III. Chapter 3. Electrosynthesis of Heterocycles from Arylalkenes
3.3. Synthesis of indoles from 2-alkenylanilines
donating group (10e) and withdrawing group (10f) were tolerated with satisfying yields. Furthermore, indole with C2-alkyl group was also examined. To our delight, satisfying yield of 65% was found from cyclohexyl bearing substrate (10g). It is worth mentioning that 2-alkenylaniline substrates bearing electron rich groups on the other side of the aniline moiety afforded the mixture of 2- and 3- substituted indoles (10h, 10h’, 10i, 10i’), which is the similar result with the previously reported method of Youn group.26 This result indicates the existence of carbocation intermediate and migratorial process in the course of reaction.40-42 Encouraged by these results, we further investigated the scope with tri- substituted alkenes. β,β-disubstituted 2-alkenylanilines afforded 2,3-disubstituted indoles (10j~10m) via 1,2-aryl migration, which was an expected result according to the previous reports.40-42
Table 3-4. Substrate scope of indolesa
[a] Reaction conditions: alkene (0.10 mmol) in MeCN (3.0 mL) under N, room temperature, with BuNPF (0.1 M) as
3.3.3. Mechanistic investigations and proposed mechanistic pathway
To shed light on the reaction mechanism, electrochemical measurements with cyclic voltammogram and control experiments were carried out (Figure 3-2). As a result, a strong oxidation peak was found, indicating 9a was prone to oxidation (1.49 V vs SCE). In the presence of radical scavenger TEMPO or BHT, all reactions were inhibited, which indicate the reactions involve radical intermediates.
Figure 3-2. Mechanistic investigations for the synthesis of indole
According to the results of mechanistic investigations, a plausible mechanism is described in Scheme 3-4. Single electron oxidation on the anodic surface affords radical cation Int-9a which subsequently goes through cyclization and deprotonation to Int-9b. Another anodic oxidation and deprotonation will afford indole product 10a.
Scheme 3-4. Proposed mechanistic pathway for the synthesis of indole
3.4. Synthesis of benzothiophenes from 2-alkenyaryl disulfides
3.4.1. Reaction optimization of synthesis for benzothiophene
We started our investigation by screening for optimal conditions with symmetrical disulfide 11a as a model substrate (Table 3-5). As a result, the use of a graphite anode and a nickel cathode with Et4NOTs as the electrolyte in DCE solvent at a constant current of 2 mA was optimal to afford 12a in 70% yield (Entry 13). Isolated yields diminished and prolonged reaction times were required to consume 11a when a graphite cathode was used (Entry 8). Increasing the current to 3 mA did not speed up the reaction but only decreased the yield to 60% (Entry 19). Benzothiophene 12a was not found in the reaction performed under air (Entry 17), and the reaction did not proceed without electric current (Entry 23).
Table 3-5. Optimization of electrosynthesis for benzothiophenea
Entry Additive Electrolyte Solvent l (mA)/t (h) Anode/Cathode Yieldb
1 - Bu4NPF6 DCM 2 mA/10.5 h Graphite/Graphite 31%
2 - Bu4NPF6 DCE 2 mA/9 h Graphite/Graphite 36%
3 - Bu4NPF6 DMF 2 mA/8 h Graphite/Graphite trace
4 - Bu4NPF6 HFIP 2 mA/10 h Graphite/Graphite 15%
5 - Bu4NPF6 MeOH 2 mA/8 h Graphite/Graphite 40%
6 - Bu4NBF4 DCE 2 mA/13 h Graphite/Graphite 40%
7 - Bu4NClO4 DCE 2 mA/12 h Graphite/Graphite 30%
8 - Et4NOTs DCE 2 mA/10.5 h Graphite/Graphite 43%
9 - Bu4NBF4 MeOH 2 mA/12 h Graphite/Graphite 27%
10 - Bu4NClO4 MeOH 2 mA/12 h Graphite/Graphite 28%
11 - Et4NOTs MeOH 2 mA/10 h Graphite/Graphite 26%
12 - Et4NOTs DCE 2 mA/7 h Graphite/Glassy-C 42%
13 - Et4NOTs DCE 2 mA/8 h Graphite/Ni 70%
14 - Et4NOTs DCE 2 mA/8 h Graphite/Fe 38%
15 - Et4NOTs DCE 2 mA/18 h Graphite/Ni-foam 43%
16 - Et4NOTs DCE 2 mA/15 h RVC/Ni 57%
17c - Et4NOTs DCE 2 mA/8 h Graphite/Ni n.d.
18d - Et4NOTs DCE 2 mA/15 h Graphite/Ni 46%
19 - Et4NOTs DCE 3 mA/8 h Graphite/Ni 60%
20 - Et4NOTs DCE 1 mA/34 h Graphite/Ni 50%
21 1 eq. 2,4,6- collidine
Et4NOTs DCE 2 mA/13 h Graphite/Ni 45%
3.4.2. Substrate scope of benzothiophenes
With optimal reaction condition in hand, we moved on to the scope of symmetrical disulfides (Table 3-6). First, substrates with various types of esters were investigated and all showed satisfying yields (12a ~ 12d). Disulfide with electron-withdrawing nitro substituent afforded corresponding benzothiophene in good yield (12e), as well as electron-donating methoxy group (12f). Moreover, substrates with amide groups (12g, 12h) including synthetically useful Weinreb amide (12h) were successfully transformed into corresponding benzothiophenes. Next, we turned our attention to disulfides without carbonyl-activated moieties. Substrate with a cyano group (12i) afforded corresponding benzothiophene in 62% yield. Gratifyingly, acyl-protected alcohols were tolerated in moderate yields (12j, 12k). Low yields were found in the case of silyl protected alcohol (12l) and free alcohol (12m). Furthermore, 2-phenylbenzothiophene (12n) was afforded in 46% yield.
Table 3-6. Substrate scope of benzothiophenesa
[a] Reaction conditions: disulfide (0.10 mmol), electrolyte (0.1 M) in DCE (3.0 mL) under N2, room temperature, constant current = 2 mA, Isolated yields are given. [b] 1.05 mmol scale.
3.4.3. Mechanistic investigations and proposed mechanistic pathway
To gain understanding of the reaction mechanism, cyclic voltammetry analysis and control experiments were carried out (Figure 3-3). It turned out that symmetrical disulfide 11a is prone to oxidation showing two oxidation potentials of 0.05 V and 1.30 V (vs SCE). In the presence of radical scavenger TEMPO or BHT, both reactions were inhibited (Figure 3-3b).
Figure 3-3. Mechanistic investigations for the synthesis of benzothiophene
The chemistry of electrogenerated acid (EGA) was investigated by many organic chemists and can be applied to various acid-catalyzed reactions.43 After reviewing the previous report of EGA-catalyzed activation of diaryl disulfide to generate reactive ArS+ species,44 we hypothesized that EGA may participate during the course of the reaction. Furthermore, according to the previous reports, electrolysis of 1,2-dichloroethane affords HCl and chloroethane via sequential cathodic reduction and anodic oxidation.45, 46 In this regard, 0.1 M solution of Et4NOTs in 1,2-dichloroethane was pre-electrolyzed under the standard reaction condition for 2.5 h. Then, electrolysis was stopped and 11a was added and stirred for extra 5 h. It turned out that the reaction did not proceed and 12a was not found (Scheme 3- 5). Moreover, according to the previous report, in the presence of 1 equiv. base, EGA-mediated reaction should be fully suppressed.47 In this regard, we added 1 equiv. of 2,4,6-collidine which is a non- oxidizable base48 under the standard reaction condition. Although isolated yield was diminished and prolonged reaction time was required to fully consume 11a, the reaction wasn’t completely inhibited and 12a was obtained in a moderate yield of 45% (Scheme 3-5). These experimental results suggest that the EGA-mediated reaction mechanism is not the major pathway.
Based on the previous reports,49, 50 and results of mechanistic investigations, a plausible reaction mechanism is illustrated in Scheme 3-6. To gain further insight, we carried out density functional theory calculations. According to the cyclic voltammogram result, 11a can lose an electron on the anodic surface to Int-11a where localized spin densities were found on the S atoms. The first intramolecular cyclization to Int-11b exhibited activation free energy of 10.3 kcal/mol and slightly endergonic ΔG (0.9 kcal/mol). Next, two reaction pathways were considered. Cleavage of S-S bond of Int-11b to furnish Int-11c and Int-11e was unfavored with endergonic ΔG of 27.9 kcal/mol. Meanwhile, the second intramolecular cyclization to afford Int-11c and Int-11d showed activation free energy of 15.3 kcal/mol and exergonic ΔG of -13.1 kcal/mol. Subsequent deprotonation of Int-11d would give desired product 12a (ΔG= -43.3 kcal/mol). We believe that the radical intermediate Int-11c would go through anodic oxidation and deprotonation to afford 12a.
Scheme 3-6. Proposed mechanistic pathway and DFT calculations
3.5. Conclusion
In conclusion, we developed a cost-efficient and sustainable synthesis of benzofurans, indoles and benzothiophenes from arylalkenes under oxidant- and metal-free electrolysis. Developed methods allow the synthesis of heterocycles with various substituents under mild conditions. Detailed mechanistic studies were carried out and allowed us to gain understandings of the reaction mechanisms.
3.6. Experimental data
3.6.1. General procedures Electrode materials/dimensions
Graphite, nickel electrodes with dimensions of 8 cm x 5.2 cm x 2 cm were employed.
Photographed images of ElectraSyn 2.0
[From left to right] ElectraSyn 2.0; ElectraSyn vial (5 mL); ElectraSyn 2.0 vial cap, electrode holders with graphite electrodes; The electrode holders were plugged into the vial cap.
General Procedure (E) for benzofuran synthesis
The reaction was carried out in an undivided cell, under inert atmosphere. A 5 mL vial was charged with the 2-alkenyl phenol derivative 7 (0.1 mmol, 1 equiv.), Et4NOTs (0.3 mmol, 0.1 M), isobutyronitrile (3 mL), sulfuric acid (0.5 mmol, 5 equiv.), and a stir bar, and was closed with a cap attached with a graphite anode and a graphite cathode. The solution was stirred at 900 rpm for 1 minute at room temperature before current was turned on. The electrolysis was performed at a constant current of 1.0 mA. Upon full consumption of the phenol starting material as determined by thin-layer chromatography analysis, electrolysis was terminated, diluted with ethyl acetate (10 mL) and was added saturated NaHCO3 (10 mL). The crude mixture was partitioned between ethyl acetate and water, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate three times, and the combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography.
General Procedure (F) for indole synthesis
The reaction was carried out in an undivided cell, under inert atmosphere. A 5 mL vial was charged with the 2-alkenyl aniline derivative 9 (0.1 mmol, 1 equiv.), Bu4NPF6 (0.3 mmol, 0.1 M), acetonitrile (3 mL) and a stir bar, and was closed with a cap attached with a graphite anode and a graphite cathode. The solution was stirred at 900 rpm for 1 minute at room temperature before current was turned on. The electrolysis was performed at a constant current of 0.6 mA. Upon full consumption of the aniline starting material as determined by thin-layer chromatography analysis, electrolysis was terminated, diluted with ethyl acetate (10 mL) and was added water (10 mL). The crude mixture was partitioned between ethyl acetate and water, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate three times, and the combined organic layers were dried over Na2SO4, filtered and concentrated.
The crude material was purified by flash chromatography.
General Procedure (G) for indole synthesis
The reaction was carried out in an undivided cell, under inert atmosphere. A 5 mL vial was charged with the 2-alkenyl aniline derivative 9 (0.1 mmol, 1 equiv.), Et4NOTs (0.3 mmol, 0.1 M), isobutyronitrile (3 mL), trifluoroacetic acid (0.4 mmol, 4 equiv.), and a stir bar, and was closed with a cap attached with a graphite anode and a graphite cathode. The solution was stirred at 900 rpm for 1 minute at room temperature before current was turned on. The electrolysis was performed at a constant current of 0.6 mA. Upon full consumption of the aniline starting material as determined by thin-layer chromatography analysis, electrolysis was terminated, diluted with ethyl acetate (10 mL) and was added saturated NaHCO3 (10 mL). The crude mixture was partitioned between ethyl acetate and water, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate three times, and the combined organic layers were dried over Na SO, filtered and concentrated. The crude material was purified by
flash chromatography.
General Procedure (H) for benzothiophene synthesis
The reaction was carried out in an undivided cell, under inert atmosphere. A 5 mL vial was charged with the alkenyl disulfide 11 (0.1 mmol, 1 equiv.), Et4NOTs (0.3 mmol, 0.1 M), 1,2-dichloroethane (3 mL), and a stir bar, and was closed with a cap attached with a graphite anode and a nickel cathode. The solution was stirred at 900 rpm for 1 minute at room temperature before current was turned on. The electrolysis was performed at a constant current of 2.0 mA. Upon full consumption of the disulfide starting material as determined by thin-layer chromatography analysis, electrolysis was terminated. The reaction mixture was transferred into the round bottom flask and the electrodes were washed several times with ethyl acetate which was combined into the same round bottom flask. The combined solution was concentrated under reduced pressure and purified by flash chromatography.
3.6.2. Procedures of the mechanistic investigations Cyclic voltammetry studies
The cyclic voltammograms for 7a and 9a were recorded in an electrolyte solution of Bu4NPF6 (0.1 M) in anhydrous acetonitrile (4 mL) with 0.04 mmol of substrate using a glassy carbon working electrode, a Pt wire counter electrode, and a 3 M KCl Ag/AgCl reference electrode with scan rate of 100 mV/s.
The obtained value was converted to SCE by subtracting 0.04 V.
The cyclic voltammogram for 11a was recorded in an electrolyte solution of Et4NOTs (0.1 M) in anhydrous 1,2-dichloroethane (3 mL) with 0.1 mmol of substrate using a glassy carbon working electrode, a Pt wire counter electrode, and a 3 M KCl Ag/AgCl reference electrode with scan rate of 100 mV/s. The obtained value was converted to SCE by subtracting 0.04 V.
Radical scavenger experiments
Experiments were carried out with the General Procedure (E), (F), (H) with 1 equiv. TEMPO or BHT as additives. Durations of electrolysis were matched with the optimal reaction times of each substrate.
Electrolysis of (E)-Stilbene
The experiment was carried out with General Procedure (E) for 6.5 h using (E)-Stilbene instead of 2- alkenyl phenol and 1 equiv. H2SO4 instead of 5 equiv. H2SO4.
1,2-diphenylethane-1,2-diyl bis(4-methylbenzenesulfonate) (7ab)
23% yield; Inseparable mixture of isomers (2:1.1); white solid; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.3 Hz, 2.2H), 7.45 (d, J = 8.3 Hz, 4H), 7.24 – 7.02 (m, 15.5H), 6.95 (d, J = 7.6 Hz, 4H), 6.89 (d, J
= 7.5 Hz, 2.2H), 5.59 (s, 1.1H), 5.56 (s, 2H), 2.37 (s, 9.3H); 13C NMR (100 MHz, CDCl3) δ 144.5, 144.5, 133.4, 133.4, 129.4, 129.4, 128.9, 128.8, 128.1, 128.0, 127.9, 127.7, 127.7, 127.6, 83.5, 83.4, 21.6;
Reaction of 7a with the Koser’s reagent
To a solution of (E)-2-styrylphenol (19.6 mg, 0.1 mmol, 1 equiv.) in isobutyronitrile (3 mL, 0.033M)
was added the Koser’s reagent (39.2 mg, 0.1 mmol, 1 equiv.) and the mixture was stirred for 2.5 h at room temperature. The mixture was diluted with ethyl acetate (10 mL) and washed with a saturated solution of NaHCO3 (10 mL) and was dried over Na2SO4, concentrated in vacuo. The crude material was purified through the flash chromatography to yield 2-phenylbenzofuran as a white solid. 31%
yield.
Base additive experiment
Experiment was carried out with the General Procedure (H) with 1 equiv. 2,4,6-collidine as additive.
Pre-electrolysis of solvent-electrolyte system
Experiment was carried out with the General Procedure (H) without disulfide 11a for 2.5 h. Then, electrolysis was stopped and 11a was added and stirred for 5 h.
3.6.3. DFT calculations Computational details
All DFT calculations were carried out in the Gaussian 09 software (Rev D.01)51 using the M06-2X functional.52 Geometry optimization was performed with the 6-311+g(d,p) basis set for H, C, O, S atoms,53 which were obtained from the EMSL Basis Set Exchange.54, 55 Frequency calculations were performed for every optimized geometry with the same level of theory to obtain vibrational frequencies and thermochemical data at 298.15K. The SMD solvation model with the solvent of dichloroethane (ε=10.125) was used for all calculations.56 The transition states were identified by having one imaginary frequency, and intrinsic reaction coordinate (IRC)57, 58 calculations were performed to connect transition states with corresponding intermediates. Each intermediate was verified as minima by having no imaginary frequency, and the geometries of intermediates with possibility of multiple conformations were optimized with several different starting geometries to find the lowest energy conformation.
Table 3-7. Tables of energies in Hartree
Structure E H298 G298
-1869.873193 -1869.508514 -1869.593819
-1,869.859109 -1869.495860 -1869.577418
-1,869.873625 -1869.509673 -1869.592401
-1,869.847982 -1869.486236 -1869.568081
-935.025716 -934.845755 -934.897292
-934.847447 -934.665789 -934.715927
-934.778944 -934.597733 -934.650653
-934.470104 -934.300031 -934.349363
-895.311612 -895.157061 -895.206654
-894.865941 -894.723543 -894.771131
3.6.4. Characterization of products
2-phenylbenzofuran (8a)
General procedure (E), 5 h, 77% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.2 Hz, 2H), 7.59 (d, J = 7.4 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.28 (td, J = 8.1, 7.7, 1.4 Hz, 1H), 7.23 (td, J = 7.5, 1.1 Hz, 1H), 7.03 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 155.9, 154.9, 130.5, 129.2, 128.8, 128.5, 124.9, 124.2, 122.9, 120.9, 111.2, 101.3; HRMS (DART) calcd for C14H11O+ 195.0804, observed 195.0804;
2-(p-tolyl)benzofuran (8b)
General procedure (E), 6 h, 76% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.29 – 7.19 (m, 4H), 6.96 (s, 1H), 2.40 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 156.2, 154.8, 138.6, 129.5, 129.3, 127.7, 124.9, 124.0, 122.8, 120.7, 111.1, 100.5, 21.4; HRMS (DART) calcd for C15H13O+ 209.0961, observed 209.0960;
2-(4-(tert-butyl)phenyl)benzofuran (8c)
General procedure (E), 5 h, 82% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 7.5 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.26 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 6.98 (s, 1H), 1.36 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 156.2, 154.8, 151.8, 129.3, 127.7, 125.7, 124.7, 124.0, 122.8, 120.7, 111.1, 100.7, 34.8, 31.2; HRMS (DART) calcd for C18H19O+ 251.1430, observed 251.1425;
2-(4-methoxyphenyl)benzofuran (8d)
General procedure (E), 5 h, 75% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.7 Hz, 1H), 7.52 (dd, J = 21.5, 8.0 Hz, 1H), 7.29 – 7.15 (m, 2H), 6.98 (d, J = 8.8 Hz, 1H), 6.89 (s, 1H), 3.86 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 160.0, 156.0, 154.7, 129.5, 126.4, 123.7, 123.3, 122.8, 120.5, 114.2, 111.0, 99.7, 55.3; HRMS (DART) calcd for C15H13O2+ 225.0910, observed 225.0908;
5-methoxy-2-phenylbenzofuran (8e)
General procedure (E), 5 h, 75% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.2 Hz, 2H), 7.47 – 7.39 (m, 3H), 7.34 (t, J = 7.4 Hz, 1H), 7.04 (d, J = 2.6 Hz, 1H), 6.97 (s, 1H), 6.89 (dd, J = 8.9, 2.6 Hz, 1H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.7, 156.0, 149.9, 130.5, 129.7, 128.7, 128.5, 124.8, 113.0, 111.6, 103.3, 101.4, 55.9; HRMS (DART) calcd for C15H13O2+ 225.0910, observed 225.0911;
5-methoxy-2-(4-methoxyphenyl)benzofuran (8f)
General procedure (E), 5 h, 73% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.9 Hz, 1H), 7.02 (d, J = 2.6 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.85 (dd, J = 8.9, 2.6 Hz, 1H), 6.82 (s, 1H), 3.86 (s, 3H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.9, 156.8, 156.0, 149.7, 130.0, 126.3, 123.4, 114.2, 112.2, 111.3, 103.2, 99.8, 55.9, 55.3; HRMS (DART) calcd for C16H15O3+ 255.1016, observed 255.1019;
2-(4-fluorophenyl)benzofuran (8g)
7.58 (d, J = 7.4 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.31 – 7.20 (m, 2H), 7.14 (t, J = 8.4 Hz, 2H), 6.96 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 162.9 (d, J = 248.7 Hz), 155.0, 154.8, 129.2, 126.8, 126.7 (d, J = 8.2 Hz), 124.3, 123.0, 120.9, 115.9 (d, J = 22.0 Hz), 111.1, 101.0 (d, J = 1.6 Hz); HRMS (DART) calcd for C14H10FO+ 213.0710, observed 213.0713;
2-(4-(trifluoromethyl)phenyl)benzofuran (8h)
General procedure (E), 7 h, 35% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.33 (t, J = 7.0 Hz, 1H), 7.28 – 7.22 (m, 1H), 7.15 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 155.1, 154.2, 133.7, 130.1 (q, J = 32.6 Hz), 128.8, 125.8 (q, J = 3.8 Hz), 125.1, 124.9, 124.0 (q, J = 270.6 Hz), 123.2, 121.3, 111.3, 103.2;
HRMS (DART) calcd for C15H10F3O+ 263.0678, observed 263.0675;
2-phenyl-6-(trifluoromethyl)benzofuran (8i)
General procedure (E), 5 h, 61% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 8.4, 1.2 Hz, 2H), 7.80 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.52 – 7.45 (m, 3H), 7.41 (t, J = 7.3 Hz, 1H), 7.07 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 158.6, 153.9, 132.2, 129.7, 129.3, 128.9, 126.3 (d, J = 33.4 Hz), 125.2, 121.2, 119.9 (q, J = 3.7 Hz), 108.7 (q, J = 4.3 Hz), 101.0; HRMS (DART) calcd for C15H10F3O+ 263.0678, observed 263.0678;
Methyl 2-phenylbenzofuran-5-carboxylate (8j)
General procedure (E), 5 h, 55% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 7.7 Hz, 2H), 7.54 (d, J = 8.6 Hz, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 7.07 (s, 1H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.3, 157.4, 157.3, 129.8,
129.2, 129.0, 128.8, 126.0, 125.3, 125.0, 123.3, 111.0, 101.5, 52.1; HRMS (DART) calcd for C16H13O3+
253.0859, observed 253.0860;
2-(4-chlorophenyl)benzofuran (8k)
General procedure (E), 6 equiv. H2SO4 was used, 6.5 h, 67% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.29 (t, J = 7.7 Hz, 1H), 7.23 (t, J = 7.1 Hz, 1H), 7.01 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 154.9, 154.7, 134.3, 129.0, 129.0, 128.9, 126.1, 124.5, 123.1, 121.0, 111.2, 101.7; HRMS (DART) calcd for C14H10ClO+ 229.0415, observed 229.0416;
2-(thiophen-3-yl)benzofuran (8l)
General procedure (E), 8 equiv. H2SO4 was used, 7 h, 40% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 7.73 (dd, J = 3.0, 1.2 Hz, 1H), 7.58 – 7.54 (m, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.46 (dd, J = 5.1, 1.2 Hz, 1H), 7.39 (dd, J = 5.1, 3.0 Hz, 1H), 7.30 – 7.19 (m, 2H), 6.84 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 154.5, 152.7, 132.2, 129.1, 126.5, 125.1, 124.1, 122.9, 121.4, 120.8, 111.0, 101.0; HRMS (DART) calcd for C12H9OS+ 201.0369, observed 201.0370;
2-(4-methoxyphenyl)-6-(trifluoromethyl)benzofuran (8m)
General procedure (E), 4 equiv. H2SO4 was used, 4 h, 56% yield; White solid; m.p. 132 – 137 ℃; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.8 Hz, 2H), 7.76 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.93 (s, 1H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.5,
2-(4-methoxyphenyl)-5-nitrobenzofuran (8n)
General procedure (E), 4.5 h, 33% yield; Yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 2.3 Hz, 1H), 8.18 (dd, J = 9.0, 2.4 Hz, 1H), 7.81 (d, J = 8.9 Hz, 2H), 7.56 (d, J = 9.0 Hz, 1H), 7.01 (d, J = 8.9 Hz, 2H), 6.98 (s, 1H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.8, 159.4, 157.5, 144.3, 129.9, 126.8, 121.9, 119.6, 116.8, 114.5, 111.1, 99.9, 55.4; HRMS (DART) calcd for C15H12NO4+ 270.0761, observed 270.0765;
5-nitro-2-phenylbenzofuran (8o)
General procedure (E), 6.5 h, 22% yield; Yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 2.0 Hz, 1H), 8.23 (dd, J = 9.0, 3.1 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 9.0 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H), 7.43 (t, J = 7.3 Hz, 1H), 7.14 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 159.3, 157.6, 144.3, 129.7, 129.2, 129.0, 125.3, 120.1, 117.3, 111.4, 110.0, 101.6; HRMS (DART) calcd for C14H10NO3+
240.0655, observed 240.0654;
2-(benzofuran-2-yl)phenol (8p)
General procedure (E), 8 equiv. H2SO4 was used, 4.5 h, 56% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 8.1, 1.6 Hz, 1H), 7.61 (dd, J = 7.3, 1.6 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.35 – 7.26 (m, 3H), 7.13 (s, 1H), 7.10 (s, 1H), 7.04 – 6.95 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 154.3, 154.0, 153.3, 130.3, 128.5, 127.2, 124.5, 123.4, 121.0, 120.8, 117.4, 116.0, 111.0, 103.3; HRMS (DART) calcd for C14H11O2+ 211.0754, observed 211.0755;
2-phenyl-1-tosyl-1H-indole (10a)
General procedure (F), 8.5 h, 77% yield, 85% yield (3 equiv. trifluoroacetic acid as additive); White solid; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.4 Hz, 1H), 7.52 – 7.47 (m, 2H), 7.46 – 7.39 (m, 4H), 7.34 (t, J = 7.8 Hz, 1H), 7.27-7.25 (m, 3H), 7.04 (d, J = 8.3 Hz, 2H), 6.54 (s, 1H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.5, 142.1, 138.2, 134.6, 132.4, 130.5, 130.3, 129.2, 128.6, 127.5, 126.8, 124.7, 124.3, 120.6, 116.6, 113.6, 21.5; HRMS (DART) calcd for C21H18NO2S+ 348.1053, observed 348.1054;
1-(methylsulfonyl)-2-phenyl-1H-indole (10b)
General procedure (F), 15.5 h, 48% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.6 Hz, 1H), 7.61 – 7.54 (m, 3H), 7.45 – 7.33 (m, 5H), 6.72 (s, 1H), 2.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.9, 138.0, 131.9, 130.3, 130.1, 128.8, 127.7, 125.1, 124.5, 121.0, 115.8, 113.0, 39.4;
HRMS (DART) calcd for C15H14NO2S+ 272.0740, observed 272.0746;
tert-butyl 2-phenyl-1H-indole-1-carboxylate (10c)
General procedure (G), 9 h, 42% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.44 – 7.30 (m, 6H), 7.25 (t, J = 7.4 Hz, 1H), 6.55 (s, 1H), 1.30 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 150.2, 140.5, 137.4, 135.0, 129.2, 128.7, 127.8, 127.5, 124.3, 122.9, 120.4, 115.2, 109.9, 83.3, 27.5; HRMS (DART) calcd for C19H20NO2+ 294.1489, observed 294.1490;
General procedure (F), 3 equiv. of trifluoroacetic acid was added, 10 h, 95% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.4 Hz, 1H), 7.45 – 7.34 (m, 6H), 7.29 – 7.25 (m, 3H), 7.05 (d, J = 8.1 Hz, 2H), 6.54 (s, 1H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.7, 140.8, 138.3, 134.7, 134.4, 131.4, 130.8, 130.4, 129.2, 127.8, 126.7, 125.0, 124.4, 120.8, 116.6, 114.0, 21.5; HRMS (DART) calcd for C21H17ClNO2S+ 382.0663, observed 382.0664;
5-(tert-butyl)-2-phenyl-1-tosyl-1H-indole (10e)
General procedure (F), 9.5 h, 81% yield; White solid; m.p. 55-60 ℃; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 9.4 Hz, 1H), 7.49 – 7.38 (m, 7H), 7.27 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.50 (s, 1H), 2.29 (s, 3H), 1.36 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 147.3, 144.4, 141.9, 136.1, 134.9, 132.5, 130.3, 130.2, 129.1, 128.5, 127.4, 126.8, 122.8, 116.8, 116.0, 113.7, 34.6, 31.6, 21.5; HRMS (DART) calcd for C25H26NO2S+ 404.1679, observed 404.1678;
2-phenyl-1-tosyl-5-(trifluoromethyl)-1H-indole (10f)
General procedure (F), 3 equiv. of trifluoroacetic acid was added, 10 h, 65% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.49 – 7.39 (m, 5H), 7.26 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 6.59 (s, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.1, 143.6, 139.6, 134.7, 131.6, 130.5, 130.0, 129.4, 129.1, 127.5, 126.8, 126.5 (q, J
= 32.3 Hz), 121.3 (q, J = 3.6 Hz), 118.1 (q, J = 4.1 Hz), 116.6, 112.7, 21.5; HRMS (DART) calcd for C22H17F3NO2S+ 416.0927, observed 416.0929;
2-cyclohexyl-1-tosyl-1H-indole (10g)
General procedure (F), 3 equiv. of trifluoroacetic acid was added, 15 h, 65% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 7.2 Hz, 1H), 7.26 – 7.13 (m, 4H), 6.40 (s, 1H), 3.31 (tt, J = 11.2, 2.9 Hz, 1H), 2.32 (s, 3H), 2.10 (d, J = 11.6 Hz, 2H), 1.88 – 1.72 (m, 3H), 1.52 – 1.20 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 148.5, 144.4, 137.2, 136.2, 130.1, 129.6, 126.1, 123.7, 123.5, 120.1, 115.3, 107.3, 37.4, 34.4, 26.6, 26.2, 21.5; HRMS (DART) calcd for C21H24NO2S+ 354.1522, observed 354.1519;
2-(4-(tert-butyl)phenyl)-1-tosyl-1H-indole (10h) and 3-(4-(tert-butyl)phenyl)-1-tosyl-1H-indole (10h’)
General procedure (G), 7 h, 88% (5:1) total yield; White solid; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 7.2 Hz, 0.2H), 7.79 (d, J = 8.7 Hz, 0.6H), 7.67 (s, 0.2H), 7.55 (d, J = 8.3H, 0.4 H), 7.49 (d, J = 8.1H, 0.4H), 7.44 – 7.40 (m, 4.6 H), 7.36 – 7.31 (m, 1.2H), 7.27 – 7.19 (m, 4H), 7.03 (d, J = 8.2 Hz, 2H), 6.51 (s, 1H), 2.33 (s, 0.6H), 2.28 (s, 3H), 1.39 (s, 9H), 1.37 (s, 1.8H); 13C NMR (100 MHz, CDCl3) δ 151.6, 150.6, 144.9, 144.4, 142.3, 138.2, 135.5, 135.2, 134.6, 130.6, 130.1, 130.0, 129.8, 129.4, 129.1, 127.5, 126.8, 125.8, 124.8, 124.5, 124.4, 124.2, 123.9, 123.4, 122.7, 120.5, 116.6, 113.8, 113.3, 34.7, 34.6, 31.3, 31.3, 21.5, 21.5; HRMS (DART) calcd for C25H26NO2S+ 404.1679, observed 404.1681;
2-(4-methoxyphenyl)-1-tosyl-1H-indole (10i) and 3-(4-methoxyphenyl)-1-tosyl-1H-indole (10i’)
(s, 0.25H), 7.52 (d, J = 8.7 Hz, 0.5H), 7.44 – 7.30 (m, 4.5H), 7.28 – 7.20 (m, 3.5H), 7.03 (d, J = 8.1 Hz, 2H), 7.00 (d, J = 8.7 Hz, 0.5H), 6.95 (d, J = 8.7 Hz, 2H), 3.88 (s, 3H), 3.86 (s, 0.75H), 2.34 (s, 0.75H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.0, 159.1, 144.9, 144.4, 142.0, 138.1, 135.4, 135.2, 134.7, 131.6, 130.6, 129.8, 129.5, 129.1, 129.0, 126.8, 126.7, 125.4, 124.7, 124.7 124.5, 124.2, 123.7, 123.4, 122.3, 120.4, 120.3, 116.6, 114.3, 113.8, 112.9, 112.8, 55.3, 55.3, 21.5, 21.5; HRMS (DART) calcd for C22H20NO3S+ 378.1158, observed 378.1156;
2,3-diphenyl-1-tosyl-1H-indole (10j)
General procedure (F), 48 h, 54% yield (from 1j); 21 h, 55% yield (from 1j’); White solid; 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.38 – 7.26 (m, 7H), 7.25 – 7.19 (m, 4H), 7.12 – 7.05 (m, 4H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.5, 137.2, 136.8, 135.3, 132.6, 132.1, 130.9, 130.4, 129.8, 129.3, 128.4, 128.1, 127.2, 126.9, 125.1, 124.7, 124.1, 119.9, 116.2, 21.5; HRMS (DART) calcd for C27H22NO2S+ 424.1366, observed 424.1366;
2,3-bis(4-methoxyphenyl)-1-tosyl-1H-indole (10k)
General procedure (F), 10 h, 83% yield; White solid; m.p. 186 – 191 ℃; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 7.3 Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 7.2 Hz, 2H), 7.07 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 7.2 Hz, 2H), 6.79 (dd, J = 14.8, 7.3 Hz, 4H), 3.84 (s, 3H), 3.76 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.6, 158.4, 144.4, 137.2, 136.4, 135.4, 133.3, 130.9, 130.7, 129.2, 126.9, 125.0, 124.9, 124.0, 123.2, 119.8, 116.2, 113.7, 112.8, 55.1, 21.5; HRMS (DART) calcd for C29H26NO4S+ 484.1577, observed
484.1581;
2,3-bis(4-fluorophenyl)-1-tosyl-1H-indole (10l)
General procedure (F), 48 h, 73% yield; White solid; m.p. 198 – 203 ℃; 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 6.4 Hz, 1H), 7.42 (d, J = 5.6 Hz, 1H), 7.35 – 7.27 (m, 3H), 7.18 (dd, J = 8.7, 5.4 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 7.04 (dd, J = 8.4, 5.5 Hz, 2H), 6.96 (dt, J = 17.5, 8.7 Hz, 4H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.8 (d, J = 248.9 Hz), 161.8 (d, J = 246.9 Hz), 144.8, 137.1, 135.7, 135.3, 133.8 (d, J = 8.3 Hz), 131.4 (d, J = 8.0 Hz), 130.1, 129.4, 128.3 (d, J = 3.4 Hz), 126.8, 126.6 (d, J = 3.5 Hz), 125.4, 124.3, 123.9, 119.7, 116.2, 115.4 (d, J = 21.4 Hz), 114.6 (d, J
= 21.7 Hz), 21.5; HRMS (DART) calcd for C27H20F2NO2S+ 460.1177, observed 460.1180;
1-(methylsulfonyl)-2,3-diphenyl-1H-indole (10m)
General procedure (F), 22 h, 75% yield; White solid; m.p. 214 – 219 ℃; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.49 – 7.10 (m, 12H), 2.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 136.8, 136.6, 132.4, 131.7, 130.7, 130.2, 129.8, 128.7, 128.3, 127.6, 127.1, 125.4, 124.4, 124.4, 120.2, 115.5, 40.5; HRMS (DART) calcd for C21H18NO2S+ 348.1053, observed 348.1054;
Methyl benzo[b]thiophene-2-carboxylate (12a)
General procedure (H), 8 h, 70% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.88 (t, J = 5.2 Hz, 2H), 7.51 – 7.35 (m, 2H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.2, 142.1, 138.6, 133.3, 130.6, 126.9, 125.5, 124.8, 122.7, 52.4; HRMS (DART) calcd for C10H9O2S+ 193.0318, observed 193.0316;
Ethyl benzo[b]thiophene-2-carboxylate (12b)
General procedure (H), 11 h, 54% yield; Light yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.90 – 7.80 (m, 2H), 7.48 – 7.34 (m, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.8, 142.2, 138.7, 133.9, 130.3, 126.8, 125.5, 124.8, 122.7, 61.5, 14.3; HRMS (DART) calcd for C11H11O2S+ 207.0475, observed 207.0479;
tert-butyl benzo[b]thiophene-2-carboxylate (12c)
General procedure (H), 8 h, 49% yield; Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.89 – 7.77 (m, 2H), 7.47 – 7.29 (m, 2H), 1.61 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 162.0, 142.1, 138.8, 135.8, 129.6, 126.6, 125.3, 124.7, 122.6, 82.3, 28.2; HRMS (DART) calcd for C13H15O2S+ 235.0788, observed 235.0788;
Benzyl benzo[b]thiophene-2-carboxylate (12d)
General procedure (H), 8 h, 60% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.93 – 7.77 (m, 2H), 7.52 – 7.32 (m, 7H), 5.39 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 162.6, 142.3, 138.7, 135.6, 133.4, 130.7, 128.6, 128.4, 128.2, 127.0, 125.5, 124.9, 122.7, 67.1; HRMS (ESI) calcd for C16H12NaO2S+ 291.0451, observed 291.0452;
Methyl 5-nitrobenzo[b]thiophene-2-carboxylate (12e)