Structure of 39105-39-0
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| CAS No. : | 39105-39-0 |
| Formula : | C12H13ClO |
| M.W : | 208.68 |
| SMILES Code : | O=C(C1=CC2=C(CCC2)C=C1)CCCl |
| English Name : | 3-Chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one |
| MDL No. : | MFCD00029138 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85% | With sulfuric acid at 55℃; for 16h; | 2 Step 2: 1,2,3,5,6,7-Hexahydro-s-indacen-1-one Into a 1,000 mL round-bottom flask was placed a solution of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (53.50 g, 253.0 mmol, 1.0 equiv.) in conc. H2SO4 (300 mL). The resulting solution was stirred for 16 h at 55 °C and then was quenched by adding the reaction mixture carefully to 1,500 mL of water/ice. The solids were collected by filtration and then dried under an infrared lamp for 24 h. This resulted in 37.4 g (85%) of 1,2,3,5,6,7-Hexahydro-s-indacen-1-one as a yellow solid. |
| 82% | With sulfuric acid at 55℃; for 24h; | 1 Step 1. 1,2,3,5,6,7-Hexahydro-s-indacen-1-one. A solution of 3-chloro-1-indan-5-yl-propan-1- one (40 g, 191.68 mmol) in c. H2SO4 (260 ml) was stirred at 55° C for 24 h. The RM was added dropwise to ice - water (2 l) and the resulting mixture was extracted (EtOAc, 500 ml x 3). The organic phase was washed (brine, 200 ml x 3), dried (Na2SO4) and concentrated in vacuo to give 3,5,6,7-tetrahydro-2H-s-indacen-1-one as a white solid. Y = 82 %.1H NMR (400 MHz, MeOD) d 7.50 (s, 1H), 7.36 (s, 1H), 3.11 - 3.09 (m, 2H), 2.99 - 2.93 (m, 4H), 2.69 - 2.66 (m, 2H), 2.16 - 2.11 (m, 2H). |
| 69.17% | With sulfuric acid In water at 70℃; for 12h; | B Step B: 2,3,6,7-tetrahydro-s-indacen-1(5H)-one To concentrated H2SO4 (1.84 kg, 18.39 mol, 98 wt.% in aqueous solution, 37.25 eq) was added 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (103 g, 493.57 mmol, 1 eq). Then the reaction mixture was stirred at 70 °C for 12 hours. The reaction mixture was poured into ice-water (4.5 L) and the resulting suspension was filtered. The filter cake was dissolved in EtOAc (500 mL) and washed with saturated aqueous Na2CO3 solution (500 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 200 mL). The combined organic layers were concentrated in vacuum to give the title compound (60 g, 69.17% yield, 98% purity on LCMS) as a yellow solid.1H NMR (400 MHz, CDCl3): d 7.58 (s, 1 H), 7.30 (s, 1 H), 3.08-2.96 (m, 2 H), 2.95-2.91 (m, 4 H), 2.70 (t, 2 H) and 2.15-2.05 (m, 2 H).LCMS: m/z 173.2 (M+H)+(ES+). |
| 69% | With sulfuric acid In water at 70℃; for 12h; | B Step B: 2,3,6,7-Tetrahydro-s-indacen-1(5H)-one To a concentrated H2SO4 solution (1.84 kg, 18.39 mol, 98 wt % in aqueous solution, 37.25 eq) was added to 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (103 g, 493.57 mmol, 1 eq). The reaction mixture was stirred at 70 °C for 12 hours, poured into ice-water (4.5 L) and filtered. The filter cake was dissolved in EtOAc (500 mL) and saturated aqueous Na2CO3 solution (500 mL) was added. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 200 mL). The combined organic layers were concentrated in vacuo to give the title compound (60 g, 69 % yield, 98 % purity on LCMS) as a yellow solid. 1H NMR (400 MHz, CDCl3) d 7.58 (s, 1 H), 7.30 (s, 1 H), 3.08-2.96 (m, 2 H), 2.95-2.91 (m, 4 H), 2.70 (t, 2 H) and 2.15-2.05 (m, 2 H). LCMS: m/z 173.2 (M+H)+ (ES+). |
| 69.17% | With sulfuric acid In water at 70℃; for 12h; | Step B: 2,3,6,7-tetrahydro-s-indacen-1(5H)-one To conc. H2SO4 (1.84 kg, 18.39 mol, 98 wt.% in aq solution, 37.25 eq) was added 3- chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (103 g, 493.57 mmol, 1 eq). Then the reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was poured into ice-water (4.5 L) and the resulting suspension was filtered. The filter cake was dissolved in EtOAc (500 mL) and washed with sat aq Na2CO3 solution (500 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 200 mL). The combined organic layers were concentrated in vacuum to give the title compound (60 g, 69.17% yield, 98% purity on LCMS) as a yellow solid. LCMS: m/z 173.2 (M+H)+ (ES+). 1H NMR (CDd3): d 7.58 (s, 1H), 7.30 (s, 1H), 3.08-2.96 (m, 2H), 2.95-2.91 (m, 4H), 2.70 (t, 2H), 2.15-2.05 (m, 2H). |
| 62% | With sulfuric acid at 55℃; for 40h; | 61.2; 62.2 A mixture of 3-chloro-l-(2,3-dihydro-l//-inden-5-yl)propan-l-one (35.0 g, 167.72 mmol) in concentrated H2SO4 (210 mL) was stirred at 55°C for 40 h. After cooling to room temperature, the mixture was quenched with ice water (300 ml,) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were dried over anhydrous NazSCL, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (10% EtOAc in petroleum ether) to give the title compound (18 g, 62% yield) as a yellow solid. NMR (400 MHz, CDCI3) d = 7.57 (s, 1H), 7.30 (s, 1H), 3.08 (t, ./= 6.0 Hz, 2H), 2.98 - 2.91 (m, 4H), 2.69 (t J= 5.6 Hz, 2H), 2.17 - 2.10 (m, 2EI). MS: m/z 172.8 (M H ). |
| 43% | With sulfuric acid | |
| With sulfuric acid | ||
| With sulfuric acid at 90℃; for 4h; | ||
| 37.4 g | With sulfuric acid at 55℃; for 16h; | 2 Step 2: 1,2,3,5,6,7-Hexahydros-indacen-1-one Into a 1000-mL round-bottom flask, was placed a solution of 3-chloro-1-(2,3-dihydro-1H-inden- 5-yl)propan-1-one (53.5 g, 253 mmol) in cc. H2SO4 (300 mL). The resulting solution was stirred for 16 h at 55oC and then was quenched by the addition of 1500 mL of water/ice. The solids were collected by filtration and then was dried over infrared lamp for 24 h. This resulted in 37.4 g (85%) of the title compound as a yellow solid |
| 37.4 g | With sulfuric acid at 55℃; for 16h; | 2 Step 2: 1,2,3,5,6,7-Hexahydro-s-indacen-1-one Into a 1000-mL round-bottom flask was placed a solution of 3-chloro-1-(2,3-dihydro-1H-inden-5- yl)propan-1-one (53.5 g, 253 mmol) in conc. H2S04 (300 mL). The resulting solution was stirred for 16 h at 55°C and was then quenched by adding the reaction mixture carefully to 1500 mL of water/ice. The solids were collected by filtration and then was dried over infrared lamp for 24 h.This resulted in 37.4 g (85%) of the title compound as a yellow solid. |
| With sulfuric acid at 60℃; for 24h; | ||
| 112.2 g | With sulfuric acid at 55℃; for 16h; | A.2 Into a 1000-mL round-bottom flask was placed a solution of 3-chloro-l-(2,3-dihydro-l i7- inden-5-yl)propan-l-one (160.5 g, 759.0 mmol) in cone. H2SO4 (900 mL). The resulting solution w'as stirred for 16 h at 55°C and was then quenched by adding the reaction mixture carefully to 4500 mL of water/ice. The solids were collected by filtration and dried over infrared lamp for 24 h. This resulted in 1 12 2 g (85%) of the title compound as a yellow solid. |
| 37.4 g | With sulfuric acid at 55℃; for 16h; | 2 Step 2: l,2,3,5,6,7-Hexahydros-indacen-l-one Into a lOOO-mL round-bottom flask, was placed a solution of 3-chloro-l-(2,3-dihydro-lH-inden- 5-yl)propan-l-one (53.5 g, 253 mmol) in cc. H2SO4 (300 mL). The resulting solution was stirred for 16 h at 55°C and then was quenched by the addition of 1500 mL of water/ice. The solids were collected by filtration and then was dried over infrared lamp for 24 h. This resulted in 37.4 g (85%) of the title compound as a yellow solid. |
| With sulfuric acid at 20 - 70℃; | ii; ii Reaction Scheme 2 - Steps ii and iii (Method B) 3-Chloro-i-(2,3-dihydro-ifT-inden-5-yl)propan-i-one (12) (350 g) and cone sulfuric acid (5 vol, 3185 g) were charged into a round bottom flask at 25 ± 5 °C. The reaction mixture was heated to 70 ± 2°C and stirred for 8-10 hours. The absence of 3-chloro-i- (2,3-dihydro-ifT-inden-5-yl)propan-i-one (12) was confirmed by HPLC (Limit: < 2.0 %)· The reaction mixture was cooled to 0-5 °C. A nitration mixture was prepared from cone sulfuric acid (0.33 vol, 210.2 g) and cone. HN03 (0.5 vol, 248.5 g) at 10-15 °C. The nitration mixture was added to the above reaction mixture at 0-5 °C over a period of 45-60 minutes. The reaction mixture was maintained at 0-5 °C for 2 hours. The absence of 1,2,3,5,6,7-hexahydro-s-indacen-i-one (13) was confirmed by HPLC (Limit: < 2.0 %). After completion of the reaction, the reaction mixture was added into ice cold water (25 vol, 8.75 L) and maintained at 15 ± 10 °C for 1 hour. The product was extracted into ethyl acetate (1 x 10 vol: 3.5 L, 2 x 5 vol: 1.75 L). The combined organic layers were washed with 10% NaHC03 solution (10 vol, 3.5 L) at 25 ± 5 °C and dried over Na2S04 (175 g). The solvent was distilled off (up to 1 vol, 350 mL) under vacuum at below 45 °C and then co-distilled with n-heptane (2 vol, 700 mL) completely. n-Heptane (2 vol, 700 mL) was added and the reaction mixture was stirred for 1 hour at 25 ± 5 °C. The solid product was filtered, washed with n-heptane (0.5 vol, 175 mL) and dried under vacuum for 2 hours at 45-50 °C. The crude product was dissolved in methanol (2.0 vol, 700 mL) at 55-60 °C. Charcoal 5% was added and the reaction mixture was refluxed for 1 hour and then cooled to 45 °C. The reaction mixture was filtered through a hyflow bed and washed twice with methanol (2x (0.5 vol, 175 mL)). The filtrate was cooled to 0-5 °C and maintained for 2-3 hours at 0-5 °C. The solid product was filtered, washed with cold methanol (0.25 vol, 87.5 mL) and dried under vacuum for 3 hours at 45-50 °C. Final Product: 8-nitro-i,2,3,5,6,7-hexahydro-s-indacen-i-one (14) and 4- nitro-i,2,3,5,6,7-hexahydro-s-indacen-i-one (15) Brown solid Weight ratio of 14:15 was 7:1. Combined Output (14+15): 217 g Combined Yield (14+15): 60 % lH NMR (DMSO-d6; 400 MHz): 7.66 (s, lH), 3.08 (t, 2H), 2.98 (t, 2H) 2.88 (t, 2H), 2.72 (t, 2H) and 2.12 (m, 2H). Moisture content (by Karl Fischer titration): 0.72 HPLC purity: 96.44 % | |
| With sulfuric acid at 65 - 70℃; Large scale; | 2.ii Reaction scheme 2 - step (ii) and step (iii) Sulfuric acid (300.0 L) was charged at 25 to 30 °C into a 2.0 KL clean and dry glass- lined reactor. 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (9) (60.0 Kg) was charged lot wise at 25 to 30 °C and the reaction mixture was maintained for 30 minutes at 25 to 30 °C. The reaction mixture was slowly heated to 65 to 70 °C and maintained at 65 to 70 °C for 24 hours. The absence of 3-chloro-1-(2,3-dihydro-1H-inden-5- yl)propan-1-one (9) was confirmed by HPLC (Limit: Then the reaction mixture was cooled to o to 5 °C. A nitration mixture*1 was added slowly at o to 5 °C and the reaction mixture was maintained at o to 5 °C for 1 hour. The absence of 1,2,3,5,6,7-hexahydro-s-indacen-1-one (10) was confirmed by HPLC (Limit: ≤ 1.0 %). | |
| With sulfuric acid at 25 - 70℃; Large scale; | 2.b Sulfuric acid (300.0 L) was charged at 25 to 30°C into a 2.0 KL clean and dry glass- lined reactor.3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (9) (60.0 Kg) was charged lot wise at 25 to 30°C and the reaction mixture was maintained for 30 minutes at 25 to 30°C. The reaction mixture was slowly heated to 65 to 70°C and maintained at 65 to 70°C for 24 hours. The absence of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan- 1-one (9) was confirmed by HPLC (Limit: ≤ 1.0 %). | |
| 65.4 % | With sulfuric acid In dichloromethane Reflux; | Synthesis of tert-butyl 3-methylpiperazine-1-carboxylate (9) H2SO4 was added to DCM (15 mL, 0.28 mmol). And PTC (330 mg, 0.97 mmol) was added to DCM. The mixture was stirred at 0 °C for 3 min. 8 (2.0 g, 9.58 mmol) was added portionwise at 0 °C. The mixture was stirred at reflux overnight. The mixture was added into ice then extracted with DCM, the DCM layer was dried over Na2SO4. Purified by flash column chromatography (Hexane: Ethyl acetate = 20:1) as a brown solid (9, 1.68 g, 65.4%). |
| 65.4 % | With sulfuric acid In dichloromethane Reflux; | Synthesis of tert-butyl 3-methylpiperazine-1-carboxylate (9) H2SO4 was added to DCM (15 mL, 0.28 mmol). And PTC (330 mg, 0.97 mmol) was added to DCM. The mixture was stirred at 0 °C for 3 min. 8 (2.0 g, 9.58 mmol) was added portionwise at 0 °C. The mixture was stirred at reflux overnight. The mixture was added into ice then extracted with DCM, the DCM layer was dried over Na2SO4. Purified by flash column chromatography (Hexane: Ethyl acetate = 20:1) as a brown solid (9, 1.68 g, 65.4%). |
| 49 % | With sulfuric acid at 60℃; | Preparation of 3,5,6,7-tetrahydro-s-indacen-1(2H)-one(M2) M1 (3.00 g, 14.4 mmol) was added in portions to concentrated sulfuric acid (30 mL) and stirred at 60 for 48 hours. Upon completion of the reaction, the mixture was slowly diluted with ice water at 0 . Subsequently, the pH was adjusted to 7 using a saturated NaOH aqueous solution. Following ethyl acetate (EA) extraction, the resulting product was further purified through column chromatography on silica gel, affording compound M2 (1.21 g, 49%). ESI-MS calculated for [M+H]+: 173.1, found: 173.1. |
| 49 % | With sulfuric acid at 60℃; | Preparation of 3,5,6,7-tetrahydro-s-indacen-1(2H)-one(M2) M1 (3.00 g, 14.4 mmol) was added in portions to concentrated sulfuric acid (30 mL) and stirred at 60 for 48 hours. Upon completion of the reaction, the mixture was slowly diluted with ice water at 0 . Subsequently, the pH was adjusted to 7 using a saturated NaOH aqueous solution. Following ethyl acetate (EA) extraction, the resulting product was further purified through column chromatography on silica gel, affording compound M2 (1.21 g, 49%). ESI-MS calculated for [M+H]+: 173.1, found: 173.1. |
| With sulfuric acid at 25 - 70℃; | Sulfuric acid (300.0 L) was charged at 25 to 30 °C into a 2.0 KL clean and dry glass- lined reactor. 3-chloro-i-(2,3-dihydro-iH-inden-5-yl)propan-i-one (9) (60.0 Kg) was charged lot wise at 25 to 30 °C and the reaction mixture was maintained for 30 minutes at 25 to 30 °C. The reaction mixture was slowly heated to 65 to 70 °C and maintained at 65 to 70 °C for 24 hours. The absence of 3-chloro-i-(2,3-dihydro-iW-inden-5-yl)- propan-i-one (9) was confirmed by HPLC (Limit: Then the reaction mixture was cooled to o to 5 °C. A nitration mixture*1was added slowly at o to 5 °C and the reaction mixture was maintained at o to 5 °C for 1 hour. The absence of 1,2,3,5,6,7-hexahydro-s-indacen-i-one (10) was confirmed by HPLC (Limit: Demineralised water (900.0 L) was charged at 25 to 30 °C into a 2.0 KL clean and dry glass-lined reactor. The water was cooled to o to 5 °C. The reaction mixture was added slowly added to the reactor at o to 5 °C. Toluene (480.0 L) was added and the temperature was raised to 30 to 35 °C. The reaction mixture was maintained at 30 to 35 °C for 30 minutes and allowed to settle at 30 to 35 °C for 30 minutes. The reaction mixture was filtered through a Celite bed (prepared with Celite (6.0 Kg) and toluene (30.0 L)). The Celite bed was washed with toluene (60.0 L). The solid was filtered and sucked dry for 30 min. The reaction mixture was charged to a 2.0 KL clean and dry glass-lined reactor. The reaction mixture was allowed to settle at 30 to 35 °C for 30 minutes. The layers were separated (aqueous layer (AL-i) and organic layer (OL-i)) and OL-i was kept aside. Toluene (60.0 L) was charged to AL-i. The reaction mixture was stirred at 35 to 40 °C for 30 minutes and allowed to settle at 35 to 40 °C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)) and OL-2 was kept aside. OL-i and OL-2 were combined to form OL-3.A 5 % saturated sodium bicarbonate solution (prepared from demineralised water (300.0 L) and sodium bicarbonate (15.0 Kg)) was slowly charged to OL-3 at 30 to 35 °C. The reaction mixture was stirred at 35 to 40 °C for 30 minutes and allowed to settle at 35 to 40 °C for 30 minutes. The reaction mixture was filtered through a Celite bed (prepared with Celite (6.0 Kg) and demineralised water (60.0 L)). The Celite bed was washed with toluene (60.0 L). The reaction mixture was charged to a 3.0 KL clean and dry glass-lined reactor. The reaction mixture was allowed to settle at 30 to 35 °C for 30 minutes. The layers were separated (aqueous layer (AL-3) and organic layer (OL-4)) and OL-4 was kept aside.Toluene (60.0 L) was charged to AL-3. The layers were separated (aqueous layer (AL-4) and organic layer (OL-5)) and OL-5 was kept aside. OL-4 and OL-5 were combined to form OL-6. Brine solution (prepared from demineralised water (300.0 L) and sodium chloride (12.0 Kg) at 25 to 30 °C. The reaction mixture was stirred at 30 to 35 °C for 30 minutes and allowed to settle at 30 to 35 °C for 30 minutes. The layers were separated (aqueous layer (AL-5) and organic layer (OL-7)) and OL-7 was kept aside. OL-7 was dried over anhydrous Na2SO4(9.0 Kg) and the anhydrous Na2SO4was washed with toluene (30.0 L) at 25 to 30 °C. The solvent was distilled under vacuum at below 40 to 45 °C until 5 % remained. Methanol (60.0 L) was charged to the reaction mixture at 40 to 45 °C and down to 60 L of reaction mass. Methanol (120.0 L) was charged to the reaction mixture at 40 to 45 °C and the reaction mixture was cooled to 5 to 10 °C and maintained at 5 to 10 °C for 30 minutes. The solid product was filtered, washed with cooled methanol (30.0 L), and dried in a hot air oven at 40 to 45 °C for 6 hours to afford 38.87 Kg of a mixture of 8-nitro-i,2,3,5,6,7- hexahydro-s-indacen-i-one (11a) and 4-nitro-i,2,3,5,6,7-hexahydro-s-indacen-i-one (nb)Combined Yield (na+nb): 62.24 %Weight ratio (na:iib): 9:1HPLC purity: 95.9 %Moisture content: 0.19 % ‘H NMR: (500 MHz, CDC13): 8 7.44(8, 1H), 2.21(m, 2H), 2.78 (t, 2H), 3.02 (m, 4H), 3.13 Ct, 2H)*1: To prepare the nitration mixture, sulfuric acid (27.0 L) was charged at 25 to 30 °C into a 160 L clean and dry glass-lined reactor. The reaction mixture was cooled to o to 5 °C. Nitric acid (27.0 L) at o to 5 °C was added slowly and the reaction mixture was maintained for 30 minutes at o to 5 °C to afford the nitration mixture. | |
| 90 g | With sulfuric acid at 20 - 90℃; | QQ 3,5,6,7-Tetrahydro-2H-s-indacen-1-one 3,5,6,7-Tetrahydro-2H-s-indacen-1-one Concentrated sulfuric acid (550 mL) was added dropwise, with stirring over a time period of 2 hours to 137 grams of 3-chloro-1-indan-5-yl-propan-1-one. The resulting thick black solution was heated to 90°C until hydrogen chloride evolution ceased (usually 1-4 hours). The mixture was then cooled to room temperature and poured onto 5 kg of ice. The resulting slurry was stirred overnight and filtered. The solid was washed with water until the water ran clear through the filter. The tan solid was then dried in vacuo and recrystallized from hexane to afford 90 grams of the title compound, m.p. 72.4-74.8°C. |
| With sulfuric acid at 70℃; for 12h; | ||
| 1.21 g | With sulfuric acid In water at 60℃; for 48h; | 1.2 Step 2: Synthesis of 3,5,6,7-tetrahydro-2H-S-inda-1-one M1 (3.00g, 14.4mmol) was added to concentrated sulfuric acid (30mL) in batches and stirred at 60°C for 48h. After the end of the reaction, ice water was slowly added to dilute at 0°C, then pH=7 was adjusted with saturated NaOH aqueous solution, and the compound M2 (1.21g, 49%) was purified by silica gel column chromatography. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sulfuric acid at 70℃; for 3.5h; Yield given. Yields of byproduct given; | ||
| With sulfuric acid at 55 - 60℃; for 48h; | ||
| With sulfuric acid at 80 - 90℃; for 1h; regioselective reaction; |
| With sulfuric acid at 55 - 60℃; for 48h; | ||
| 1: 112.2 g 2: 10 g | With sulfuric acid at 55℃; for 16h; | 2 Step 2: 1,2,3,5,6,7-Hexahydro-s-indacen-l-one Into a 1-L round-bottom flask was placed a solution of 3-chloro-l-(2,3-dihydro-lH-inden-5- yl)propan-l-one (160.5 g, 759 mmol) in cone. H2S04(900 mL). The resulting solution was stirred for 16 h at 55°C and then was quenched by adding the reaction mixture carefully to 4500 mL of water/ice. The solids were collected by filtration and dried over infrared lamp for 24 h. The crude mixture was purified by chromatography and eluted with ethyl acetate/petroleum ether (1 : 100). This resulted in 10 g (7.6%) of l,6,7,8-tetrahydro-as-indacen-3(2H)-one (compound 113"a) and 112.2 g (85%) of the title compound (compound 113") as a yellow solid. NMR (400 MHz, DMSO-i) δ 7.44 (s, 1H), 7.39 (s, 1H), 3.13 - 2.79 (m, 8H), 2.70 - 2.55 (m, 2H), 2.20 - 1.90 (m, 2H).1H MR (400 MHz, DMSO-d) δ 7.49 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 3.19 - 2.98 (m, 4H), 2.93 - 2.80 (m, 3H), 2.68 - 2.54 (m, 2H), 2.15 - 1.95 (m, 2H). |
| 1: 112.2 g 2: 10 g | With sulfuric acid at 55℃; for 16h; | 2 Step 2: 3,5,6,7-tetrahydro-s-indacen-1(2H)-one and 1,6,7,8-tetrahydro-as-indacen-3(2H)-one Into a 1,000 mL round-bottom flask was placed a solution of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (160.50 g, 759.0 mmol, 1.0 equiv.) in conc. H2SO4 (900 mL). The resulting solution was stirred for 16 h at 55 °C and then was quenched by adding the reaction mixture carefully to 4,500 mL of water/ice. The solids were collected by filtration and dried under an infrared lamp for 24 h. The solids were purified by flash column chromatography, eluting with ethyl acetate/petroleum ether (1:100) to give 112.2 g of 3,5,6,7-tetrahydro-s-indacen-1(2H)-one and 10 g of 1,6,7,8-tetrahydro-as-indacen-3(2H)-one as a yellow solid.Major: 1H NMR (400 MHz, DMSO-d6) d 7.44 (s, 1H), 7.39 (s, 1H), 3.13-2.79 (m, 6H), 2.70-2.55 (m, 2H), 2.20-1.90 (m, 2H).Minor: 1H NMR (400 MHz, DMSO-d6) d 7.49 (d, 1H), 7.31 (d, 1H), 3.19-2.98 (m, 4H), 2.93-2.80 (m, 2H), 2.68-2.54 (m, 2H), 2.15-1.95 (m, 2H). |
| 1: 112.2 g 2: 10 g | With sulfuric acid at 55℃; for 16h; | 2 Step 2: 1,2,3,5,6,7-Hexahydro-s-indacen-1-one The solution of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (160.5 g, 759 mmol) in conc. H2SO4 (900 mL) in a 1000-mL round-bottom flask was stirred for 16 h at 55 °C. The reaction was quenched by adding the reaction mixture carefully to 4500 mL of water/ice. The solids were collected by filtration and dried over infrared lamp for 24 h. The crude mixture was purified by chromatography and eluted with EtOAc/ PE (1:100). This resulted in 10 g (7.6%) of 1,6,7,8- tetrahydro-as-indacen-3(2H)-one (Cpd 46A) and 112.2 g (85%) of the title compound as a yellow solid. Compound 46:1H NMR (400 MHz, DMSO-d6) d 7.44 (s, 1H), 7.39 (s, 1H), 3.20-2.75 (m, 6H), 2.70-2.60 (m, 2H), 2.20-1.90 (m, 2H). Compound 46A:1H NMR (400 MHz, DMSO-d6) d 7.49 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 3.20-2.90 (m, 4H), 2.90-2.75 (m, 2H), 2.70-2.60 (m, 2H), 2.20-1.90 (m, 2H) |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 73% | Stage #1: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one With sulfuric acid at 60℃; for 48h; Stage #2: With nitric acid at 0 - 5℃; for 1h; Stage #3: With methanesulfonic acid; Pd(OH)2/C In methanol; water for 5h; | 3 1,2,3, 5,6,7-hexahydro-s-indacen-4-amine A mixture of 8-nitro-l,2,3,5,6,7-hexahydro-s-indacen-l-one and 4-nitro-l,2,3,5,6,7- hexahydro-s-indacen-l-one (7.00 g, 0.032 mol) was suspended in MeOH (70 ml). This was treated with 20 % palladium hydroxide on carbon (50 % water wet. 1.72 g, 0.012 mol) then methanesulfonic acid (3.41 g, 0.035 mol). The mixture was hydrogenated at 35 psi for 5 h. The catalyst was removed by filtration and washed with MeOH. The filtrate was diluted with water (350 ml) and then the pH adjusted to 11 with 2 N NaOH. The resulting slurry was filtered and the crude solids were recrystallised from MeOH/water (9:1) to afford of 1,2,3, 5,6,7-hexahydro-s-indacen-4-amine as colourless, crystal needles.Y = 73 %MS ES+: 174.1 1H NMR (400 MHz, DMSO-d6) δ 6.35 (s, 1H), 4.52 (s, 2H), 2.72 (t, J = 7 Hz, 4H), 2.59 (t, J = 7 Hz, 4H), 2.00 - 1.93 (m, 4H). |
| Multi-step reaction with 2 steps 1.1: H2SO4 / 48 h / 55 - 60 °C 2.1: HNO3; H2SO4 / 2 h / 0 - 5 °C 2.2: 8.8 kg / methanesulfonic acid; H2 / palladium hydroxide on carbon / methanol; H2O / 9 h / 2585.74 Torr | ||
| Multi-step reaction with 2 steps 1.1: sulfuric acid / 48 h / 60 °C 1.2: 0 - 5 °C 2.1: Pd(OH)2/C; methanesulfonic acid; hydrogen / methanol / 5 h / 1810.07 Torr |
| Multi-step reaction with 2 steps 1.1: sulfuric acid / 16 h / 55 °C 2.1: sulfuric acid; nitric acid / 2 h / 0 °C 2.2: 16 h / 20 °C / 2585.81 Torr | ||
| Stage #1: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one With sulfuric acid at 60℃; for 48h; Stage #2: With nitric acid at 0 - 5℃; for 1h; Stage #3: With methanesulfonic acid; 20% Pd/C; hydrogen In methanol; water for 5h; | 1.3 Step 3. l,2,3,5,6,7-Hexahydro-s-indacen-4-amine. A mixture of 8-nitro- 1,2,3,5,6,7- hexahydro-s-indacen-l-one and 4-nitro-l,2,3,5,6,7-hexahydro-s-indacen-l-one (7.00 g, 32 mmol, 1 eq.) was suspended in MeOH (70 ml). The solution was treated with 20 % palladium hydroxide on carbon (50 % water wet. 1.72 g, 12 mmol, 0.4 eq.) and methanesulfonic acid (3.41 g, 35 mmol, 1.1 eq.). The mixture was hydrogenated at 35 psi for 5 h. The catalyst was removed by filtration over a pad of Celite and the filtering bed was washed with MeOH. The filtrate was diluted with water (350 ml) and the pH adjusted to 11 with 2 M NaOH. The resulting slurry was filtered and the crude solid was recrystallised from MeOH/water (9: 1) to afford of 1,2,3,5,6,7- hexahydro-s-indacen-4-amine as colourless needles. Y = 73 %. MS ES+: 174.1. lH NMR (400 MHz, DMSO-) δ 6.35 (s, 1H), 4.52 (s, 2H), 2.72 (t, J= 7 Hz, 4H), 2.59 (t, J= 7 Hz, 4H), 2.00 - 1.93 (m, 4H). | |
| Multi-step reaction with 2 steps 1.1: sulfuric acid / 16 h / 55 °C 2.1: sulfuric acid; nitric acid / 2 h / 0 °C 2.2: 16 h / 25 °C / 2585.81 Torr | ||
| Multi-step reaction with 3 steps 1: sulfuric acid / 20 - 70 °C 2: sulfuric acid; nitric acid / 0 - 5 °C 3: palladium-carbon; hydrogen; sulfuric acid / methanol / 25 - 30 °C / Autoclave | ||
| Stage #1: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one With sulfuric acid at 60℃; for 48h; Stage #2: With nitric acid at 0 - 5℃; for 1h; | Step 3. l,2,3,5,6,7-Hexahydro-s-indacen-4-amine. A mixture of 8-nitro-l,2,3,5,6,7- hexahydro-s-indacen-l-one and 4-nitro-l,2,3,5,6,7-hexahydro-s-indacen-l-one (7.00 g, 32 mmol, 1 eq.) was suspended in MeOH (70 ml). The solution was treated with 20 % palladium hydroxide on carbon (50 % water wet. 1.72 g, 12 mmol, 0.4 eq.) and methanesulphonic acid (3.41 g, 35 mmol, 1.1 eq.). The mixture was hydrogenated at 35 psi for 5 h. The catalyst was removed by filtration over a pad of Celite and the filtering bed was washed with MeOH. The filtrate was diluted with water (350 ml) and the pH adjusted to 11 with 2 M NaOH. The resulting slurry was filtered and the crude solid was recrystallised from MeOH/water (9: 1) to afford of 1, 2, 3, 5,6,7- hexahydro-s-indacen-4-amine as colourless needles (Y = 73 %). NMR (400 MHz, DMSO-ifc) d ppm 6.35 (s, 1H), 4.52 (s, 2H), 2.72 (t, / = 7 Hz, 4H), 2.59 (t, / = 7 Hz, 4H), 2.00 - 1.93 (m, 4H). MS ES+: 174.1. | |
| Multi-step reaction with 2 steps 1.1: sulfuric acid / 24 h / 65 - 70 °C / Large scale 2.1: sulfuric acid; nitric acid / methanol / 30 min / 0 - 5 °C / Large scale 2.2: 32 h / 20 °C / 100 Torr / Large scale | ||
| Multi-step reaction with 2 steps 1.1: sulfuric acid / 24 h / 25 - 70 °C / Large scale 2.1: sulfuric acid; nitric acid / 1 h / 0 - 5 °C / Large scale 2.2: 32 h / 20 °C / 5171.62 Torr / Large scale | ||
| Multi-step reaction with 4 steps 1: sulfuric acid / dichloromethane / Reflux 2: sulfuric acid; nitric acid / dichloromethane / 3 h / 0 °C 3: trifluoroacetic acid / 20 °C / Inert atmosphere 4: 10% Pd/C; hydrogen / dichloromethane / 8 h / 0 - 20 °C | ||
| Multi-step reaction with 2 steps 1.1: sulfuric acid / 48 h / 60 °C 2.1: sulfuric acid; potassium nitrate / 2 h / 0 °C 2.2: 12 h / 66 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1.1: sulfuric acid / 24.5 h / 25 - 70 °C 2.1: sulfuric acid; nitric acid / 1 h / 0 - 30 °C / Large scale 2.2: 30 min / 25 - 30 °C / Large scale 2.3: 32 h / 20 °C / 5171.62 Torr / Large scale | ||
| Multi-step reaction with 2 steps 1.1: sulfuric acid / 16 h / 55 °C 2.1: sulfuric acid; nitric acid / 2 h / 0 - 20 °C 2.2: 16 h / 20 °C | ||
| Multi-step reaction with 3 steps 1: sulfuric acid / 12 h / 70 °C 2: sulfuric acid; nitric acid / 1 h / 0 °C 3: Pd(OH)2/C; hydrogen; methanesulfonic acid / methanol / 24 h / 20 °C / 760.05 Torr | ||
| Multi-step reaction with 2 steps 1.1: sulfuric acid / water / 48 h / 60 °C 2.1: sulfuric acid; potassium nitrate / water / 2 h / 0 °C 2.2: 12 h / 66 °C / Inert atmosphere |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: H2SO4 / 48 h / 55 - 60 °C 2: HNO3; H2SO4 / 2 h / 0 - 5 °C | ||
| Multi-step reaction with 2 steps 1: sulfuric acid / 16 h / 55 °C 2: sulfuric acid; nitric acid / 2 h / 0 °C | ||
| Multi-step reaction with 2 steps 1: sulfuric acid / water / 12 h / 70 °C 2: sulfuric acid; nitric acid / 1 h / 0 - 10 °C |
| Multi-step reaction with 2 steps 1: sulfuric acid / 40 h / 55 °C 2: sulfuric acid; nitric acid / 1 h / 0 °C | ||
| Multi-step reaction with 2 steps 1: sulfuric acid / dichloromethane / Reflux 2: sulfuric acid; nitric acid / dichloromethane / 3 h / 0 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 5 steps 1.1: H2SO4 / 48 h / 55 - 60 °C 2.1: HNO3; H2SO4 / 2 h / 0 - 5 °C 2.2: 8.8 kg / methanesulfonic acid; H2 / palladium hydroxide on carbon / methanol; H2O / 9 h / 2585.74 Torr 3.1: 80 g / Et3N / tetrahydrofuran / 4 h / Heating 4.1: MeONa / tetrahydrofuran 4.2: 4.9 g / tetrahydrofuran / 4 h / Heating 5.1: 8.33 g / aq. HCl | ||
| Multi-step reaction with 5 steps 1.1: H2SO4 / 48 h / 55 - 60 °C 2.1: HNO3; H2SO4 / 2 h / 0 - 5 °C 2.2: 8.8 kg / methanesulfonic acid; H2 / palladium hydroxide on carbon / methanol; H2O / 9 h / 2585.74 Torr 3.1: dimethylaminopyridine / acetonitrile / 0.09 h / 20 °C 3.2: acetonitrile / 0.52 h / 20 °C 4.1: MeONa / tetrahydrofuran 4.2: 4.9 g / tetrahydrofuran / 4 h / Heating 5.1: 8.33 g / aq. HCl |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 1: 42% 2: 11% 3: 5% | Stage #1: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one With sulfuric acid at 55 - 60℃; for 48h; Stage #2: With sulfuric acid; nitric acid at 0 - 5℃; for 1h; | |
| 1: 36% 2: 5% 3: 3.5% | Stage #1: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one With sulfuric acid at 60℃; for 48h; Stage #2: With sulfuric acid; nitric acid at 0 - 5℃; | 2 Step 2. Mixture of 8-nitro- 1,2,3, 5,6, 7-hexahydro-s-indacen-l -one (Intermediate lb), 4-nitro- 1.2.3.5.6.7- hexahydro-s-indacen-1-one (Intermediate 1c) and 5-nitro-l,2,3,6,7,8- hexahydroas-indacen-3-one (Intermediate 1d) 3-chloro-1-(2,3-dihydro-lH-inden-5-yl)propan-1-one (Intermediate la) (82 g, 0.39 mol) was added portion wise as a solid to a concentrated sulfuric acid (71 ml, 1.34 mol). The resulting mixture was heated to 60 °C for two days. Then RM was cooled to 0 °C and a mixture of nitric acid (26 ml, 0.59 mol) and sulfuric acid (26 ml, 0.49 mol) was added dropwise. RM was stirred for one hour, temperature was kept between 0 °C and 5 °C. The RM was slowly added to a mixture of water and DCM with ice bath cooling. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine and saturated sodium bicarbonate. The organic layers were dried over Na2S04 and filtered. The crude mixture was purified by FCC (hexane/ethyl acetate). Obtained fractions was crystallized from MeOH. Obtained: 8-nitro- 1,2,3, 5, 6, 7-hexahydro-s-indacen-l -one (Intermediate lb), (30.77g; 0.14 mol; 36 %) UPLC-MS: purity 98 %, 218 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 3.15 - 3.08 (m, 2H), 3.04 (t, J = 7.5 Hz, 2H), 2.90 (t, J = 7.5 Hz, 2H), 2.77 - 2.71 (m, 2H), 2.13 (p, J = 7.5 Hz, 2H); 4-nitro-l,2,3,5,6,7-hexahydro-s- indacen-1-one (Intermediate lc), (5.19 g; 0.02 mol; 5 %) UPLC-MS: purity 100 %, 218 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 3.41 - 3.36 (m, 2H), 3.34 - 3.29 (m, 3H), 3.02 (t, J = 7.5 Hz, 2H), 2.77 - 2.69 (m, 2H), 2.13 (p, J = 7.6 Hz, 2H); 5-nitro- 1.2.3.6.7.8- hexahydroas-indacen-3-one (Intermediate Id), (3.00 g; 0.01 mol; 3.5 %) UPLC-MS: purity 100 %, 218 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 3.39 (t, J = 7.6 Hz, 2H), 3.14 - 3.09 (m, 2H), 3.01 (t, J = 7.7 Hz, 2H), 2.81 - 2.73 (m, 2H), 2.19 (p, J = 7.7 Hz, 2H). |
| 1: 36% 2: 5% 3: 4% | Stage #1: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one With sulfuric acid at 60℃; for 48h; Stage #2: With nitric acid at 0 - 5℃; for 1h; | 2 Mixture of 8-nitro-l,2,3,5,6,7-hexahydro-s-indacen-l-one, 4-nitro-l,2,3,5,6,7-hexahydro-s- indacen-l-one and 5-nitro-l,2,3,6,7,8-hexahydroas-indacen-3-one 3-chloro-l-(2,3-dihydro-lH-inden-5-yl)propan-l-one (82 g, 0.39 mol) was added portion wise to concentrated sulfuric acid (71 ml, 1.34 mol). The resulting mixture was heated to 60°C for 2 days. The RM was cooled to 0°C and a mixture of nitric acid (26 ml, 0.59 mol) and sulfuric acid (26 ml, 0.49 mol) was added dropwise. The RM was stirred at a temperature between 0°C and 5°C for 1 h. The RM was slowly added to a mixture of water and DCM with ice bath cooling. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed sequentially with brine and saturated sodium bicarbonate. The organic layers were dried over Na2SO4and filtered. The crude mixture was purified by FCC (hexane/ethyl acetate). The products were further purified by crystallisation from MeOH to give the desired products.8-nitro-l,2,3,5,6,7-hexahydro-s-indacen-l-one:Y= 36 %MS ES+: 2181H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 3.15 - 3.08 (m, 2H), 3.04 (t, J = 8 Hz, 2H), 2.90 (t, J = 8 Hz, 2H), 2.77 - 2.71 (m, 2H), 2.17 - 2.10 (m, 2H).4-nitro-l,2,3,5,6,7-hexahydro-s-indacen-l-one:Y= 5 %MS ES+: 2181H NMR (400 MHz, DMS0-d6) δ 7.82 (s, 1H), 3.41 - 3.36 (m, 2H), 3.34 - 3.29 (m, 3H), 3.02 (t, J = 8 Hz, 2H), 2.77 - 2.69 (m, 2H), 2.17 - 2.10 (m, 2H). 5-nitro-l,2,3,6,7,8-hexahydroas-indacen-3-one:Y = 4 %MS ES+: 2181H NMR (400 MHz, DMS0-d6) δ 8.09 (s, 1H), 3.39 (t, J = 8 Hz, 2H), 3.14 - 3.09 (m, 2H), 3.01 (t, J = 8 Hz, 2H), 2.81 - 2.73 (m, 2H), 2.23 - 2.15 (m, 2H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: sulfuric acid / 16 h / 55 °C 2: methanesulfonic acid; 10 wt% Pd(OH)2 on carbon; hydrogen / methanol / 16 h / 20 °C 3: bromine; iodine / tetrachloromethane / 2.17 h / 0 °C / Inert atmosphere | ||
| Multi-step reaction with 3 steps 1: sulfuric acid / 16 h / 55 °C 2: methanesulfonic acid; palladium hydroxide, 20 wt% on carbon; hydrogen / methanol / 16 h / 20 °C 3: bromine; iodine / tetrachloromethane / 2.17 h / 0 °C / Inert atmosphere | ||
| Multi-step reaction with 3 steps 1: sulfuric acid / 16 h / 55 °C 2: hydrogen; methanesulfonic acid; 20% palladium hydroxide-activated charcoal / methanol / 16 h / 20 °C 3: tetrachloromethane; iodine; bromine / 2.17 h / Inert atmosphere |
| Multi-step reaction with 3 steps 1: sulfuric acid / water / 12 h / 70 °C 2: hydrogen; methanesulfonic acid; palladium hydroxide, 20 wt% on carbon / methanol / 12 h / 25 °C / 775.74 Torr 3: iodine; bromine / tetrachloromethane / 2 h / 0 °C | ||
| Multi-step reaction with 3 steps 1: sulfuric acid / 24 h / 60 °C 2: palladium(II) hydroxide; methanesulfonic acid; hydrogen / methanol / 16 h / 20 °C 3: iodine; bromine / tetrachloromethane / 2 h / 0 °C | ||
| Multi-step reaction with 3 steps 1: sulfuric acid / 16 h / 55 °C 2: methanesulfonic acid; 10 wt% Pd(OH)2 on carbon; hydrogen / methanol / 16 h / 20 °C 3: iodine; bromine / tetrachloromethane / 2.17 h / 0 °C / Inert atmosphere | ||
| Multi-step reaction with 3 steps 1: sulfuric acid / 16 h / 55 °C 2: methanesulfonic acid; 10 wt% Pd(OH)2 on carbon; hydrogen / methanol / 16 h / 20 °C 3: iodine; bromine / tetrachloromethane / 2.17 h / 0 °C / Inert atmosphere | ||
| Multi-step reaction with 3 steps 1: sulfuric acid / 16 h / 55 °C 2: hydrogen; 20% palladium hydroxide-activated charcoal; methanesulfonic acid / methanol / 16 h / 20 °C 3: bromine; iodine / tetrachloromethane / 2.17 h / 0 °C | ||
| Multi-step reaction with 3 steps 1: sulfuric acid / water / 12 h / 70 °C 2: hydrogen; palladium hydroxide, 20 wt% on carbon; methanesulfonic acid / methanol / 12 h / 25 °C / 775.74 Torr 3: iodine; bromine / tetrachloromethane / 2 h / 0 °C | ||
| Multi-step reaction with 3 steps 1: sulfuric acid / 24 h / 55 °C 2: methanesulfonic acid; 10 wt% Pd(OH)2 on carbon; hydrogen / water; methanol / 48 h / 25 °C 3: iodine; bromine / tetrachloromethane / 2.17 h / 0 °C / Inert atmosphere |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1.1: sulfuric acid / 16 h / 55 °C 2.1: sulfuric acid; nitric acid / 2 h / 0 °C 2.2: 16 h / 20 °C / 2585.81 Torr 3.1: 4-nitro-4-methyl-2,3,5,6-tetrabromo-2,5-cyclohexadien-1-one / ethanol / 12 h / 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1.1: sulfuric acid / 16 h / 55 °C 2.1: sulfuric acid; nitric acid / 2 h / 0 °C 2.2: 16 h / 20 °C / 2585.81 Torr 3.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 12 h / 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 36% | Stage #1: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one With sulfuric acid at 60℃; for 48h; Stage #2: With nitric acid at 0 - 5℃; for 1h; | 1.2 Step 2. 8-nitro-l,2,3,5,6,7-hexahydro-s-indacen-l-one and 4-nitro-l,2,3,5,6,7-hexahydro-s- indacen-l-one. 3-Chloro-l-(2,3-dihydro-lH-inden-5-yl)propan-l-one (82 g, 0.39 mol, 1 eq.) was added portion wise to concentrated sulfuric acid (71 ml, 1.34 mol, 3.4 eq.). The resulting mixture was heated to 60°C for 2 days. The RM was cooled to 0°C and a mixture of nitric acid (26 ml, 0.59 mol, 1.5 q.) and concentrated sulfuric acid (26 ml, 0.49 mol, 1.25 eq.) was added drop wise. The RM was stirred for 1 h, maintaining temperature between 0°C and 5°C. The RM was slowly added to a mixture of water and DCM with ice bath cooling. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed sequentially with brine and saturated sodium bicarbonate. The organic layers were dried over Na2S04 and filtered. The crude mixture was purified by FCC (hexane/ethyl acetate). The desired products were further purified by crystallisation from MeOH. 8-Nitro-l,2,3,5,6,7- hexahydro-s-indacen-l-one : Y = 36 %. MS ES+: 218. NMR (400 MHz, DMSO-) δ 7.67 (s, 1H), 3.15 - 3.08 (m, 2H), 3.04 (t, J = 8 Hz, 2H), 2.90 (t, J= 8 Hz, 2H), 2.77 - 2.71 (m, 2H), 2.17 - 2.10 (m, 2H). 4-Nitro-l,2,3,5,6,7-hexahydro-s-indacen-l-one : Y = 5 %. MS ES+: 218. NMR (400 MHz, DMSO) δ 7.82 (s, 1H), 3.41 - 3.36 (m, 2H), 3.34 - 3.29 (m, 3H), 3.02 (t, J= 8 Hz, 2H), 2.77 - 2.69 (m, 2H), 2.17 - 2.10 (m, 2H). |
| Multi-step reaction with 2 steps 1: sulfuric acid / 16 h / 55 °C 2: sulfuric acid; nitric acid / 2 h / 0 °C | ||
| Multi-step reaction with 2 steps 1: sulfuric acid / 20 - 70 °C 2: sulfuric acid; nitric acid / 0 - 5 °C |
| Stage #1: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one With sulfuric acid at 60℃; for 48h; Stage #2: With nitric acid at 0 - 5℃; for 1h; | Step 2. 8-Nitro-l,2,3,5,6,7-hexahydro-s-indacen-l-one and 4-nitro-l,2,3,5,6,7- hexahydro-s-indacen-l-one. 3-Chloro-l-(2,3-dihydro-lH-inden-5-yl)propan-l-one (82 g, 0.39 mol, 1 eq.) was added portionwise to concentrated sulphuric acid (71 ml, 1.34 mol, 3.4 eq.). The resulting mixture was heated to 60° C for 2 days. The RM was cooled to 0° C and a mixture of nitric acid (26 ml, 0.59 mol, 1.5 q.) and concentrated sulphuric acid (26 ml, 0.49 mol, 1.25 eq.) was added dropwise. The RM was stirred for 1 h, maintaining temperature between 0° C and 5° C. The RM was slowly added to a mixture of water and DCM with ice bath cooling. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed sequentially with brine and saturated sodium bicarbonate. The organic layers were dried over Na2SC>4 and filtered. The crude mixture was purified by FCC (hexane/ethyl acetate). The desired products were further purified by crystallisation from MeOH. 8-Nitro-l,2,3,5,6,7-hexahydro-s-indacen-l-one: Y = 36 %. NMR (400 MHz, DMSO-rie) d ppm 7.67 (s, 1H), 3.15 - 3.08 (m, 2H), 3.04 (t, / = 8 Hz, 2H), 2.90 (t, / = 8 Hz, 2H), 2.77 - 2.71 (m, 2H), 2.17 - 2.10 (m, 2H). MS ES+: 218. 4-Nitro-l,2,3,5,6,7-hexahydro-s-indacen-l-one: Y = 5 %. NMR (400 MHz, DMSO-rie) d ppm 7.82 (s, 1H), 3.41 - 3.36 (m, 2H), 3.34 - 3.29 (m, 3H), 3.02 (t, / = 8 Hz, 2H), 2.77 - 2.69 (m, 2H), 2.17 - 2.10 (m, 2H). MS ES+: 218. | |
| Stage #1: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one With sulfuric acid at 55℃; for 48h; Stage #2: With nitric acid at 0 - 10℃; for 2h; | S1.2 Step 2: Synthesis of 8-nitro-3,5,6, 7-tetrahydro-s-indacen-l (2ff)-one and 4-nitro-3,5,6, 7 -tetrahydro-s- indacen-1 ( 2H) -one A solution of 3-chloro-l-(2,3-dihydro-lH-inden-5-yl)propan-l-one (1.80 kg, 8 63 mol) in H2SO4 (9.00 L) was stirred at 55°C tor 48 hrs. The mixture was then charged w th HNO3 (600 g, 9.52 mol) dropwise at 0 °C~10 °C. After stirring at 0°C - 10°C for 2 hours, the reaction solution was poured into water (20.0 L) and DCM (5.00 L). The aqueous phase was separated and extracted with DCM (5 x 2.00 L). The combined organic phase was washed with water (5.00 L), 2 N NaOH aqueous (5.00 L), and concentrated in vacuo to ~ 5.00 L. Me OH (5.00 L) was added and the evaporation continued. Once the volume was ~ 5.00 L, the mixture was cooled to 0°C. The solid was collected by suction filtration to give 8~nitro-3,5,6,7-tetrahydro-s~indacen-l(2H)-one and 4-nitro-3,5,6,7-tetrahydro-s-mdaecn-l(2H)-one (700 g, 37.2% yield) as a browm solid. MS: m/z 218.0 (M+H+) | |
| Multi-step reaction with 2 steps 1: sulfuric acid / 24 h / 65 - 70 °C / Large scale 2: sulfuric acid; nitric acid / methanol / 30 min / 0 - 5 °C / Large scale | ||
| Multi-step reaction with 2 steps 1: sulfuric acid / 16 h / 55 °C 2: sulfuric acid; nitric acid / 2 h / 0 - 20 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1.1: sulfuric acid / 16 h / 55 °C 2.1: sulfuric acid; nitric acid / 2 h / 0 °C 2.2: 16 h / 25 °C / 2585.81 Torr 3.1: N-iodo-succinimide / N,N-dimethyl-formamide / 3 h / 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1: sulfuric acid / 20 - 70 °C 2: sulfuric acid; nitric acid / 0 - 5 °C 3: 5%-palladium/activated carbon; hydrogen; sulfuric acid / methanol / 25 - 30 °C / Autoclave 4: carbonic acid dimethyl ester / 31.17 h / 50 - 95 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1.1: sulfuric acid / 48 h / 55 °C 1.2: 2 h / 0 - 10 °C 2.1: Selectfluor / methanol / 12 h / 70 °C / Inert atmosphere | ||
| Multi-step reaction with 3 steps 1: sulfuric acid / 40 h / 55 °C 2: sulfuric acid; nitric acid / 1 h / 0 °C 3: Selectfluor / methanol / 12 h / 70 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1.1: sulfuric acid / 48 h / 55 °C 1.2: 2 h / 0 - 10 °C 2.1: Selectfluor / methanol / 12 h / 70 °C / Inert atmosphere 3.1: caesium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C | ||
| Multi-step reaction with 4 steps 1: sulfuric acid / 40 h / 55 °C 2: sulfuric acid; nitric acid / 1 h / 0 °C 3: Selectfluor / methanol / 12 h / 70 °C / Inert atmosphere 4: caesium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C |