C-bonds can be formed by oxidative cross-coupling that undergoes a direct reaction at C-H/C-H, and since oxidative cross-coupling does not require pre-functionalization and only H2 emerges as a by-product, research has been done to develop a new efficient synthesis method . We have developed two different types of oxidative reactions: 1) metal-free iodine-mediated reaction 2) electrochemical cycloaddition of hydrogen atom transfer. The electrochemical cycloaddition of hydrogen atom transfer is the mild and efficient reaction without the use of transition metals or oxidizing agents.
Both routes resulted in highly selective radical-radical cross-coupling with reactive radical intermediates toward indolopyran and 2,3-dihydrofuran.
Oxidative cross-coupling reactions
Iodine mediated C-C bond formation
Peroxide oxidizes iodine to form hypoiodic acid (HOI), which can be used as an oxidant (Scheme 1-5). Furan or dihydrofuran derivatives are synthesized after addition of intramolecular radicals followed by oxidation. In addition, the tertiary amine can be oxidized by hypoiodic acid to form iminium iodide (Scheme 1-6).
The N-methyl group is converted into iminium iodide, which undergoes intramolecular cycloaddition and oxidation to form indolequinone13.
Electrochemistry in organic synthesis
Direct electrolysis between the substrate and the electrode surface is a heterogeneous electron transfer (ET) process. Some of the resulting reactive intermediates diffuse into the bulk solution and participate in the next reaction. The first mediator, a chromium salt, was developed for the quinone synthesis in 1900,20 and other mediators such as triarylamine21 and N-oxyradical22 were developed in the 1970s and 1980s.
At the end of the 20th century, the groups of Steckhan, Little23, 24, Schafer25 and Moeller26 reported on electrochemical cyclization to synthesize more complex molecules.
Hydrogen atom transfer in electrochemistry
The enantioselectivity of the reaction can be improved by using the chiral ligand, tetrafluorobenzobarrelene (Fc-tfb*) substituted with a ferrocenyl group. The reaction between NAI and C/O/S nucleophiles catalyzed by Pd(II)/Ag(I) catalyst systems or multimetallic Ir-Sn3 complexes was reported by the Pratihar44 and Roy45 group (Scheme 1-22). In 2007, the Yoshida group developed the reaction of the NAI "cation pool" with organometallic compounds (Scheme 1-32)58.
With optimized conditions, we performed the reaction with various compounds 1 and active methylene (AMC) 2 (Table 2-1). First, to investigate the reaction intermediate, 3'a was synthesized and a standard reaction was performed with half the amount of iodine (Scheme 2-1a (i)). To investigate the formation of the radical intermediate 1a, the reaction between the anion 1'a and the well-known Togni reagent as an electron acceptor was carried out (Scheme 2-1b).
Similar to the reaction with indole 1, other types of AMC were also well tolerated (5h and 5i). A solution of enamine 4 (0.1 mmol, 1.0 equiv) in anhydrous acetonitrile was then added under nitrogen and the reaction mixture was stirred at room temperature. As the loading amount of nBu4NN3 was decreased, the reaction yield decreased (Table 3-1, entry 16).
Depending on the reaction temperature, dihydroaristolactam and aristolactam derivatives could be synthesized by Pd-mediated cross-coupling using functionalized lactam 3ai (Scheme 3-1b). We performed control experiments and density functional theory (DFT) calculations to investigate the reaction mechanism. The reaction was completely inhibited by the radical scavenger, 2,6-di-tert-butyl-4-methylphenol (BHT), and the 1α-BHT adduct was detected by HRMS (Scheme 3-2b).
We performed the current on/off experiment (Scheme 3-3 and Figure 3-3) and found that the reaction mainly proceeds via a non-chain mechanism. Similar to the reaction with the alkene, this reaction without azide provided only trace amounts of 9aa and 8'aa in 18% yield (Scheme 3-4a). When the reaction was determined to be complete by TLC, MeOH (0.05 M) was added and the solvent was removed under reduced pressure.
Biologically active γ-lactam derivatives
Previous functionalization methods for γ-lactam derivatives
Electrochemical α-amido functionalization methods
The binary system of stoichiometric benzylsilane and catalytic benzylstannane showed new possibilities for the reaction of organometallic compounds. After establishing the substrate scope of indolopyran 3 , we investigated the reaction between acetylacetone 2a and enamine 4a instead of 1a . The cathodic reduction of tert-butyl peroxide produces the more basic tert-butoxide, which encourages the reaction.
After completion of the reaction, the reaction mixture was diluted with DCM, washed with saturated NaHCO3, dried and concentrated in vacuo.
Chapter 2. Synthesis of dihydropyran[4,3-b]indole and 2,3-Dihydrofurans based on Oxidative
Iodine-mediated oxidative cross-coupling reaction
- Substrate scope
- Mechanistic studies
- Proposed mechanism
It was found that N-H-indole 1g was well tolerated, while other substituent groups including benzyl, aryl and acetyl reduced the reaction yield (3h-3j). Instead of acetylacetone 2a, the reaction proceeds smoothly with ketoester, ketosulfone, and ketophosphonate to synthesize the various substituted 2,3-dihydrofurans (5h-5j). It was found to yield 3a in 97% yield, indicating that 3′a is an intermediate in the formation of 3a.
On the other hand, the RRCC between the 4′′a and 2′′a affords 5′a, which undergoes oxa-Michael addition to generate 2,3-dihydrofuran 5a (Figure 2-2b).
Electrochemical hydrogen atom transfer mediated reaction
- Reaction optimization
- Substrate scope
- Mechanistic studies
- Proposed mechanism
Synthetic application
Substrate synthesis
They used NHPI as a HAT mediator to form benzyl radicals which were iodinated by iodine. The use of HAT mediator allows the reaction to proceed under relatively low potential which does not affect the iodine compounds. Using sodium iodide as HAT mediator, we were able to form indole radical intermediate that reacts with AMC radical.
Chlorine radical abstracts hydrogen from C(sp3)-H to form the carbon radical, which undergoes Minisci-type reaction with the heteroarene. In addition, they found that Grignard reagent can be used as a nucleophile in the “cation pool” method55. The resulting alkyl radical undergoes radical addition to NAI to form a radical cation intermediate.
Conclusions
The desired indole lonate derivatives 1 were synthesized in high yield with substituted indole and diazo compounds.
Procedure
After complete consumption of the indole starting material, as determined by thin layer chromatography analysis, the electrolysis was completed, the solvent was removed under reduced pressure.
Experimental data
In the case of electrolyte, nBu4NPF6 also performed the reaction, as did nBu4NBF4, but when LiClO4 was used, the conversion rate of the starting material 1a decreased (Table 3-1, entries 4 and 5). The reaction proceeded in DMF, a polar aprotic solvent, but no product was obtained in polar protic MeOH or nonpolar solvent DCM. The desired product 3aa was not obtained without nBu4NN3 or electricity, indicating that the reaction is an azide-mediated electrocatalytic reaction (Table 3-1, entries 17 and 18).
In addition to methyl ester, other electron-withdrawing groups such as ketone, amide, nitrile, phosphonate, phenylsulfone, and sulfonamide-substituted alkenes proceed the reaction well (3aw-3aac). Although an initial experiment using 1a and 8a as substrates gave sulfonamide 9aa in 33% yield under the standard conditions of the reaction with alkenes, a much improved 75% yield was obtained when carried out at a higher concentration of 0.1 M. For to determine the role of nBu4NN3, we ran the reaction without azide and found no conversion of 1a (Scheme 3-2a).
These experimental results support the reaction involving HAT from the azido radical formed by oxidation of azide. When the current is turned off, the reaction continues slightly, suggesting that a chain mechanism may also be involved to a small extent. On the other hand, to elucidate the reaction mechanism between 1a and 8a, we performed the DFT calculation to compare the energy barrier between radical–radical coupling pathway a and radical addition pathway b (Figures 3–6b).
Prepare according to the general procedure (D) using 2-methylisoindolin-1-one 1a (0.4 mmol, 1.0 equiv.) and (E)-N-(4-bromobenzylidene)-4-methylbenzenesulfonamide 8f (3 equiv.). Prepare according to the general procedure (D) using 2-methylisoindolin-1-one 1a (0.4 mmol, 1.0 equiv.) and (E)-4-methyl-N-(thiophen-2-ylmethylene)benzenesulfonamide 8i (3 equiv.) ).
Chapter 3. Electrochemical C(sp 3 )-H Functionalization of ɣ-Lactams based on Hydrogen
Optimization for 3-substituted lactams
Using a catalytic amount of nBu4NN3 (30 mol%) as HAT mediator, the desired product 3aa is obtained in 82% yield at constant current mode (3 mA, glassy carbon (GC) as anode and carbon felt (CF) as cathode) in MeCN (0.1 M nBu4NBF4). When we changed the cathode or anode to graphite, the conversion of 1a was low (Table 3-1, item 9-11). Yield determined by HPLC analysis of the crude reaction mixture using triphenylphosphine, GC = glassy carbon, CF = carbon felt, NR = no reaction, DABCO = 1,4-diazabicyclo[2.2.2]octane.
Substrate scope of 3-substituted lactams
Substrate scope of polycyclic compound
Substrate scope of sulfonamide
Synthetic application
Mechanistic studies
- Mechanistic studies of coupling reaction with alkene
- Mechanistic studies of coupling reaction with N-sulfonyl imine
During standard reaction with 8a, we observed the formation of imine dimer 8'aa in 22% yield, suggesting the formation of a radical species derived from 8a. This was further confirmed by performing a reaction in the absence of 1a, leading to the formation of 8'aa in 29% yield (Schemes 3–4b). In addition, the formation of a radical species derived from 1a was confirmed by observation of the corresponding BHT adduct (Scheme 3–4c).
DFT calculations and proposed reaction mechanism
Conclusions
Procedure for the electrolysis
Upon complete consumption of the lactam starting material, as determined by thin layer chromatography analysis, the electrolysis was terminated and the solvent was removed under reduced pressure. The solution was stirred at 900 rpm for 10 min at room temperature before turning on the power. Upon complete consumption of the isoindolinone starting material, as determined by thin layer chromatography analysis, the electrolysis was terminated and the solvent was removed under reduced pressure.
After complete consumption of the aldimine starting material as determined by thin layer chromatography analysis, additional aldimine 8 (1.5 equiv) was added. After the completion of the reaction, the solution was diluted with DCM and washed with saturated solution of NaHCO 3 . The crude material was purified by flash chromatography to give the desired product methyl 3-(3-oxoisoindolin-1-yl)-3-phenylpropanoate.
After completion of the reaction, the solution is diluted with ethyl acetate and washed with water. The crude material was purified by flash chromatography to afford the desired product 1-phenyl-1,9b-dihydro-3H-pyrrolo[2,1-a]isoindole-3,5(2H)-dione 8c.
Faradaic efficiency
The dr value was determined by 1H NMR using the integral of the methyl groups; The relative stereochemistry could not be assigned. 1.1:1, yellow oil; The dr value was determined by 1H NMR using the integral of the methyl groups;. Prepared according to General Procedure (A) using methyl 2-methyl-1-oxoisoindoline-5-carboxylate 1e (0.1 mmol, 1.0 equiv.) and methyl cinnamate 2a (1.5 equiv.).
1.8:1, yellow oil; The dr value was determined by 1H NMR using the integral of methyl groups. Prepare according to the general procedure (A) using 2-methyl-1-oxoisoindoline-5-carbonitrile 1f (0.1 mmol, 1.0 equivalent) and methyl cinnamate 2a (1.5 equivalent). 1.3:1, clear oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry.
Prepared according to general procedure (D) using 2-methylisoindolin-1-one 1a (0.4 mmol, 1.0 equiv.) and N-(4-methoxybenzylidene)-4-methylbenzenesulfonamide 8b (3.0 equiv.). Prepared according to general procedure (D) using 2-methylisoindolin-1-one 1a (0.4 mmol, 1.0 equiv.) and N-(3-methoxybenzylidene)-4-methylbenzenesulfonamide 8c (3.0 equiv.). Prepared according to general procedure (D) using 2-methylisoindolin-1-one 1a (0.4 mmol, 1.0 equiv) and N-(4-chlorobenzylidene)-4-methylbenzenesulfonamide 8e (3.0 equiv).
3:2, yellow oil; The dr value was determined by 1H NMR using the integral of methyl groups;. Prepared according to the general procedure (D) using 2-methylisoindolin-1-one 1a (0.4 mmol, 1.0 equiv) and N -benzylidene methanesulfonamide 8h (3.0 equiv) at constant voltage mode (6V). Prepared according to the general procedure (D) using 2-methylisoindolin-1-one 1a (0.4 mmol, 1.0 equiv) and N-(furan-2-ylmethylene)-4-methylbenzenesulfonamide 8j (3 ,0 equiv.).
Prepared according to general procedure (D) using 2-methylisoindolin-1-one 1a (0.4 mmol, 1.0 equiv) and (E)-N-(cyclohexylmethylene)-4-methylbenzenesulfonamide 8k (3 equiv) in voltage mode constant (6V).
Experimental data
