Chapter 1. Strategies for the Synthesis of Heterocycles
Previous methods for the synthesis of heterocycles from arylalkenes
- Synthesis of phthalides from 2-alkenylbenzoic acids
- Synthesis of isochroman-1-ones from 2-alkenylbenzoic acids
- Synthesis of isoindolin-1-ones from 2-alkenylbenzamides
- Synthesis of benzofurans from 2-alkenylphenols
- Synthesis of indoles from 2-alkenylanilines
- Synthesis of benzothiophenes from arylalkenes
Arylalkenes can be ready substrates that are widely used in the synthesis of various types of heterocycles. In this chapter, previously described strategies for the synthesis of heterocycles with arylalkenes will be described. In 2014, the Rueping group reported the synthesis of fluorinated phthalides with 2-vinylbenzoic acids and Selectfluor (Scheme 1-2a).11 Selectfluor reacts with an alkene to generate a fluoro-carbenium intermediate, which then cyclizes to the desired product.
Visible Light-Mediated Synthesis of Phthalides with 2-Alkenylbenzoic Acids Recent advances in visible light-mediated reactions have inspired synthetic chemists to develop elegant strategies for the synthesis of heterocycles. In 2018 and 2021, Wu and Rao independently reported the visible light-mediated synthesis of sulfonated phthalides using the Ir(ppy)3 photocatalyst (Scheme 1-3).13,. Due to their widespread use, the development of efficient strategies for the synthesis of indoles is one of the popular interests of the synthetic community.
Conclusion
Reduced yield was found from the reaction carried out under air (Entry 4) and the reaction did not proceed without electric current (Entry 16). To shed light on the reaction mechanisms, we performed electrochemical measurements with cyclic voltammograms and control experiments (Figure 2-1). To shed light on the reaction mechanism, cyclic voltammogram electrochemical measurements and control experiments were performed (Figure 3-2).
Benzothiophene 12a was not found in the reaction performed under air (entry 17) and the reaction did not proceed without electric current (entry 23). To gain insight into the reaction mechanism, cyclic voltammetry analyzes and control experiments were performed (Figure 3-3). Detailed mechanistic studies were performed, providing insight into the reaction mechanisms.
Chapter 2. Electrosynthesis of Carbonyl-containing Heterocycles from Arylalkenes
Synthesis of phthalides and isochroman-1-ones from 2-alkenylbenzoic acids
- Reaction optimization of synthesis for phthalide
- Substrate scope of phthalides
- Reaction optimization of synthesis for isochroman-1-one
With optimized reaction conditions in hand, we explored the scope with 2-alkenylbenzoic acid 1 with substituents with different electronic effects (Table 2-2). Acids with electron-donating groups showed good yields (2c ~ 2e), while substrates with electron-withdrawing groups such as keto- or trifluoromethyl- showed reduced yields (2g and 2h). Encouraged by the satisfactory results of the electrosynthesis of phthalides, we challenged ourselves to the optimization of the 6-endo-cyclization pathway, which would give isochroman-1-ones (Tables 2-3).
To our delight, electrolysis of 1a at a constant current of 2 mA, with a graphite anode and a graphite cathode in hexafluoroisopropanol (HFIP) solvent in an undivided cell with Bu4NPF6 as electrolyte provided isochroman-1-one 3a in 57% yield (Introduction 2). As a result, isochroman-1-ones were obtained in satisfactory yields from various 2-alkenylbenzoic acids with different functional groups including electron-rich tert-butyl ( 3d ), methoxy ( 3e ), and electron-deficient fluoro ( 3l ) and useful chloride group (3b). Furthermore, b , β -substituted 2-alkenylbenzoic acids gave the corresponding isochroman-1-ones in good yields ( 3i , 3j ) including the valuable spirocyclic compound ( 3j ).
Synthesis of isoindolin-1-ones from 2-alkenylbenzamides
- Reaction optimization of synthesis for isoindolin-1-one
- Substrate scope of isoindolin-1-ones
- Mechanistic investigations and proposed mechanistic pathway
To gain further understanding of the reaction mechanism, cyclic voltammetry analysis and control experiments were performed (Figure 2-2). E )- N -methyl-2-styrylbenzamide 4a was prone to oxidation, showing an oxidation potential of 1.45 V (vs. SCE). This result indicates the possibility of hydrogen atom transfer (HAT) process between Int-4b and acetonitrile solvent. Radical cation Int-4a following the anodic oxidation of 4a (Ep/2ox = 1.45 V vs SCE) gives Int-4b via cyclization and deprotonation.
Conclusion
Experimental data
- General procedures
- Procedures of the mechanistic investigations
- Characterization of products
Upon complete consumption of the benzoic acid starting material, as determined by thin layer chromatography analysis, the electrolysis was terminated. The reaction mixture was transferred to the round-bottom flask and the electrodes were washed several times with ethyl acetate, which was combined in the same round-bottom flask. Upon complete consumption of the benzoic acid starting material, as determined by thin layer chromatography analysis, the electrolysis was terminated.
After full consumption of the benzamide starting material as determined by thin layer chromatography analysis, electrolysis was terminated. The control experiment without electricity revealed that the electron transfer on the electrode surface is the key factor of the reaction (Entry 26). To gain understanding of the reaction mechanism, cyclic voltammetry analysis and control experiments were performed (Figure 3-1). E)-2-styrylphenol 7a was prone to oxidation showing oxidation potential of 1.18 V (versus SCE).
In the presence of the radical scavenger TEMPO or BHT, all reactions were inhibited (Figure 3-1b), indicating that the reaction is a radical pathway. Interestingly, reaction 7a was poorly compatible with electrolytes other than Et4NOT (Table 3-1). Although only a catalytic amount of tosylate is required for the reaction, the reaction was optimized with Et4NOTs as the electrolyte for cost-effectiveness, as Et4NOTs is much cheaper than Bu4NPF6.
The control experiment without electric current showed that electricity was essential for the reaction (entry 17). After complete consumption of the phenolic starting material, as determined by thin layer chromatography analysis, the electrolysis was stopped, diluted with ethyl acetate (10 ml) and saturated NaHCO3 (10 ml) was added. After complete consumption of the aniline starting material, as determined by thin layer chromatography analysis, the electrolysis was stopped, diluted with ethyl acetate (10 ml) and water (10 ml) was added.
After complete consumption of the aniline starting material as determined by thin layer chromatography analysis, electrolysis was terminated, diluted with ethyl acetate (10 mL) and saturated NaHCO3 (10 mL) was added. After full consumption of the disulfide starting material as determined by thin layer chromatography analysis, electrolysis was terminated. Hu, K.; Zhang, Y.; Zhou, Z.; Yang, Y.; Zha, Z.; Wang, Z., Iodine-mediated electrochemical C(sp2)-H-amination: Switchable synthesis of indolines and indoles.
Chapter 3. Electrosynthesis of Heterocycles from Arylalkenes
Synthesis of benzofurans from 2-alkenylphenols
- Reaction optimization of synthesis for benzofuran
- Substrate scope of benzofurans
- Mechanistic investigations and proposed mechanistic pathway
After extensive investigation, the optimized reaction condition was obtained (Et4NOTs, 5 equivalents of sulfuric acid, 1.0 mA and isobutyronitrile), yielding 2-phenylbenzofuran 8a in 77% yield (Table 3-1). The choice of different electrodes, reaction solvent or electrolyte resulted in inferior yields and the reaction under air showed poor performance (entry 25). First, we investigated the electronic effects on the R2 group and found that electron-rich substrates are favored (8b ~ 8g).
Considering the previous report of indole synthesis with 2-alkenylanilines in the presence of the modified Koser reagent via 2- or 3-arylsulfonate indoline intermediates,38 we predicted that the tosylate might aid in benzofuran formation. As a result, 7ab was isolated in unoptimized yield of 23%, suggesting that the radical cation of the oxidized alkene may be blocked by the tosylate. Then, the Koser reagent 7ac which was previously reported to transform alkenes into the corresponding vic-bis(tosyloxy)39 and 2-alkenylanilines into the corresponding indoles38 was added to 7a under i-PrCN solvent (Scheme 3- 2c).
Cyclic voltammetry analysis suggested that 7a may lose an electron on the anodic surface to obtain Int-7a. After the initial formation of Int-7a (Ep/2ox = 1.10 V vs. SCE), the radical cation is captured by tosylate. Oxidation of Int-7d yields Int-7e and then Int-7f via cyclization, which undergoes elimination to yield benzofuran 8a.
Synthesis of indoles from 2-alkenylanilines
- Reaction optimization of synthesis for indole
- Substrate scope of indoles
- Mechanistic investigations and proposed mechanistic pathway
It should be noted that 2-alkenylaniline substrates bearing electron-rich groups on the other side of the aniline moiety gave a mixture of 2- and 3-substituted indoles (10h, 10h', 10i, 10i'), which is a similar result to the previous method reported by the Youn group.26 This result indicates the existence of a carbocation intermediate and a migration process during the reaction.40-42 Encouraged by these results, we further explored the scope with trisubstituted alkenes. Increasing the current to 3 mA did not accelerate the reaction, but only reduced the yield to 60% (entry 19). Electrogenerated acid (EGA) chemistry has been explored by many organic chemists and can be applied to a variety of acid-catalyzed reactions.43 After reviewing a previous report on EGA-catalyzed activation of diaryl disulfide to generate reactive ArS+ species,44 we hypothesized that EGA may participate during the course of the reaction. .
Although isolated yield was diminished and extended reaction time was required to fully consume 11a , the reaction was not completely inhibited and 12a was obtained in a moderate yield of 45% ( Schemes 3–5 ). In conclusion, we developed a cost-effective and sustainable synthesis of benzofurans, indoles and benzothiophenes from arylalkenes under oxidant- and metal-free electrolysis. The experiment was carried out by general procedure (E) for 6.5 hours using (E)-Stilbene instead of 2-alkenylphenol and 1 equiv.
Awasthi, A.; Singh, M.; Rathee, G.; Chandra, R., Recent advances in synthetic methodologies of 3-substituted phthalides and their application to the total synthesis of biologically active natural products. A.; Phillips, K.; Guilbaud, S.; Poelakker, J.; Wirth, T., An easy-to-use electrochemical flow microreactor: Efficient isoindolinone synthesis and flow functionalization. Zeng, F.; Alper, H., Palladium-catalyzed C-S domino coupling/carbonylation reactions: An efficient synthesis of 2-carbonylbenzo[b]thiophene derivatives.
Mitsudo, K.; Matsuo, R.; Yonezawa, T.; Inoue, H.; Mandai, H.; Suga, S., Electrochemical synthesis of thienoacene derivatives: Transition metal-free dehydrogenative C-S.
Synthesis of benzothiophenes from 2-alkenylaryl disulfides
- Reaction optimization of synthesis for benzothiophene
- Substrate scope of benzothiophenes
- Mechanistic investigations and proposed mechanistic pathway
Conclusion
Experimental data
- General procedures
- Procedures of the mechanistic investigations
- DFT calculations
- Characterization of products
The crude mixture was partitioned between ethyl acetate and water, and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were dried over NaSO, filtered and concentrated.
The mixture was diluted with ethyl acetate (10 mL) and washed with a saturated solution of NaHCO3 (10 mL) and dried over Na2SO4, concentrated in vacuo. All DFT calculations were performed in Gaussian software 09 (Rev D.01)51 using the M06-2X function.52 Geometry optimization was performed with the 6-311+g(d,p) basis set for H, C, O , S atoms,53 which were obtained by EMSL basis group exchange.54, 55 Frequency calculations were performed for each optimized geometry at the same level of theory to obtain vibrational frequencies and thermochemical data at 298.15K. For all calculations, the SMD solution model with dichloroethane solvent (ε=10.125) was used.56 Transition states were identified by having an imaginary frequency and the intrinsic reaction coordinate (IRC)57, 58 calculations were performed to link the states of the transition with the relevant mediators.
Xiong, Y.-S.; Zhang, B.; Yu, Y.; Weng, J.; Lu, G., Construction of sulfonyl phthalides via copper-catalyzed oxysulfonylation of 2-vinylbenzoic acids with sodium sulfinates. Zhang, J.; Zhou, K.; Wu, J., Generation of sulfonated isobenzofuran-1(3H)-ones under photocatalysis by the addition of sulfur dioxide. Kou, X.; Li, Y.; Wu, L.; Zhang, X.; Yang, G.; Zhang, W., Palladium-catalyzed aerobic amino oxygenation of alkenes for the preparation of isoindolinones.
Zhang, X.; Cui, T.; Zhao, X.; Liu, P.; Sun, P., Electrochemical Difunctionalization of Alkenes by a Four-Component Reaction Cascade Rearrangement: Rapid Access to Functionalized Imides. Ling, F.; Liu, T.; Xu, C.; He, J.; Zhang, W.; Ling, C.; Liu, L.; Zhong, W., Divergent electrolysis for the controllable coupling of thiols with 1,2-dichloroethane: a mild approach to sulfide and sulfoxide.
