields via the bisulfur/biselenium cyclization of alkynyl diols with I2/Na2S2O3 or selenium. Using this strategy, substitution patterns were obtained for backbone modification in functional materials.

Graphical Abstract

1. Introduction

Efficient, sustainable methods for thienothiophene (TT) synthesis have been increasingly developed because these compounds are crucial in the fields of fine chemicals, biodiagnostics, and electronic and optoelectronic devices. TTs have four regional isomers based on the position of two sulfur atoms: thieno[3,2-b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, and thieno[3,4-c]thiophene [1,2,3,4]. Among these, thieno[3,2-b]thiophene derivatives have garnered considerable interest due to their well-known optoelectronic applications. These are also widely used in organic solar cells, organic field-effect transistors, photovoltaic devices [5,6,7,8], and as porous hydrogen-storage hosts and polymer semiconductors [9,10,11]. However, methods to efficiently construct the core nucleus of this derivative are highly limited, thereby hampering its further research and applications in the material chemistry and fine chemical industries. Therefore, the step-efficiency synthesis of thieno[3,2-b]thiophenes via the direct use of simple, commercial raw materials has gained popularity.
The majority of synthesis strategies for thieno[3,2-b]thiophenes involve multistep synthesis such as nucleophilic substitution and the cyclization reaction. Moreover, 3-bromothiophenes are used as starting materials in these reactions, which usually yield low synthesis efficiency and overall yield (Scheme 1a) [12,13,14,15]. For instance, Rutherford et al. proposed a typical method for thieno[3,2-b]thiophene synthesis where 3-bromothiophene was used as a starting material and subsequently reacted with n-BuLi, sulfur powder, BrCH2COOMe, POCl3, MeONa, and LiOH to obtain the desired products via four-step synthesis. However, more reaction steps were required to synthesize its substituted derivatives [16]. Moreover, multistep synthesis and many additional chemical reagents are required in such methods, thereby hindering the production efficiency and green chemistry requirements. To overcome these limitations, the step-efficiency synthesis method was proposed to produce thieno[3,2-b]thiophenes via the tandem bisulfide cyclization of unsaturated hydrocarbons. To our knowledge, Lozac’h et al. was the first to directly transform alkynyl diols into thieno[3,2-b]thiophenes in 1955 [17,18]. They synthesized only small amounts of thieno[3,2-b]thiophenes using elemental sulfur as a sulfurizing agent; the reaction proceeded in an autoclave and a high temperature of 200 °C (Scheme 1b). Although this method provided very low yields, it is still used to synthesize functional materials due to the advantages of step efficiency [19,20,21]. The trisulfur radical anion (S3•−) is an efficient sulfurization reagent for synthesizing thiophenes via the interaction between sulfur/base [22,23,24,25], Na2S·9H2O [26,27], and K2S [28,29]; an alkaline environment is usually required to obtain S3•−. User-friendly sulfinates are also used as efficient sulfinyl or sulfonyl radicals for radical addition on unsaturated hydrocarbons [30,31,32,33] and C–H/C–X sulfenylation [34,35,36], which better complement S3•− radicals. The Na2S2O3 is generally used to generate acyl-Bunte salts or thiol intermediates [37,38,39]; however, its use in synthesizing sulfur-containing heterocycles has rarely been reported. Based on the sulfur cyclization reaction in our previous work [40,41,42,43], a facile approach was reported herein for producing thieno[3,2-b]thiophenes and selenopheno[3,2-b]selenophenes using Na2S2O3 and Se powder as the efficiency sulfurizing and selenating reagent in good yields (Scheme 1c).

2. Results and Discussion

2,5-Dimethylhex-3-yne-2,5-diol 1a and various sulfur sources were used as the model substrates to optimize the reaction conditions to evaluate this bisulfur cyclization hypothesis (Table 1). A series of experiments was conducted to determine the optimal sulfur sources, solvents, additives, and reaction temperature and time. First, bisulfur cyclization proceeded at a reaction temperature of 150 °C to afford 3,6-dimethylthieno[3,2-b]thiophene 2a in a 21% yield (Table 1, entry 1), consistent with previous reports [17,18]. Then, a series of sulfur sources was tested including S8, potassium ethylxanthate (EtOCS2K), thiourea, K2S, Na2S·9H2O, and Na2S2O3 (Table 1, entries 1–6). The reaction proceeded most efficiently when Na2S2O3 was used as the sulfur reagent, affording the target product 2a in a 31% yield (Table 1, entry 6). However, the reaction yield was not improved by further increasing the number of equivalents of Na2S2O3 (Table 1, entry 7). Surprisingly, when I2 (1 equiv.) was used as an additive, the reaction yield improved considerably (Table 1, entries 8–9). The remaining additive NH4I did not effectively promote bisulfur cyclization (Table 1, entry 10). The results indicated that protonic acids, such as HCl, also promoted bisulfur cyclization and afforded 2a in a 57% yield (Table 1, entry 11). Notably, the yield of 2a decreased to 61% on reducing the amount of I2 (entry 12); in contrast, when the amount of I2 was increased, the yield increased only slightly (entry 13). Using Na2S2O3 as the sulfur reagent and NMP as the solvent afforded 2a in high yields, making them ideal for bisulfur cyclization. The other solvents—DMSO, DMF, DMAc, and CH3COOH—reduced the yield of 2a (Table 1, entries 14–17). The screening of various reaction temperatures revealed that it was crucial for bisulfur cyclization (Table 1, entries 18–19). The yield of 2a decreased slightly when the reaction time was reduced or extended (Table 1, entries 20–21). When the oxidant DDQ was added, the yield of the reaction did not change significantly (Table 1, entry 22). Thus, the optimized reaction conditions were 1a (0.5 mmol), Na2S2O3 (1.0 mmol), and I2 (0.5 mmol) in 2.0 mL of NMP at 140 °C for 8 h (Table 1, entry 20).
Using these optimized reaction conditions (Table 1, entry 20), the versatility of the proposed method for the bisulfur cyclization of various alkynyl diols was validated. The corresponding results are shown in Scheme 2. First, dialkyl alkynyl diols (i.e., 1a, 1-phenyldodec-4-yn-6-ol (1b), and 2-methyl-5-propyloct-3-yne-2,5-diol (1c)) yielded their respective thieno[3,2-b]thiophene products in 59–81% yields (Scheme 2, 2a–2c). These dialkyl alkynyl diols were not derived from isomerization during dehydration and bisulfur cyclization because they follow Zaitsev’s rule for hydroxyl elimination [44]. Subsequently, 2,3,4,5-tetramethyl substituted thieno[3,2-b]thiophene (2d) was obtained in a 79% yield after 8 h. Single-crystal X-ray diffraction analysis was performed to verify the structure of 2d (Scheme 2; CCDC: 2358238). Then, a series of tetrasubstituted thieno[3,2-b]thiophene derivatives with different alkyl combinations was efficiently obtained in moderate yields using high chemo and regioselectivity modes (Scheme 2, 2e–2j). The reactivity of different alkynyl diols containing a cyclic substituent on the alkyl side chains was also investigated. Various cyclohexane substituents were well-tolerated in the reaction, affording thieno[3,2-b]thiophenes in moderate yields (Scheme 2, 2k–2m). The molecular structure of thieno[3,2-b]thiophene 2k was verified via single-crystal X-ray diffraction (CCDC: 2358239). Alkynyl diols with heterocycle substituents on the R3 groups also successfully underwent sulfur cyclization, affording thiophene-substituted thieno[3,2-b]thiophene (2n) and furan-substituted thieno[3,2-b]thiophene (2o) in moderate yields. Subsequently, additional classes of aryl-substituted alkynyl diols were used as starting materials to obtain aryl-substituted thieno[3,2-b]thiophenes. The reaction of aryl-substituted alkynyl diols with sulfur powder afforded acetophenone as the major product, with only thieno[3,2-b]thiophenes in a 3% yield [18]. When the electron-rich aromatic side chains (R3 or R1 group) linked to the hydroxyl group were reacted with I2/Na2S2O3, the corresponding thieno[3,2-b]thiophene products were obtained in 69%yields (Scheme 2, 2p–2r). This reaction tolerated various substituents including –Me and –OMe groups. Bisulfur cyclization also proceeded smoothly when the benzyl substituent was linked to the hydroxyl group, affording triphenyl substituted thieno[3,2-b]thiophenes 2s and 2t in 79% and 77% yields, respectively.
Alkynyl diols 1a and 1d were used as starting materials to synthesize selenopheno[3,2-b]selenophene derivatives. Using Se powder as the “Se” source, selenopheno[3,2-b]selenophenes were afforded under similar reaction conditions. When 2,5-dimethylhex-3-yne-2,5-diol and ethyloct-4-yne-3,6-diol were used as starting materials, selenium cyclization was successfully completed to obtain the corresponding 3,6-disubstituted and 2,3,4,5-tetrasubstituted selenopheno[3,2-b]selenophene 3a and 3b in 69% and 64% yields, respectively (Scheme 3). To confirm the chemical structure of selenopheno[3,2-b]selenophene 3a, the product was crystallized and analyzed via single-crystal X-ray diffraction (CCDC: 2358237).
As an important building block, the newly formed thieno[3,2-b]thiophene 2a was used in various synthetic transformations (Scheme 4). The iodination of thieno[3,2-b]thiophene 2a afforded 2,5-diiodo-3,6-dimethylthieno[3,2-b]thiophene 4a, which could be effectively transformed in transition metal-catalyzed coupling reactions. For instance, 2,5-diiodo-3,6-dimethylthieno[3,2-b]thiophene 4a smoothly reacted with terminal alkynes via Sonogashira coupling to afford 4b and 4d in 78% and 56% yields, respectively. Then, acetylene-substituted thieno[3,2-b]thiophene (4c) was obtained via a desilylation of thieno[3,2-b]thiophene 4b in a 92% yield; 4b is an important organic synthon that can be used in optoelectronic materials. The Pd-catalyzed Suzuki–Miyaura coupling reaction between 4a and phenylboronic acid afforded 3,6-dimethyl-2,5-diphenylthieno[3,2-b]thiophene 4e in a 68% yield. These products can be converted into oligothiophenes that are potentially valuable in optoelectronic materials [45,46].
To investigate the sulfur cyclization mechanism for synthesizing thieno[3,2-b]thiophenes, several control experiments were conducted (Scheme 5). The reaction temperature and time were initially reduced, which yielded iodine alkyne 5a, 5b, thiophene 5c, and thieno[3,2-b]thiophene 2a (Scheme 5a). Then, in the absence of Na2S2O3, 2,5-dimethylhex-3-yne-2,5-diol 1a and I2 underwent iodination at 140 °C to afford 1,4-diiodobut-2-yne 5b in a 78% yield (Scheme 5b). Unfortunately, 1,4-diiodobut-2-yne 5b did not yield 2a under standard reaction conditions, indicating that 5b is not a reaction intermediate (Scheme 5c). The expected product 2a was formed when using 2,5-dimethylhexa-1,5-dien-3-yne as the substrate, suggesting that alkynyldiene may be an intermediate in the reaction (Scheme 5d). Na2S4O6 can be rapidly produced via the redox reaction of Na2S2O3 with I2 under neutral or weakly acidic conditions, as opposed to the iodination of alkynyl diol 1a (Scheme 5e). As Na2S2O3 readily underwent the redox reaction with I2 to afford sodium tetrathionate (Na2S4O6), Na2S4O6 was used in the absence of I2 to obtain thieno[3,2-b]thiophene 2a in a 73% yield (Scheme 5f). This confirms that Na2S4O6 is a key intermediate for generating a reactive sulfur reagent for bisulfur cyclization. To further verify this result, phenylacetylene was reacted with Na2S4O6 under a transition-metal catalysis free condition; the reaction afforded 2,4-diphenylthiophene 5d in a 35% yield, indicating that the process can be completed by the tandem sulfur radical addition to alkynes (Scheme 5g) [47]. The plausible mechanism for the synthesis of 5d is shown in Scheme 5j. Although sulfur cyclization is not an H-abstraction process, deuteration experiments suggested that hydrogen–deuterium exchange occurred during the reaction (Scheme 5h). Nevertheless, this is more likely due to the direct hydrogen-deuterium exchange reaction of the 2-position C(sp2)-H bond of thieno[3,2-b]thiophenes [48,49]. Furthermore, when radical scavengers such as butylated hydroxytoluene (BHT) and 2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) were added, dehydration and cyclization were subdued, and most of the raw materials were recycled. This indicates that sulfur cyclization may proceed via a radical pathway (Scheme 5i).
Based on these control experiments and previous reports, a plausible mechanism was developed (Scheme 6). First, Na2S2O3 reacted with I2 to afford Na2S4O6, which may thermally decompose into reactive sulfur radicals (i–iv) under high-temperature conditions. As the breaking and bonding of sulfur radicals are reversible, the resulting sulfur radical must be sufficiently stable to be captured by the unsaturated bond. Moreover, the sulfite radical anion (i) is relatively stable among the four sulfur radicals reported herein [50,51,52,53,54]. Therefore, i and perthiyl radical (ii) can be obtained via the heterolytic cleavage of Na2S4O6 according to the reaction pathway (Scheme 6, Equation (2)). The dehydrogenation process leads to alkynyldiene intermediate A. Then, the more reactive perthiyl radical (RSS•) was added to C=C double bonds of alkynyldiene A, which gave the intermediate B [55,56,57]. Intermediate B captured a proton from Z-SH or solvents to yield the intermediate C, which subsequently generated a sulfur radical via S–S bond homolysis and released NaO3S2•. In this process, the Z-SH represents any thiol in the medium (sulfide or H2S, etc.). This sulfur radical was intramolecularly added to the C≡C triple bond formation of intermediate D, which immediately underwent radical coupling with the perthiyl radical (ii) to afford intermediate E. This intermediate then underwent a second intramolecular radical cyclization to yield the alkenyl sulfide intermediate F and released NaO3S2•. Finally, thieno[3,2-b]thiophene 2a was produced via sequential H-abstraction and further oxidation aromatization of the intermediate G [28,58,59,60]. It should be noted that although the reaction requires the removal of two molecules of H2O, it is possible that the dehydration process is not simultaneous.

3. Materials and Methods

3.1. General Methods (Chemistry)

The general methods are described in the Supplementary Materials.

3.2. General Procedures for the Preparation of Compounds 2a–2t

A mixture of 2,5-dimethylhex-3-yne-2,5-diol (71 mg, 0.5 mmol), Na2S2O3 (158 mg, 1.0 mmol), I2 (127 mg, 0.5 mmol), and NMP (2 mL) was added successively into a 20 mL Schlenk tube. The Schlenk tube was then immersed in an oil bath at 140 °C with stirring for 8 h. After cooling down to room temperature, the reaction was quenched with 10 mL of brine and extracted with ethyl acetate (2 × 5 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (Hexane, Rf = 0.7) on silica gel, which furnished product 2a (68 mg, 81% yield) as a pale yellow solid. The following compounds 2b–2v were prepared by a similar method, unless otherwise noted.
  • 3,6-Dimethylthieno[3,2-b]thiophene (2a), Yellow solid (68 mg, 81% yield); Rf = 0.7 (Hexane); 1H NMR (500 MHz, CDCl3) δ 6.96 (s, 2H), 2.36 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 140.0 (2C), 130.3 (2C), 121.8 (2C), 14.6 (2C). ESI-HRMS (m/z) [M + H]+ calcd. for C8H9S2+, 169.0140, found: 169.0138.
  • 3-Ethyl-2,6-dimethylthieno[3,2-b]thiophene (2b), Yellow liquid (71 mg, 72% yield); Rf = 0.7 (Hexane); 1H NMR (400 MHz, CDCl3) δ 6.87 (s, 1H), 2.69 (q, J = 7.6 Hz, 2H), 2.48 (s, 3H), 2.34 (s, 3H), 1.27 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 139.3, 136.1, 133.9, 132.2, 129.9, 119.7, 20.9, 14.7, 14.1, 13.4. ESI-HRMS (m/z): [M]+ calcd. for C10H12S2+, 196.0374, found: 196.0368.
  • 2-Ethyl-6-methyl-3-propylthieno[3,2-b]thiophene (2c), Brown liquid (66 mg, 59% yield); Rf = 0.7 (Hexane); 1H NMR (400 MHz, CDCl3) δ 6.87 (s, 1H), 2.86 (q, J = 7.5 Hz, 2H), 2.70–2.62 (m, 2H), 2.34 (s, 3H), 1.82–1.66 (m, 2H), 1.32 (t, J = 7.5 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 142.5, 130.0, 129.9, 119.1, 29.6, 22.4, 22.3, 16.4, 14.7, 14.0. ESI-HRMS (m/z) [M]+ calcd. for C12H16S2+, 224.0688, found: 224.0679.
  • 2,3,5,6-Tetramethylthieno[3,2-b]thiophene (2d), Yellow solid (77 mg, 79% yield); Rf = 0.7 (Hexane); MP: 136–137 °C. 1H NMR (500 MHz, CDCl3) δ 2.45 (s, 6H), 2.21 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 136.1 (2C), 132.0 (2C), 125.3 (2C), 14.0 (2C), 12.5 (2C). ESI-HRMS (m/z) [M + K]+ calcd. for C10H12KS2+, 235.0012, found: 235.0022.
  • 2-Ethyl-5,6-dimethyl-3-propylthieno[3,2-b]thiophene (2e), Brown liquid (87 mg, 73% yield); Rf = 0.7 (Hexane); 1H NMR (400 MHz, CDCl3) δ 2.83 (q, J = 7.5 Hz, 2H), 2.62–2.59 (m, 2H), 2.43 (s, 3H), 2.20 (s, 3H), 1.70 (q, J = 7.5 Hz, 2H), 1.30 (t, J = 7.5 Hz, 3H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 140.3, 136.7, 135.1, 132.2, 129.5, 125.38, 29.7, 22.3, 22.2, 16.5, 14.0, 14.0, 12.5. ESI-HRMS (m/z) [M + H]+ calcd. for C13H19S2+, 239.0923, found: 239.0921.
  • 2,5-Diethyl-3,6-dimethylthieno[3,2-b]thiophene (2f), Yellow solid (83 mg, 74% yield); Rf = 0.7 (Hexane); MP: 79–81 °C. 1H NMR (500 MHz, CDCl3) δ 2.83 (q, J = 7.5 Hz, 4H), 2.23 (s, 6H), 1.30 (t, J = 7.6 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 139.9 (2C), 136.2 (2C), 124.5 (2C), 22.3 (2C), 16.0 (2C), 12.4 (2C). ESI-HRMS (m/z) [M + H]+ calcd. for C12H17S2+, 225.0766, found: 225.0766.
  • 2,6-Diethyl-5-methyl-3-propylthieno[3,2-b]thiophene (2g), Brown liquid (79 mg, 63% yield); Rf = 0.7 (Hexane); 1H NMR (400 MHz, CDCl3) δ 2.83 (q, J = 7.5 Hz, 2H), 2.68–2.58 (m, 4H), 2.44 (s, 3H), 1.75–1.63 (m, 2H), 1.31–1.23 (m, 6H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 140.3, 135.7, 135.5, 131.8, 131.7, 129.4, 29.7, 22.3, 22.1, 20.9, 16.4, 14.0, 13.8, 13.4. ESI-HRMS (m/z) [M + H]+ calcd. for C14H21S2+, 253.1079, found: 253.1077.
  • 2,5-Diisopropyl-3,6-dimethylthieno[3,2-b]thiophene (2h), Yellow solid (93 mg, 74% yield); Rf = 0.7 (Hexane); MP: 141–142 °C. 1H NMR (500 MHz, CDCl3) δ 3.35–3.29 (m, 2H), 2.25 (s, 3H), 1.33 (s, 6H), 1.32 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 146.1 (2C), 135.9 (2C), 123.7 (2C), 28.9 (2C), 24.5 (4C), 12.6 (2C). ESI-HRMS (m/z) [M + H]+ calcd. for C14H21S2+, 253.1079, found: 253.1077.
  • 2,5-Diethyl-3,6-dipropylthieno[3,2-b]thiophene (2i), Brown liquid (101 mg, 72% yield); Rf = 0.7 (Hexane); 1H NMR (500 MHz, CDCl3) δ 2.83 (q, J = 7.5 Hz, 4H), 2.64–2.58 (m, 4H), 1.76–1.64 (m, 4H), 1.29 (t, J = 7.5 Hz, 6H), 0.97 (t, J = 7.4 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 140.4 (2C), 135.7 (2C), 129.5 (2C), 29.7 (2C), 22.3 (2C), 22.2 (2C), 16.5 (2C), 14.1 (2C). ESI-HRMS (m/z) [M + H]+ calcd. for C16H25S2+, 281.1392, found: 281.1391.
  • 2-Ethyl-5-isopropyl-6-methyl-3-propylthieno[3,2-b]thiophene (2j), Brown liquid (92 mg, 69% yield); Rf = 0.7 (Hexane); 1H NMR (500 MHz, CDCl3) δ 3.36–3.22 (m, 1H), 2.83 (q, J = 7.5 Hz, 2H), 2.64–2.60 (m, 2H), 2.23 (s, 3H), 1.71 (q, J = 7.5 Hz, 2H), 1.33–1.27 (m, 9H), 0.98 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 146.1, 140.4, 136.7, 135.0, 129.8, 123.4, 29.8, 28.9, 24.5 (2C), 22.3, 22.2, 16.6, 14.1, 12.6. ESI-HRMS (m/z) [M + H]+ calcd. for C15H23S2+, 267.1236, found: 267.1233.
  • 1,2,3,4,6,7,8,9-Octahydrobenzo[b]benzo[4,5]thieno[2,3-d]thiophene (2k), Yellow solid (77 mg, 62% yield); Rf = 0.7 (Hexane); MP: 126–128 °C. 1H NMR (400 MHz, CDCl3) δ 2.88–2.85 (m, 4H), 2.67–2.63 (m, 4H), 1.97–1.82 (m, 8H). 13C NMR (100 MHz, CDCl3) δ 135.3 (2C), 134.9 (2C), 127.8 (2C), 26.0 (2C), 24.6 (2C), 23.5 (2C), 22.5 (2C). ESI-HRMS (m/z) [M + H]+ calcd. for C14H17S2+, 249.0766, found: 249.0767.
  • 2-Propyl-1,2,3,4,6,7,8,9-octahydrobenzo[b]benzo[4,5]thieno[2,3-d]thiophene (2l), Yellow solid (103 mg, 71% yield); Rf = 0.7 (Hexane); MP: 99–101 °C. 1H NMR (400 MHz, CDCl3) δ 2.95–2.90 (m, 1H), 2.86–2.82 (m, 2H), 2.72–2.66 (m, 1H), 2.64–2.28 (m, 3H), 2.52–2.44 (m, 1H), 2.00–1.95 (m, 1H), 1.92–1.83 (m, 5H),1.52–1.37 (m, 5H), 0.94 (t, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 135.3, 135.2, 127.9, 127.8, 38.1, 34.6, 32.3, 28.9, 26.0, 24.6, 24.3, 23.5, 22.5, 20.1, 14.2. ESI-HRMS (m/z) [M + H]+ calcd. for C17H23S2+, 291.1235, found: 291.1233.
  • 2-(Tert-butyl)-1,2,3,4,6,7,8,9-octahydrobenzo[b]benzo[4,5]thieno[2,3-d]thiophene (2m), Yellow solid (112 mg, 74% yield); Rf = 0.7 (Hexane); MP: 136–138 °C. 1H NMR (400 MHz, CDCl3) δ 2.92–2.84 (m, 3H), 2.78–2.72 (m, 1H), 2.65–2.54 (m, 4H), 2.09–2.05 (m, 1H), 1.92–1.85 (m, 4H), 1.64–1.56 (m, 1H), 1.49–1.38 (m, 1H), 0.98 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 136.2, 135.3, 135.2, 134.5, 127.9, 127.9, 45.5, 32.5, 27.6, 27.3 (3C), 26.0, 25.5, 24.6, 24.1, 23.5, 22.5. ESI-HRMS (m/z) [M + H]+ calcd. for C18H25S2+, 305.1392, found: 305.1391.
  • 3-Methyl-6-(thiophen-2-yl)thieno[3,2-b]thiophene (2n), Black liquid (86 mg, 73% yield); Rf = 0.7 (Hexane); 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.39–7.38 (m, 1H), 7.29–7.28 (m, 1H), 7.13–7.10 (m, 1H), 7.06 (s, 1H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 140.8, 137.5, 136.6, 130.0, 128.7, 127.7, 124.2, 123.8, 122.6, 121.0, 14.6. ESI-HRMS (m/z) [M + H]+ calcd. for C11H9S3+, 236.9861, found: 236.9861.
  • 2-Methyl-5-(6-methylthieno[3,2-b]thiophen-3-yl)furan (2o), Yellow solid (66 mg, 56% yield); Rf = 0.7 (Hexane); MP: 114–116 °C. 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.04 (s, 1H), 6.51 (s, 1H), 6.09 (s, 1H), 2.39 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 151.7, 147.8, 140.6, 129.8, 125.6, 122.5, 118.9, 107.4, 106.8, 14.6, 13.6. ESI-HRMS (m/z) [M + H]+ calcd. for C12H11OS2+, 235.0246, found: 235.0247.
  • 3-Methyl-6-(p-tolyl)thieno[3,2-b]thiophene (2p), Brown solid (73 mg, 68% yield); Rf = 0.5 (Hexane); MP: 135–137 °C. 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.64 (s, 1H), 7.44 (s, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.04 (s, 1H), 2.40 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 140.9, 137.4, 137.1, 135.1, 132.0, 130.0, 129.6 (2C), 126.3 (2C), 122.2, 121.1, 21.2, 14.6. ESI-HRMS (m/z) [M + H]+ calcd. for C14H13S2+, 213.0732, found: 213.0733.
  • 2-Ethyl-6-methyl-3-phenylthieno[3,2-b]thiophene (2q), Yellow liquid (72 mg, 56% yield); Rf = 0.5 (Hexane); 1H NMR (400 MHz, CDCl3) δ 7.56–7.34 (m, 5H), 6.90 (s, 1H), 2.97 (q, J = 7.5 Hz, 2H), 2.38 (s, 3H), 1.33 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 144.1, 139.7, 136.3, 135.3, 130.8, 130.0, 128.7 (2C), 128.6 (2C), 127.4, 120.4, 23.0, 16.7, 14.7. ESI-HRMS (m/z) [M + H]+ calcd. for C15H15S2+, 259.0610, found: 259.0609.
  • 3-(4-Methoxyphenyl)-6-phenylthieno[3,2-b]thiophene (2r), Yellow solid (111 mg, 69% yield); Rf = 0.5 (Hexane); MP: 143–145 °C. 1H NMR (400 MHz, CDCl3) δ 7.89–7.33 (m, 9H), 7.05–6.99 (m, 2H), 3.88 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 159.2, 138.2, 138.1, 134.9, 134.6, 134.5, 128.9 (2C), 127.72 (2C), 127.70, 127.4, 126.5 (2C), 122.2, 120.9, 114.4 (2C), 55.3. ESI-HRMS (m/z) [M + H]+ calcd. for C19H15OS2+, 323.0559, found: 323.0556.
  • 3-Benzyl-6-ethyl-2-phenylthieno[3,2-b]thiophene (2s), Yellow liquid (132 mg, 79% yield); Rf = 0.5 (Hexane); 1H NMR (400 MHz, CDCl3) δ 7.52–7.13 (m, 10H), 6.89 (s, 1H), 4.12 (s, 2H), 2.84–2.77 (m, 2H), 1.28–1.24 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 149.4, 139.1, 139.1, 138.94, 136.1, 134.7, 129.3 (2C), 128.6 (2C), 128.6 (2C), 128.4 (2C), 128.2, 127.6, 126.3, 115.6, 34.2, 24.3, 15.7. ESI-HRMS (m/z) [M + H]+ calcd. for C21H19S2+, 335.0923, found: 335.0919.
  • 3,6-Dibenzyl-2-phenylthieno[3,2-b]thiophene (2t), Yellow liquid (145 mg, 77% yield); Rf = 0.5 (Hexane); 1H NMR (500 MHz, CDCl3) δ 7.51–7.27 (m, 9H), 7.25–7.15 (m, 6H), 6.91 (s, 1H), 4.14 (s, 2H), 4.11 (s, 2H). 13C NMR (125 MHz, CDCl3) δ 145.9, 140.1, 139.7, 139.5, 138.8, 136.1, 133.6, 134.6, 129.3 (2C), 128.6 (2C), 128.6 (2C), 128.5 (2C), 128.4 (2C), 128.2, 127.7 (2C), 126.6, 126.3, 117.5, 37.1, 34.1. ESI-HRMS (m/z) [M]+ calcd. for C26H20S2+, 396.1001, found: 396.0998.

3.3. General Procedures for the Preparation of Compounds 3a–3b

A mixture of 2,5-dimethylhex-3-yne-2,5-diol (71 mg, 0.5 mmol), Se powder (78 mg, 1.0 mmol), I2 (127 mg, 0.5 mmol), and NMP (2 mL) was added successively into a 20 mL Schlenk tube. The Schlenk tube was inserted in a constant temperature and pressure reactor at 140 °C with stirring for 8 h. After the reaction had completed, this was cooled down to room temperature, and quenched with 10 mL of brine and extracted with ethyl acetate (2 × 5 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by medium pressure preparative chromatography (hexane, Rf = 0.7) on silica gel, which furnished product 3a (91.1 mg, 69% yield) as a yellow solid.
  • 3,6-Dimethylselenopheno[3,2-b]selenophene (3a), Yellow solid (87 mg, 69% yield); Rf = 0.7 (Hexane); MP: 96–98 °C. 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 2H), 2.37 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 141.6 (2C), 135.2 (2C), 123.6 (2C), 17.2 (2C). ESI-HRMS (m/z) [M + H]+ calcd. for C8H9Se2+, 252.9148, found: 252.9158.
  • 2,3,5,6-Tetramethylselenopheno[3,2-b]selenophene (3b), Brown solid (85 mg, 64% yield); Rf = 0.7 (Hexane); MP: 101–103 °C. 1H NMR (400 MHz, CDCl3) δ 2.51 (s, 6H), 2.16 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 137.6 (2C), 135.8 (2C), 130.2 (2C), 16.2 (2C), 14.5 (2C). ESI-HRMS (m/z) [M + H]+ calcd. for C10H13Se2+, 280.9461, found: 280.9459.

3.4. Synthesis of 2,5-Diiodo-3,6-dimethylthieno[3,2-b]thiophene 4a

A mixture of 3,6-dimethylthieno[3,2-b]thiophene 2a (336 mg, 2 mmol), chloroform–acetic acid (1:1 v/v, 10 mL) was added to N-iodosuccinimide (NIS) (563 mg, 2.5 mmol) in a 50 mL round bottom flask. The round bottom flask was kept at 40 °C with stirring for 3 h. After the reaction had completed, the reaction quenched with 10 mL of brine and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by medium pressure preparative chromatography (Hexane, Rf = 0.7) on silica gel, which furnished product 4a (512 mg, 61% yield) as a pale yellow solid.
  • 2,5-Diiodo-3,6-dimethylthieno[3,2-b]thiophene (4a), White solid (512 mg, 61% yield); Rf = 0.7 (Hexane); 1H NMR (400 MHz, CDCl3) δ 2.26 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 140.9 (2C), 134.2 (2C), 76.0 (2C), 16.9 (2C).

3.5. Synthesis of ((3,6-Dimethylthieno[3,2-b]thiophene-2,5-diyl)bis(ethyne-2,1-diyl))bis(trimethylsilane) 4b

Under the N2 condition, a mixture of 2,5-diiodo-3,6-dimethylthieno[3,2-b]thiophene 4a (100 mg, 0.24 mmol), ethynyltrimetilsilane (71 mg, 0.72 mmol), PdCl2 (PPh3)2 (17 mg, 10 mol%), CuI (5 mg, 10 mol%), THF (2 mL), and Et3N (1 mL) was added successively into a 20 mL Schlenk tube. The Schlenk tube was then immersed in an oil bath at 60 °C with stirring for 12 h. After cooling down to room temperature, the solution was filtered through a small amount of silica gel. The residue was then concentrated in vacuo and the crude was purified by medium pressure preparative chromatography with n-hexane to afford the 3,6-dimethyl-2,5-bis(phenylethynyl)thieno[3,2-b]thiophene 4b (67 mg, 78% yield) as a yellow solid.
  • ((3,6-Dimethylthieno[3,2-b]thiophene-2,5-diyl)bis(ethyne-2,1-diyl))bis(trimethylsilane) (4b), Yellow solid (67 mg, 78% yield); MP:157–158 °C. Rf = 0.7 (Hexane); 1H NMR (400 MHz, CDCl3) δ 2.35 (s, 6H), 0.27 (s, 18H). 13C NMR (100 MHz, CDCl3) δ 138.0 (2C), 135.7 (2C), 121.2 (2C), 103.5 (2C), 97.6 (2C), 14.0 (2C), 0.0 (6C). ESI-HRMS (m/z) [M + Na]+ calcd. for C18H24NaS2Si2+, 383.0750, found: 383.0752.

3.6. Synthesis of 2,5-Diethynyl-3,6-dimethylthieno[3,2-b]thiophene 4c

Under the N2 condition, a mixture of (3,6-dimethylthieno[3,2-b]thiophene-2,5-diyl)bis(ethyne-2,1-diyl))bis(trimethylsilane) 4b (180 mg, 0.5 mmol), CH3OH (2 mL), and K2CO3 (1 mmol) was added successively into a 20 mL Schlenk tube. The Schlenk tube was then at room temperature stirring for 3 h. The solution was filtered through a small amount of silica gel. Then the residue was concentrated in vacuo and the crude was purified by medium pressure preparative chromatography with n-hexane to afford the 2,5-diethynyl-3,6-dimethylthieno[3,2-b]thiophene 4c in 92% yield.
  • 2,5-Diethynyl-3,6-dimethylthieno[3,2-b]thiophene (4c), White solid (46 mg, 92% yield); Rf = 0.5 (Hexane); MP:123–124 °C. 1H NMR (400 MHz, CDCl3) δ 3.62 (s, 2H), 2.39 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 138.1 (2C), 136.2 (2C), 120.2 (2C), 85.5 (4C), 13.9 (2C). ESI-HRMS (m/z) [M + Na]+ calcd. for C24H16NaS2+, 238.9960, found: 238.9951.

3.7. Synthesis of 3,6-Dimethyl-2,5-bis(phenylethynyl)thieno[3,2-b]thiophene 4d

Under the N2 condition, a mixture of 2,5-diiodo-3,6-dimethylthieno[3,2-b]thiophene 4a (100 mg, 0.24 mmol), ethynylbenzene (97 mg, 0.96 mmol), PdCl2 (PPh3)2 (17 mg, 10 mol%), CuI (5 mg, 10 mol%), THF (2 mL), and Et3N (1 mL) was added successively into a 20 mL Schlenk tube. The Schlenk tube was then immersed in an oil bath at 60 °C with stirring for 12 h. After cooling down to room temperature, the solution was filtered through a small amount of silica gel. The residue was then concentrated in vacuo and the crude was purified by medium pressure preparative chromatography with n-hexane to afford the 3,6-dimethyl-2,5-bis(phenylethynyl)thieno[3,2-b]thiophene 4d in 56% yield as a yellow solid.
  • 3,6-Dimethyl-2,5-bis(phenylethynyl)thieno[3,2-b]thiophene (4d), Yellow solid (49 mg, 56% yield); Rf = 0.7 (Hexane); MP:137–139 °C. 1H NMR (400 MHz, CDCl3) δ 7.57–7.52 (m, 4H), 7.40–7.33 (m, 6H), 2.46 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 138.5 (2C), 134.9 (2C), 131.3 (4C), 128.4 (2C), 128.4 (4C), 122.9 (2C), 121.0 (2C), 97.5 (2C), 82.9 (2C), 14.1 (2C). ESI-HRMS (m/z) [M + Na]+ calcd. for C24H16NaS2+, 391.0586, found: 391.0580.

3.8. Synthesis of 3,6-Dimethyl-2,5-diphenylthieno[3,2-b]thiophene 4e

Under the N2 condition, a mixture of 2,5-diiodo-3,6-dimethylthieno[3,2-b]thiophene 4a (100 mg, 0.24 mmol), phenylboric acid (88 mg, 0.72 mmol), Pd (PPh3)4 (55 mg, 20 mol%), Cs2CO3 (157 mg, 2 equiv.), THF (2 mL), and H2O (0.2 mL) was added successively into a 20 mL Schlenk tube. The Schlenk tube was then immersed in an oil bath at 60 °C with stirring for 12 h. After the reaction had completed, the reaction was quenched with 10 mL of brine and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum, and the crude was purified by medium pressure preparative chromatography with n-hexane to afford the 3,6-dimethyl-2,5-diphenylthieno[3,2-b]thiophene 4e in 68% yield as a yellow solid.
  • 3,6-Dimethyl-2,5-diphenylthieno[3,2-b]thiophene (4e), Yellow solid (67 mg, 68% yield); Rf = 0.7 (Hexane); MP:168–170 °C. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.3 Hz, 4H), 7.45 (t, J = 7.6 Hz, 4H), 7.36 (d, J = 7.9 Hz, 2H), 2.44 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 139.1 (2C), 138.1 (2C), 135.1 (2C), 129.1 (4C), 128.6 (4C), 127.4 (2C), 125.8 (2C), 14.0 (2C). ESI-HRMS (m/z) [M + H]+ calcd. for C20H17S2+, 321.0766, found: 321.0761.

3.9. Synthesis of 2,5-Diiodo-2,5-dimethylhex-3-yne 5b

A mixture of 2,5-dimethylhex-3-yne-2,5-diol (71 mg, 0.5 mmol), I2 (254 mg, 1.0 mmol), and NMP (2 mL) was added successively into a 20 mL Schlenk tube. The Schlenk tube was then immersed in an oil bath at 140 °C with stirring for 8 h. After cooling down to room temperature, the reaction was quenched with 10 mL of brine and extracted with ethyl acetate (3 × 5 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by medium pressure preparative chromatography (hexane/EtOAc = 30:1, Rf = 0.6) on silica gel, which furnished product 5b (141 mg, 78% yield) as a yellow liquid.
  • 2,5-Diiodo-2,5-dimethylhex-3-yne (5b), Yellow liquid (141 mg, 78% yield); Rf = 0.6 (Hexane/EtOAc = 30:1); 1H NMR (400 MHz, CDCl3) δ 1.36 (s, 12H). 13C NMR (100 MHz, CDCl3) δ 113.0 (2C), 91.2 (2C), 28.9 (42C). ESI-HRMS (m/z) [M + Na]+ calcd. for C8H12NaI2+, 384.8921, found: 384.8926.

3.10. Synthesis of 2,4-Diphenylthiophene 5d

A mixture of ethynylbenzene (51 mg, 0.5 mmol), Na2S4O6·2H2O (460 mg, 1.5 mmol), and NMP (2 mL) was added successively into a 20 mL Schlenk tube. The Schlenk tube was then immersed in an oil bath at 140 °C with stirring for 8 h. After cooling down to room temperature, the reaction was quenched with 10 mL of brine and extracted with ethyl acetate (2× 5 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by medium pressure preparative chromatography (hexane, Rf = 0.7) on silica gel, which furnished 2,4-diphenylthiophene product 5d (20.6 mg, 35% yield) as a pale yellow solid.
  • 2,4-Diphenylthiophene (5d), Yellow solid (20.6 mg, 35% yield); Rf = 0.5 (Hexane); 1H NMR (400 MHz, CDCl3) δ 7.67–7.61 (m, 4H), 7.60 (s, 1H), 7.44–7.39 (m, 5H), 7.33–7.31 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 145.0, 143.1, 135.9, 134.3, 128.9 (2C), 128.8 (2C), 127.7, 127.3, 126.3 (2C), 125.8 (2C), 122.3, 119.7. ESI-HRMS (m/z) [M + H]+ calcd. for C16H13S+, 237.0732, found: 237.0734.

3.11. Synthesis of 3,6-Dimethylthieno[3,2-b]thiophene-2,5-d2 2a-D

A mixture of 2,5-dimethylhex-3-yne-2,5-diol 1a (71 mg, 0.5 mmol), Na2S2O3 (158 mg, 1.0 mmol), I2 (127 mg, 0.5 mmol), D2O (0.5 mL), and NMP (2 mL) was added successively into a 20 mL Schlenk tube. The Schlenk tube was then immersed in an oil bath at 140 °C with stirring for 8 h. After cooling down to room temperature, the reaction was quenched with 10 mL of brine and extracted with ethyl acetate (2 × 5 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by medium pressure preparative chromatography (hexane, Rf = 0.7) on silica gel, which furnished product 2a-D (47.6 mg, 56% yield) with 27% deuteration as a yellow solid.
  • 3,6-Dimethylthieno[3,2-b]thiophene-2,5-d2 (2a-D), Yellow solid (68 mg, 81% yield); Rf = 0.7 (Hexane); 1H NMR (400 MHz, CDCl3) δ 6.96 (s, 1.68H), 2.36 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 140.0 (2C), 130.3 (2C), 121.8 (2C), 14.6 (2C). 2H NMR (77 MHz, CH2Cl2) δ 6.96 (s, 2D).

4. Conclusions

In conclusion, a method for synthesizing multisubstituted thieno[3,2-b]thiophene and selenopheno[3,2-b]selenophene derivatives using alkynyl diols and Na2S2O3 and selenium under transition metal-free conditions was proposed herein. The proposed method used iodine-mediated dehydration and sulfur cyclization to afford various functionalized thieno[3,2-b]thiophenes and selenopheno[3,2-b]selenophenes in moderate to good yields. The existing synthesis methods use 3-halothiophenes as starting materials and require multistep synthesis as well as several additional chemical reagents. In contrast, the proposed method is economical and easily yields alkynyl diols for thieno[3,2-b]thiophene synthesis with step efficiency. In this cyclization process, the role of I2 may be to react with Na2S2O3 to generate sulfur radicals, while Na2S4O6 alone can decompose to give sulfur radicals under reaction conditions. Therefore, this sulfur cyclization reaction can be effectively achieved using either the I2/Na2S2O3 or Na2S4O6 system. We aim to apply the proposed method to synthesize thieno[3,2-b]thiophene core molecules and expand their applicability in optoelectronic materials.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29235507/s1, NMR spectra of compounds 2a–2t, 3a–3b and 4a–4e, 5b, 5d. HRMS for compounds 2a–2t, 3a–3b, and 4a–4e, 5b, 5d. References [42,61,62,63] are cited in the Supplementary Materials.

Author Contributions

Y.L. and X.L. conceived the idea of the synthesis of thieno[3,2-b]thiophenes and selenopheno[3,2-b]selenophenes. Y.F., X.Z., Z.H. and M.Z. performed the experiments, colected, and analyzed the data. L.C., X.L. and Y.L. revised the manuscript and discussed the mechanistic details. All authors have read and agreed to the published version of the manuscript.

Funding

We gratefully acknowledge the Foundation of the Department of Education of Guangdong Province (2019KZDXM052) for the financial support.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data are available from the authors.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 05507 sch001
Scheme 1. Previous methods for synthesis of thieno[3,2-b]thiophene (a,b) and sulfur cyclization hypothesis (c).
Scheme 1. Previous methods for synthesis of thieno[3,2-b]thiophene (a,b) and sulfur cyclization hypothesis (c).
Molecules 29 05507 sch001
Molecules 29 05507 sch002
Scheme 2. Substrate scope of alkynyl diol derivatives. Reaction condition: alkynyl diol 1 (0.5 mmol), Na2S2O3 (1.0 mmol), I2 (0.5 mmol), and NMP (2 mL) stirred at 140 °C for 8 h in a sealed tube under an air atmosphere. Isolated yields.
Scheme 2. Substrate scope of alkynyl diol derivatives. Reaction condition: alkynyl diol 1 (0.5 mmol), Na2S2O3 (1.0 mmol), I2 (0.5 mmol), and NMP (2 mL) stirred at 140 °C for 8 h in a sealed tube under an air atmosphere. Isolated yields.
Molecules 29 05507 sch002
Molecules 29 05507 sch003
Scheme 3. Synthesis of selenopheno[3,2-b]selenophenes. (a) Synthesis of 3,6-dimethylselenopheno[3,2-b]selenophene 3a. (b) Synthesi of 2,3,5,6-tetramethylselenopheno[3,2-b]selenophene 3b.
Scheme 3. Synthesis of selenopheno[3,2-b]selenophenes. (a) Synthesis of 3,6-dimethylselenopheno[3,2-b]selenophene 3a. (b) Synthesi of 2,3,5,6-tetramethylselenopheno[3,2-b]selenophene 3b.
Molecules 29 05507 sch003
Molecules 29 05507 sch004
Scheme 4. Synthetic modifications of thienothiophene 2a.
Scheme 4. Synthetic modifications of thienothiophene 2a.
Molecules 29 05507 sch004
Molecules 29 05507 sch005
Scheme 5. Control experiments. (a) Intermediate detection reaction. (b) Iodination of 2,5-dimethylhex-3-yne-2,5-diol. (c) Sulfur cyclization of 1,4-diiodobut-2-yne. (d) Sulfur cyclization of 2,5-dimethylhexa-1,5-dien-3-yne. (e) Redox reaction of Na2S2O3 with I2. (f) Na2S4O6 reaction with 2,5-dimethylhex-3-yne-2,5-diol give thieno[3,2-b]thiophene. (g) Sulfur cyclization of phenylacetylene with Na2S4O6. (h) Deuteration experiments. (i) Radical inhibition reaction. (j) Proposed reaction mechanism for synthesis of 5d.
Scheme 5. Control experiments. (a) Intermediate detection reaction. (b) Iodination of 2,5-dimethylhex-3-yne-2,5-diol. (c) Sulfur cyclization of 1,4-diiodobut-2-yne. (d) Sulfur cyclization of 2,5-dimethylhexa-1,5-dien-3-yne. (e) Redox reaction of Na2S2O3 with I2. (f) Na2S4O6 reaction with 2,5-dimethylhex-3-yne-2,5-diol give thieno[3,2-b]thiophene. (g) Sulfur cyclization of phenylacetylene with Na2S4O6. (h) Deuteration experiments. (i) Radical inhibition reaction. (j) Proposed reaction mechanism for synthesis of 5d.
Molecules 29 05507 sch005
Molecules 29 05507 sch006
Scheme 6. Proposed reaction mechanism.
Scheme 6. Proposed reaction mechanism.
Molecules 29 05507 sch006
Table 1. Optimization reaction conditions (a).
Table 1. Optimization reaction conditions (a).
Molecules 29 05507 i001
EntryS SourcesSolventsAdditives (mmol)Yields (%) (b)
1S8NMP 21
2EtOCS2KNMP trace
3ThioureaNMP 16
4K2SNMP trace
5Na2S·9H2ONMP trace
6Na2S2O3NMP 31
7 (c)Na2S2O3NMP 33
8S8NMPI2 (0.5)63
9Na2S2O3NMPI2 (0.5)79
10Na2S2O3NMPNH4I (0.5)13
11Na2S2O3NMPHCl (1 M, 0.5 mL)57
12Na2S2O3NMPI2 (0.25)61
13Na2S2O3NMPI2 (0.75)77
14Na2S2O3DMSOI2 (0.5)12
15Na2S2O3DMFI2 (0.5)45
16Na2S2O3DMAcI2 (0.5)61
17Na2S2O3AcOHI2 (0.5)trace
18 (d)Na2S2O3NMPI2 (0.5)82
19 (e)Na2S2O3NMPI2 (0.5)55
20 (f)Na2S2O3NMPI2 (0.5)81
21 (g)Na2S2O3NMPI2 (0.5)80
22 (h)Na2S2O3NMPI2 (0.5)78
(a) Reaction conditions: 2,5-dimethylhex-3-yne-2,5-diol 1a (0.5 mmol), sulfur source (1.0 mmol), solvent (2 mL), and an additive at 150 °C for 10 h in a sealed tube under an air atmosphere. (b) Isolated yields. (c) sulfur source (1.50 mmol); (d) 140 °C, (e) 130 °C, (f) 140 °C, 8 h, (g) 140 °C, 12 h; (h) DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) (0.5 mmol) was added.
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Feng, Y.; Zhang, X.; He, Z.; Zhao, M.; Chen, L.; Li, Y.; Luo, X. Expedient Synthesis of Substituted Thieno[3,2-b]thiophenes and Selenopheno[3,2-b]selenophenes Through Cascade Cyclization of Alkynyl Diol Derivatives. Molecules 2024, 29, 5507. https://doi.org/10.3390/molecules29235507

AMA Style

Feng Y, Zhang X, He Z, Zhao M, Chen L, Li Y, Luo X. Expedient Synthesis of Substituted Thieno[3,2-b]thiophenes and Selenopheno[3,2-b]selenophenes Through Cascade Cyclization of Alkynyl Diol Derivatives. Molecules. 2024; 29(23):5507. https://doi.org/10.3390/molecules29235507

Chicago/Turabian Style

Feng, Yingqi, Xuelin Zhang, Ziqing He, Miaoshan Zhao, Lu Chen, Yibiao Li, and Xiai Luo. 2024. "Expedient Synthesis of Substituted Thieno[3,2-b]thiophenes and Selenopheno[3,2-b]selenophenes Through Cascade Cyclization of Alkynyl Diol Derivatives" Molecules 29, no. 23: 5507. https://doi.org/10.3390/molecules29235507

APA Style

Feng, Y., Zhang, X., He, Z., Zhao, M., Chen, L., Li, Y., & Luo, X. (2024). Expedient Synthesis of Substituted Thieno[3,2-b]thiophenes and Selenopheno[3,2-b]selenophenes Through Cascade Cyclization of Alkynyl Diol Derivatives. Molecules, 29(23), 5507. https://doi.org/10.3390/molecules29235507

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