Process for the preparation of indanones

Abstract

A process of forming compounds of formula I ##STR00001##
comprising the steps of addition of an amino compound H.sub.2NR to a compound of formula (II) ##STR00002##
followed by cyclization, isomerization and hydrolysis.

Claims

1. A process of making a compound of formula (I) ##STR00030## comprising the steps of: a) addition of an amino compound H.sub.2NR to a compound of formula (II) ##STR00031## followed by cyclization to a compound of formula (III); ##STR00032## wherein the wavy bond in formula (II) indicates an unspecified configuration of the adjacent double bond; and the amino compound H.sub.2NR is selected from the group consisting of alkylamides, sulfonamides and carbamates; b) isomerization of compound of formula (III) to a compound of formula (IV); ##STR00033## c) hydrolysis of compound of formula (IV) to compound of formula (I); wherein, in the compounds of formula (I), (II), (III) and/or (IV), R.sup.1 represents methyl, ethyl, ethenyl, a linear, branched or cyclic C3-10 alkyl or alkenyl group, or a phenyl group, optionally substituted; and R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 each independently represent a hydrogen atom, methyl, ethyl, ethenyl, methoxy, ethoxy, ethenoxy, a linear, branched or cyclic C3-10 alkyl, alkenyl or alkoxy group, a halogen atom or a phenyl group, optionally substituted, and wherein the process is carried out in a one-pot procedure.

2. The process according to claim 1, wherein the amino compound H.sub.2NR is an alkylamide, and R represents (CO)Me or (CO)Et.

3. The process according to claim 1, wherein the amino compound H.sub.2NR is a sulfonamide, and R represents SO.sub.2Me, SO.sub.2Et or SO.sub.2PhMe.

4. The process according to claim 1, wherein the amino compound H.sub.2NR is a carbamate, and R represents CO.sub.2Me, CO.sub.2Et.

Description

EXAMPLES

Example 1: Preparation of 6-Isobutyl-2-methyl-2,3-dihydro-1H-inden-1-oneStepwise Synthesis Using Methyl Carbamate (MeOCONH2)

Step 1: Methyl (6-isobutyl-2-methyl-1H-inden-1-yl)carbamate

(1) ##STR00012##

(2) A mixture of methyl carbamate (39.4 g, 0.519 mol, 1.05 eq.) and (E)-3-(4-isobutylphenyl)-2-methylacrylaldehyde (dehydrosilvial, 100 g, 0.494 mol, 1-2% (Z)-isomer) in dichloroethane (400 ml) was heated to 35 C. and the resulting solution was treated with iron trichloride (8.27 g, 0.049 mol, 0.1 eq.). The resulting mixture was heated to reflux (79 C.), stirred for 2 h, cooled to 15 C., treated with EtOAc (100 ml), and washed with 1N aq. HCl (80 ml). The organic phase was washed twice with aqueous saturated NaHCO.sub.3 (50 ml), twice with aqueous saturated NaCl (50 ml), dried with MgSO.sub.4, filtered, and the solvent evaporated. The crude product (120 g, brown solid) was triturated with hexane (300 ml), filtered, washed with hexane (150 ml), and dried, giving methyl (6-isobutyl-2-methyl-1H-inden-1-yl)carbamate (91 g, 92% pure, slightly brown-coloured solid, 71% yield).

(3) R.sub.f (hexane/MTBE 10:1): 0.25; .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.19 (br. s, 1H), 7.05 (br. d, J=7.6, 1H), 7.01 (br. d, J=7.3, 1H), 6.35 (br. s, 1H), 5.20 (br. d, J=9.8, 1H), 4.65 (br. d, J=9.5, 1H), 3.78 (br. s, OMe), 2.46 (d, J=7.1, CH.sub.2), 2.02 (s, Me), 1.85 (hept., J=6.7, 1H), 0.91 (d, J=6.6, CMe.sub.2); .sup.13C-NMR (100 MHz, CDCl.sub.3): 157.78 (s), 145.72 (s), 144.22 (s), 141.08 (s), 138.60 (s), 128.84 (d), 127.47 (d), 124.15 (d), 119.62 (d), 60.41 (d), 52.44 (q), 45.34 (t), 30.38 (d), 22.35 (2q), 13.96 (q); MS (EI): 260 (10), 259 (53), 244 (5), 227 (10), 216 (47), 202 (29), 185 (21), 184 (100), 170 (14), 156 (42), 142 (43), 141 (96), 128 (26), 115 (32).

Step 2: Methyl (5-isobutyl-2-methyl-1H-inden-3-yl)carbamate

(4) ##STR00013##

(5) At 50 C., a solution of methyl (6-isobutyl-2-methyl-1H-inden-1-yl)carbamate (90 g, 0.347 mol) in MeOH (230 ml) was treated dropwise with 2M aq. NaOH (87 ml, 0.174 mol, 0.5 eq.) while the reaction temperature was increased to reflux temperature to allow stirring. The resulting mixture was stirred at reflux for 2 h, cooled, treated with ice (100 g), and extracted with MTBE (1 l). The organic phase was washed with aq. sat. NH.sub.4Cl soln. (100 ml), twice with aq. sat. NaCl soln. (100 ml), dried over MgSO.sub.4, filtered, and the solvent evaporated. The crude product (85.5 g, brown solid) was triturated with hexane (300 ml), filtered, washed with hexane (150 ml), and dried, giving methyl (5-isobutyl-2-methyl-1H-inden-3-yl)carbamate (74.5 g, 89% pure, slightly brown-coloured solid, 74% yield).

(6) R.sub.f (hexane/MTBE 10:1): 0.13; .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.23 (br. d, J=7.3, 1H), 6.96 (br. s, 1H), 6.92 (br. dd, J=1.4, 7.5, 1H), 6.13 (br. s, 1H), 3.76 (br. s, OMe), 3.27 (br. s, CH.sub.2), 2.49 (d, J=7.1, CH.sub.2), 2.04 (s, Me), 1.86 (hept., J=6.7, 1H), 0.90 (d, J=6.6, CMe.sub.2); .sup.13C-NMR (100 MHz, CDCl.sub.3): 157.07 (br. s), 142.57 (s), 139.73 (s), 138.22 (s), 135.65 (br. s), 131.00 (br. s), 125.38 (d), 122.99 (d), 118.20 (br. d), 52.54 (q), 45.53 (t), 40.27 (t), 30.42 (d), 22.37 (2q), 13.77 (br. q).

(7) MS (EI): 260 (6), 259 (34), 244 (4), 227 (25), 216 (29), 202 (18), 185 (17), 184 (100), 170 (23), 156 (29), 142 (28), 141 (56), 128 (20), 115 (22).

Step 3: 6-Isobutyl-2-methyl-2,3-dihydro-1H-inden-1-one

(8) ##STR00014##

(9) A suspension of methyl (5-isobutyl-2-methyl-1H-inden-3-yl)carbamate (73 g, 0.28 mol) in methanol (70 ml) and 35% aq. sulfuric acid (87 g, 0.31 mol, 1.1 eq.) was heated at reflux (80 C.) for 1 h, cooled, and extracted with MTBE (100 ml). The org. phase was washed with 2M aq. HCl and the combined aq. phases were extracted twice with MTBE (70 ml). The combined org. phases were washed with aqueous saturated NaHCO.sub.3 (100 ml), with aqueous saturated NaCl (100 ml), filtrated, and the filtrate dried with MgSO.sub.4, filtered, and the solvent evaporated. The crude product (53 g) was distilled using a short-path Vigreux-distillation apparatus (0.1 mbar, oil bath temperature: 155 to 175 C., head temperature 98-115 C.) giving 6-isobutyl-2-methyl-2,3-dihydro-1H-inden-1-one (49.5 g, 99.6% pure, yellow oil, 87% yield).

(10) R.sub.f (hexane/MTBE 10:1): 0.48; .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.53 (br. s, 1H), 7.38 (dd, J=1.5, 7.8, 1H), 7.34 (br. dm, J=0.7, 7.8, 1H), 3.35 (m, 1H), 2.75-2.64 (m, 2H), 2.52 (d, J=7.1, CH.sub.2), 1.87 (hept., J=6.7, 1H), 1.30 (d, J=7.6, Me), 0.90 (d, J=6.6, CMe.sub.2); .sup.13C-NMR (100 MHz, CDCl.sub.3): 209.5 (s), 151.0 (s), 141.0 (s), 136.3 (s), 135.9 (d), 126.0 (d), 123.9 (d), 44.8 (t), 42.2 (d), 34.5 (t), 30.1 (d), 22.2 (2q), 16.2 (q); MS (EI): 203 (5), 202 (34), 187 (8), 160 (71), 159 (100), 145 (26), 141 (6), 131 (14), 129 (11), 128 (14), 116 (12), 115 (27), 91 (13), 77 (6).

(11) Yield over 3 steps: 46%

Example 2a: Preparation of 6-Isobutyl-2-methyl-2,3-dihydro-1H-inden-1-oneOne-Pot Synthesis Using Methyl Carbamate (MeOCONH2)

(12) ##STR00015##

(13) A mixture of (E)-3-(4-isobutylphenyl)-2-methylacrylaldehyde (dehydrosilvial, 5 g, 24.7 mmol, 1-2% (Z)-isomer) and methyl carbamate (2 g, 26 mmol, 1.05 eq.) in toluene (20 ml) was treated with iron trichloride (0.4 g, 2.47 mmol, 0.1 eq.), and heated at reflux temperature for 30 min. The reaction mixture was then cooled to 45 C., treated with 2N aq. NaOH (11 ml) and methanol (5 ml) and stirred at reflux temperature for 21 h. The resulting mixture was cooled to 55 C., treated with conc. H.sub.2SO.sub.4 (1.85 g), stirred at reflux temperature for 10 h, and cooled to 20 C. The aq. phase was separated and the org. phase was diluted with MTBE (25 ml) and washed with 2N aq. HCl. The combined aq. phases were extracted twice with MTBE (10 ml) and the combined organic phases were washed with aq. sat. NaHCO.sub.3 (10 ml), twice with aq. sat. NaCl (10 ml), dried with MgSO.sub.4, filtered, and the solvent evaporated. The crude product (5.6 g, brown oil) was distilled using a Kugelrohr apparatus (150-200 C., 0.08-0.1 mbar) giving 6-isobutyl-2-methyl-2,3-dihydro-1H-inden-1-one as characterized in Example 1 (3.97 g, 93% pure, yellow oil, 74% yield).

Example 2b: Alternatively, the Following Conditions can be Applied

(14) A mixture of (E)-3-(4-isobutylphenyl)-2-methylacrylaldehyde (dehydrosilvial, 20 g, 99 mmol, 1-2% (Z)-isomer), iron trichloride (2.455 g, 14.8 mmol, 0.15 eq.), and toluene (8 ml) was warmed to 73-75 C. and treated dropwise (25 min) with a warm solution (40 C.) of methyl carbamate (7.5 g, 99 mmol, 1.0 eq.) in toluene (22 ml). The resulting mixture was heated at 75 C. for 80 min, treated dropwise first with methanol (15 ml) and then with 32% aq. NaOH (18.54 g, 1.5 eq.) and stirred at reflux temperature (60 C.) for 30 min. The resulting mixture was treated with conc. H.sub.2SO.sub.4 (17.35 g, 1.7 eq.), stirred at reflux temperature (60 C.) for 30 min, cooled to 20 C., treated with hexane (40 ml) and 2M aq. HCl (60 ml). The aq. phase was separated and the org. phase was diluted with MTBE (25 ml) and washed with 2N aq. HCl. The combined aq. phases were extracted three times with hexane (25 ml) and the combined organic phases were washed with aq. sat. NaHCO.sub.3 (50 ml), twice with aq. sat. NaCl (50 ml), dried with MgSO.sub.4, filtered, and the solvent evaporated. The crude product (20.1 g, brown oil) was distilled using a short-path distillation apparatus (120-180 C., 0.08 mbar) giving 6-isobutyl-2-methyl-2,3-dihydro-1H-inden-1-one (16.2 g, 95% pure, yellow oil, 77% yield).

Example 3: Preparation of 6-Isobutyl-2-methyl-2,3-dihydro-1H-inden-1-oneOne-Pot Synthesis Using Ethyl Carbamate (EtOCONH2)

(15) ##STR00016##

(16) A mixture of (E)-3-(4-isobutylphenyl)-2-methylacrylaldehyde (dehydrosilvial, 3 g, 14.8 mmol, 1-2% (Z)-isomer) and ethyl carbamate (1.3 g, 14.8 mmol, 1 eq.) in toluene (30 ml) was treated with iron trichloride (360 mg, 2.2 mmol, 0.15 eq.), and heated at reflux temperature for 50 min. The reaction mixture was then cooled to 10 C., treated with 2N aq. NaOH (10 ml) and methanol (11 ml) and stirred at reflux temperature for 4 h. The resulting mixture was cooled to 15 C., treated with conc. HCl (2.5 ml), stirred at reflux temperature for 13 h, cooled, and poured into ice. The aq. phase was separated and extracted three times with MTBE. The combined organic phases were washed with aq. sat. NaHCO.sub.3, twice with aq. sat. NaCl, dried with MgSO.sub.4, filtered, and the solvent evaporated. The crude product (3.94 g, brown oil) was distilled using a Kugelrohr apparatus (170-190 C., 0.1 mbar) giving 6-isobutyl-2-methyl-2,3-dihydro-1H-inden-1-one as characterized in Example 1 (3 g, 84% pure, yellow oil, 84% yield).

Intermediate 1 (Ethyl (6-isobutyl-2-methyl-1H-inden-1-yl)carbamate)

(17) .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.18 (br. s, 1H), 7.02 (br. d, J=7.6, 1H), 6.97 (br. d, J=7.6, 1H), 6.33 (br. m, 1H), 5.18 (br. d, J=9.8, 1H), 4.69 (br. d, J=9.8, 1H), 4.20 (q, J=7.1, OCH.sub.2), 2.44 (d, J=7.3, CH.sub.2), 1.99 (s, Me), 1.83 (hept., J=6.7, 1H), 1.27 (d, J=7.1, Me). 0.89 (d, J=6.6, CMe.sub.2); .sup.13C-NMR (100 MHz, CDCl.sub.3): 157.4 (s), 145.8 (s), 144.3 (s), 141.0 (s), 138.4 (s), 128.7 (d), 124.1 (d), 119.5 (br. d), 61.1 (t), 60.3 (d), 45.3 (t), 30.3 (d), 22.3 (2q), 14.5 (q), 13.9 (br. q); MS (EI): 274 (10), 273 (52), 258 (2), 244 (13), 230 (22), 227 (15), 216 (10), 200 (16), 185 (23), 184 (100), 170 (16), 156 (35), 142 (41), 141 (77), 128 (26), 115 (30).

Intermediate 2 (Ethyl (5-isobutyl-2-methyl-1H-inden-3-yl)carbamate)

(18) .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.25 (br. d, J=7.3, 1H), 6.99 (br. s, 1H), 6.94 (br. dd, J=1.3, 7.5, 1H), 6.22 (br. s, 1H), 4.23 (q, J=7.1, 14.2, OCH.sub.2), 3.29 (br. s, CH.sub.2), 2.51 (d, J=7.1, CH.sub.2), 2.06 (s, Me), 1.88 (hept., J=6.7, 1H), 1.23 (t, J=7.0, Me). 0.92 (d, J=6.6, CMe.sub.2); .sup.13C-NMR (100 MHz, CDCl.sub.3): 157.5 (br. s), 142.7 (s), 139.8 (s), 138.3 (s), 135.4 (br. s), 131.1 (br. s), 125.4 (d), 123.0 (d), 118.3 (br. d), 61.4 (br. t), 45.6 (t), 40.3 (t), 30.5 (d), 22.4 (2q), 14.6 (q), 13.9 (br. q); MS (EI): 274 (5), 273 (27), 244 (7), 230 (9), 227 (34), 216 (4), 200 (9), 185 (18), 184 (100), 170 (24), 156 (20), 142 (20), 141 (37), 128 (17), 115 (17).

Example 4: Preparation of 6-Isobutyl-2-methyl-2,3-dihydro-1H-inden-1-oneOne-Pot Synthesis Using Methanesulfonamide (MeSO2NH2)

(19) ##STR00017##

(20) A mixture of (E)-3-(4-isobutylphenyl)-2-methylacrylaldehyde (dehydrosilvial, 50 g, 247 mmol, 1-2% (Z)-isomer) and methanesulfonamide (25.2 g, 260 mmol, 1.05 eq.) in toluene (300 ml) was treated with iron trichloride (4.13 g, 24.7 mmol, 0.1 eq.), and heated at reflux temperature (98 C.) for 4 h. The reaction mixture was then cooled to 25 C., treated with methanol (50 ml) and 2N aq. NaOH (144 ml) and stirred for 2.5 h. The resulting mixture was treated dropwise with conc. HCl (53 ml), stirred at reflux temperature for 24 h, cooled, and poured into ice. The aq. phase was separated and extracted three times with MTBE. The combined organic phases were washed with aq. sat. NaHCO.sub.3, twice with aq. sat. NaCl, dried with MgSO.sub.4, filtered, and the solvent evaporated. The crude product (57 g, brown oil) was distilled (oil bath temperature 120-130 C.) using a short-path Vigreux distillation apparatus (head temperature 100 C., 0.06 mbar) giving 6-isobutyl-2-methyl-2,3-dihydro-1H-inden-1-one as characterized in Example 1 (36.1 g, 85% pure, yellow oil, 61% yield).

Intermediate 1 (N-(6-Isobutyl-2-methyl-1H-inden-1-yl)methanesulfonamide)

(21) .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.24 (br. s, 1H), 7.01 (br. d, J=7.3, 1H), 6.98 (br. dd, J=1.2, 7.6, 1H), 6.34 (br. m, 1H), 4.73 (br. d, J=9.8, 1H), 4.50 (br. d, J=9.8, 1H), 3.10 (s, SO.sub.2Me), 2.45 (d, J=7.1, CH.sub.2), 2.05-2.04 (2d, J=1.0, Me), 1.84 (hept., J=6.7, 1H), 0.90 (d, J=6.6, Me), 0.89 (d, J=6.6, Me); .sup.13C-NMR (100 MHz, CDCl.sub.3): 144.4 (s), 143.6 (s), 140.6 (s), 138.9 (s), 129.2 (d), 127.9 (d), 124.3 (d), 119.9 (d), 62.5 (d), 45.3 (t), 42.4 (q), 30.3 (d), 22.3 (2q), 14.0 (q); MS (EI): 279 (20), 264 (1), 236 (2), 200 (89), 199 (17), 184 (7), 172 (9), 157 (33), 156 (100), 142 (24), 141 (24), 130 (18), 128 (21), 115 (20).

Intermediate 2 (N-(5-isobutyl-2-methyl-1H-inden-3-yl)methanesulfonamide)

(22) .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.25 (br. dm, J=7.8, 1H), 7.15 (br. s, 1H), 6.96 (br. dd, J=1.5, 7.6, 1H), 6.42 (br. s, 1H), 3.32 (br. s, CH.sub.2), 2.99 (s, SO.sub.2Me), 2.51 (d, J=7.1, CH.sub.2), 2.18 (s, Me), 1.86 (hept., J=6.7, 1H), 0.90 (d, J=6.6, CMe.sub.2); .sup.13C-NMR (100 MHz, CDCl.sub.3): 142.2 (s), 142.0 (s), 140.1 (s), 138.1 (s), 130.2 (s), 125.9 (d), 123.3 (d), 118.4 (d), 45.4 (t), 40.5 (q), 40.5 (t), 30.4 (d), 22.3 (2q), 14.0 (q); MS (EI): 279 (24), 264 (1), 237 (4), 236 (4), 200 (100), 172 (13), 158 (40), 156 (50), 142 (27), 130 (35), 116 (15), 115 (20).

Example 5: Preparation of 6-Isobutyl-2-methyl-2,3-dihydro-1H-inden-1-oneOne-Pot Synthesis Using Acetamide (MeCONH2)

(23) ##STR00018##

(24) A mixture of (E)-3-(4-isobutylphenyl)-2-methylacrylaldehyde (dehydrosilvial, 1 g, 4.94 mmol, 1-2% (Z)-isomer) and acetamide (0.32 g, 5.42 mmol, 1.1 eq.) in toluene (10 ml) was treated with iron trichloride (180 mg, 1.1 mmol, 0.2 eq.), and heated at reflux temperature (104 C.) for 24 h. The reaction mixture was then cooled to 10 C., treated with 2N aq. NaOH (3 ml) and stirred at 20 C. for 2 h and at reflux temperature for 2.5 h. The resulting mixture was treated with conc. HCl (1 ml), stirred at reflux temperature for 15 h, cooled, and poured into ice. The aq. phase was separated and extracted twice with MTBE. The combined organic phases were washed with aq. sat. NaHCO.sub.3, twice with aq. sat. NaCl, dried with MgSO.sub.4, filtered, and the solvent evaporated. The crude product (1.1 g, brown oil) was distilled using a Kugelrohr apparatus (170-190 C., 0.1 mbar) giving 6-isobutyl-2-methyl-2,3-dihydro-1H-inden-1-one as characterized in Example 1 (0.93 g, 84% pure, yellow oil, 65% yield).

Example 6: Preparation of 6-Isobutyl-2-methyl-2,3-dihydro-1H-inden-1-oneStepwise Synthesis Using Acetamide (MeCONH2)

Step 1: N-(6-isobutyl-2-methyl-1H-inden-1-yl)acetamide

(25) ##STR00019##

(26) A mixture of acetamide (1.6 g, 27.1 mmol, 1.1 eq.) and (E)-3-(4-isobutylphenyl)-2-methylacrylaldehyde (dehydrosilvial, 5 g, 24.7 mmol, 1-2% (Z)-isomer) in toluene (50 ml) was heated to 50 C. and the resulting solution was treated with iron trichloride (0.80 g, 4.94 mmol, 0.2 eq.). The resulting mixture was heated to reflux (100 C.), stirred for 20 h, cooled to 60 C., treated with EtOAc (20 ml), and washed with 1N aq. HCl (10 ml). The organic phase was washed with aqueous saturated NaHCO.sub.3 (10 ml), three times with aqueous saturated NaCl (10 ml) and the final organic phase (suspension) was filtered and the solid washed with EtOAc and dried giving pure N-(6-isobutyl-2-methyl-1H-inden-1-yl)acetamide (1.86 g, 31% yield) as a slightly brown-coloured solid. The filtrate was dried with MgSO.sub.4, filtered, and the solvent evaporated. The crude product (3.26 g, brown solid) was triturated with hexane (20 ml), cooled to 5 C., filtered, washed with cold hexane (10 ml), and dried, giving additional N-(6-isobutyl-2-methyl-1H-inden-1-yl)acetamide (2.58 g, 100% pure, 43% yield; total yield: 74%) as a slightly brown-coloured solid.

(27) R.sub.f (hexane/MTBE 11:1): 0.33; .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.14 (br. s, 1H), 7.05 (br. d, J=7.5, 1H), 6.98 (br. d, J=7.5, 1H), 6.37 (br. s, 1H), 5.53 (br. d, J=9.3, 1H), 5.48 (br. d, J=9.4, 1H), 2.47 (d, J=7.1, CH.sub.2), 2.08 (s, Me), 1.97 (br. s, COMe), 1.83 (hept., J=6.7, 1H), 0.89 (d, J=6.6, CMe.sub.2); .sup.13C-NMR (100 MHz, CDCl.sub.3): 170.71 (s), 145.69 (s), 144.35 (s), 141.45 (s), 138.63 (s), 128.83 (d), 127.81 (d), 124.21 (d), 119.68 (d), 58.63 (d), 45.36 (t), 30.41 (d), 23.41 (q), 22.38 (2q), 14.09 (q); MS (EI): 244 (5), 243 (30), 201 (8), 200 (10), 186 (14), 185 (17), 184 (100), 158 (31), 144 (47), 143 (30), 142 (26), 141 (73), 128 (16), 115 (21), 43 (49).

Step 2: N-(5-Isobutyl-2-methyl-1H-inden-3-yl)acetamide

(28) ##STR00020##

(29) At 20 C., a suspension of N-(6-isobutyl-2-methyl-1H-inden-1-yl)acetamide (2 g, 8.22 mmol) in MeOH (20 ml) was treated dropwise with 2M aq. NaOH (2 ml, 4.0 mmol, 0.49 eq.) and the resulting suspension heated to reflux. The resulting solution was stirred at reflux for 1 h, cooled, treated with water (5 ml), and extracted with MTBE (20 ml). The organic phase was washed with aq. sat. NH.sub.4Cl soln. (10 ml), with aq. sat. NaCl soln. (10 ml), dried over MgSO.sub.4, filtered, and the solvent evaporated. The crude product (2 g, brown solid) was triturated with hexane (20 ml), cooled to 5 C., filtered, washed with cold hexane (10 ml), and dried, giving N-(5-isobutyl-2-methyl-1H-inden-3-yl)acetamide (1.73 g, 100% pure, 87% yield) as a slightly brown-coloured solid.

(30) R.sub.f (hexane/MTBE 1:1): 0.12; .sup.1H-NMR (400 MHz, CDCl.sub.3): (main rotamer, 60%) 7.23 (br. d, J=8.0, 1H), 6.99 (br. d, J=8.0, 1H), 6.94-6.90 (m, 1H), 6.78-6.66 (br. s, 1H), 3.30 (br. s, CH.sub.2), 2.49 (d, J=7.3, CH.sub.2), 2.24 (s, Me), 2.03 (br. s, COMe), 1.86 (hept., J=6.7, 1H), 0.896 (d, J=6.6, CMe.sub.2). (minor rotamer, 40%) 7.29 (br. d, J=7.3, 1H), 6.94-6.90 (m, 2H), 6.57-6.47 (br. s, 1H), 3.34 (br. s, CH.sub.2), 2.51 (d, J=7.3, CH.sub.2), 2.09 (br. s, COMe), 1.92 (s, Me), 1.86 (hept., J=6.7, 1H), 0.901 (d, J=6.6, CMe.sub.2); .sup.13C-NMR (100 MHz, CDCl.sub.3): (main rotamer, 60%) 168.48 (s), 142.48 (s), 139.78 (s), 138.42 (s), 136.76 (s), 131.37 (s), 125.46 (d), 123.07 (d), 118.27 (d), 45.60 (t), 40.48 (t), 30.48 (d), 23.54 (q), 22.44 (2q), 14.19 (q). (minor rotamer, 40%) 173.34 (s), 142.80 (s), 140.44 (s), 139.86 (s), 136.03 (s), 133.13 (s), 126.03 (d), 123.41 (d), 118.43 (d), 45.48 (t), 40.23 (t), 30.48 (d), 22.37 (2q), 20.23 (q), 13.55 (q); MS (EI): 244 (6), 243 (36), 201 (8), 200 (16), 186 (21), 185 (15), 184 (100), 158 (38), 144 (60), 143 (41), 142 (24), 141 (49), 128 (16), 115 (17), 43 (59).

Step 3: 6-Isobutyl-2-methyl-2,3-dihydro-1H-inden-1-one

(31) ##STR00021##

(32) A suspension of N-(5-isobutyl-2-methyl-1H-inden-3-yl)acetamide (1.4 g, 5.75 mmol) in methanol (14 ml) and 35% aq. sulfuric acid (1.72 ml, 6.33 mmol, 1.1 eq.) was heated at reflux (65 C.) for 5 h, cooled, diluted with MTBE (20 ml), and washed with water (5 ml). The org. phase was washed with 2M aq. HCl and the combined aq. phases were extracted twice with MTBE (20 ml). The combined org. phases were washed with aqueous saturated NaHCO.sub.3 (10 ml), with aqueous saturated NaCl (10 ml), dried with MgSO.sub.4, filtered, and the solvent evaporated. The crude product (1.17 g, brown oil) was distilled using a Kugelrohr-distillation apparatus (0.09 mbar, 100-150 C.) giving 6-isobutyl-2-methyl-2,3-dihydro-1H-inden-1-one as characterized in Example 1 (1.03 g, 100% pure, 89% yield) as a slightly yellow oil.

(33) Yield over 3 steps: 57%

Example 7: Preparation of 6-Bromo-2-methyl-2,3-dihydro-1H-inden-1-oneOne-Pot Synthesis Using Methanesulfonamide (MeSO2NH2)

(34) ##STR00022##

(35) To a solution of (E)-3-(4-bromophenyl)-2-methylacrylaldehyde (50.0 g, 222 mmol, prepared from p-bromobenzaldehyde and propanal in the presence of NaOH in EtOH and water according to Unterhalt, B.; Ejabour, S. Archiv Pharmazie 1986, 319, 666-71) in toluene (200 ml) was added methanesulfonamide (25.4 g, 267 mmol, 1.2 eq.) and iron(III) chloride (7.21 g, 44.4 mmol, 0.2 eq.). The mixture was stirred and heated to 95 C. for 16 h. After the starting aldehyde was completely consumed, the reaction was cooled down, treated with methanol (200 ml) and a solution of sodium hydroxide (22.21 g, 555 mmol, 2.5 eq.) in water (70 ml), and stirred for 2 h at rt. The resulting mixture was then treated with methanol (200 ml) and dropwise with conc. HCl (54.7 ml, 37%, 666 mmol, 3.0 eq.), heated to 85 C., and stirred overnight. After cooling, water (200 ml) was added and the solution was extracted three times with MTBE (150 ml). The combined organic layers were washed with brine, dried with MgSO.sub.4, filtered and concentrated. Flash-chromatography (silica gel, hexane/MTBE 50:1) of the residue gave a light yellow solid (23 g) that was distilled (bulb-to-bulb distillation apparatus, 150 C., 0.08 mbar) to give 6-bromo-2-methyl-2,3-dihydro-1H-inden-1-one (20 g, 96% purity, 38% yield) as a light yellow solid.

(36) R.sub.f (hexane/MTBE 10:1): 0.3; .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.86 (br. s, 1H), 7.67 (dd, J=8.1, 1.7, 1H), 7.34 (br. d, J=8.1, 1H), 3.35 (dd, J=17.2, 7.7, 1H), 2.83-2.62 (m, 2H), 1.31 (d, J=7.4, Me); .sup.13C-NMR (75 MHz, CDCl.sub.3): 207.7 (s), 151.9 (s), 138.1 (s), 137.3 (d), 128.2 (d), 126.8 (d), 121.5 (s), 42.4 (d), 34.6 (t), 16.1 (q); MS (EI): 226 (68), 224 (70), 211 (97), 209 (100), 198 (10), 196 (11), 183 (10), 181 (8), 170 (4), 156 (3), 145 (21), 128 (4), 115 (68), 102 (22), 89 (20), 75 (12), 63 (15).

Example 8: Preparation of 4-Bromo-2-methyl-2,3-dihydro-1H-inden-1-oneOne-Pot Synthesis Using Methanesulfonamide (MeSO2NH2)

(37) ##STR00023##

(38) To a solution of (E)-3-(2-bromophenyl)-2-methylacrylaldehyde (70.0 g, 80% purity, 249 mmol, prepared from o-bromobenzaldehyde and propanal in the presence of NaOH in MeOH and water according to Li, W.-D. Z.; Duo, W.-G; Zhuang, C.-H. Org. Lett. 2011, 13, 3538-41) in toluene (200 ml) was added methanesulfonamide (28.4 g, 299 mmol, 1.2 eq.) and iron(III) chloride (8.07 g, 49.8 mmol, 0.2 eq.). The mixture was stirred and heated to 65 C. for 16 h. After the starting aldehyde was completely consumed, the reaction was cooled down, treated with methanol (200 ml) and a solution of sodium hydroxide (24.88 g, 622 mmol, 2.5 eq.) in water (80 ml), and stirred for 2 h at rt. The resulting mixture was then treated with methanol (200 ml) and dropwise with conc. HCl (63 ml, 37%, 746 mmol, 3.0 eq.), heated to 85 C., and stirred overnight. After cooling, water (200 ml) was added and the solution was extracted three times with MTBE (150 ml). The combined organic layers were washed with brine, dried with MgSO.sub.4, filtered and concentrated. Flash-chromatography (silica gel, hexane/MTBE 50:1) of the residue gave a light yellow oil (34 g) that was distilled (bulb-to-bulb distillation apparatus, 130 C., 0.11 mbar) to give 4-bromo-2-methyl-2,3-dihydro-1H-inden-1-one (32 g, 61% yield) as a yellow solid.

(39) R.sub.f (hexane/MTBE 10:1): 0.3; .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.75 (d, J=7.7, 1H), 7.70 (d, J=7.6, 1H), 7.28 (t, J=7.6, 1H), 3.35 (dd, J=17.5, 7.7, 1H), 2.83-2.67 (m, 1H), 2.66 (dd, J=17.6, 3.8, 1H), 1.34 (d, J=7.4, Me); .sup.13C-NMR (75 MHz, CDCl.sub.3): 208.5 (s), 153.2 (s), 138.4 (s), 137.4 (d), 129.2 (d), 122.8 (d), 122.2 (s), 42.0 (d), 36.0 (t), 16.2 (q); MS (EI): 226 (51), 224 (53), 211 (97), 209 (100), 198 (10), 198(4), 196 (5), 183 (7), 181 (6), 170 (3), 168 (3), 156 (1), 145 (14), 128 (3), 127 (3), 115 (61), 102 (16), 89 (18), 75 (11), 63 (14).

Example 9: Preparation of 5- and 7-bromo-2-methyl-2,3-dihydro-1H-inden-1-oneOne-Pot Synthesis Using Methanesulfonamide (MeSO2NH2)

(40) ##STR00024##

(41) Similarly to examples 7 and 8, the sequential treatment of (E)-3-(3-bromophenyl)-2-methylacrylaldehyde (60.0 g, 267 mmol, prepared in 80% yield and 98% purity from m-bromobenzaldehyde and propanal in the presence of NaOH in MeOH and water) in toluene (200 ml) with first methanesulfonamide (30.4 g, 320 mmol, 1.2 eq.)/iron(III) chloride (8.65 g, 53.3 mmol, 0.2 eq.) at 65 C. for 16 h, then with methanol (200 ml)/sodium hydroxide (26.7 g, 666 mmol, 2.5 eq.) in water (70 ml) at rt. for 2 h, finally with methanol (200 ml)/conc. HCl (24.3 ml, 37%, 800 mmol, 3.0 eq.) at 85 C. overnight led after work-up and flash-chromatography (silica gel, hexane/MTBE 50:1) of the residue to a 85:15 mixture of 5- and 7-bromo-2-methyl-2,3-dihydro-1H-inden-1-one (33.3 g, 57% yield) as a yellow oil. Distillation (bulb-to-bulb distillation apparatus, 150 C., 0.08 mbar) gave a 85:15 mixture of 5- and 7-bromo-2-methyl-2,3-dihydro-1H-inden-1-one (30 g, 50% yield) as a yellow oil.

(42) R.sub.f (hexane/MTBE 10:1): 0.3; .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.65-7.35 (m, 3H), 3.46-3.28 (m, 1H), 2.83-2.67 (m, 1H), 2.79-2.62 (m, 2H), 1.32 (d, J=7.2, 0.45H, Me), 1.30 (d, J=7.2, 2.55H, Me); .sup.13C-NMR (75 MHz, CDCl.sub.3): (5-bromo-isomer) 208.0 (s), 155.0 (s), 135.2 (s), 131.0 (d), 130.0 (s), 129.8 (d), 125.2 (d), 42.0 (d), 34.6 (t), 16.2 (q); (7-bromo-isomer) 206.2 (s), 156.1 (s), 135.1 (d), 133.6 (s), 132.4 (d), 125.6 (d), 119.7 (s), 42.7 (d), 34.1 (t), 16.3 (q); MS (EI): 5-bromo-isomer: 226 (50), 224 (52), 211 (97), 209 (100), 198 (5), 196 (6), 183 (9), 181 (8), 170 (2), 168 (3), 156 (3), 154 (2), 145 (16), 128 (5), 127 (3), 115 (50), 102 (21), 89 (17), 75 (12), 63 (14); 7-bromo-isomer: 226 (57), 224 (59), 211 (97), 209 (100), 198 (10), 198(4), 196 (5), 183 (6), 181 (5), 170 (2), 168 (2), 156 (2), 145 (10), 128 (3), 115 (51), 102 (20), 89 (16), 75 (11), 63 (11).

Example 10: Preparation of 2-Ethyl-6-isobutyl-2,3-dihydro-1H-inden-1-oneOne-Pot Synthesis Using Methanesulfonamide (MeSO2NH2)

(43) ##STR00025##

(44) To a solution of (E)-3-(4-isobutylphenyl)-2-methylacrylaldehyde (5.35 g, 24.7 mmol) in toluene (50 ml) was added methanesulfonamide (2.82 g, 29.7 mmol) and iron(III) chloride (0.80 g, 4.9 mmol). The mixture was stirred and heated to 65 C. After the aldehyde was completely consumed (monitored by GC), the reaction was cooled to rt. Then methanol (30 ml) and a solution of sodium hydroxide (2.47 g, 61.8 mmol) in water (20 ml) was added, the mixture was stirred for 2 h at rt. Further methanol (30 ml) and sulfuric acid (3.95 mL, 74.2 mmol) was added, the mixture was heated to 70 C. and stirred overnight. Water (100 ml) was added and the solution was extracted with MTBE (100 ml3). The combined organic layers were washed with brine, dried with MgSO.sub.4, filtered and concentrated to give the crude product. The residue was purified by silica gel chromatography (hexane/MTBE=50:1) to give 4.0 g of product as light yellow oil. The oil was distilled via Kugelrohr (0.15 mbar, 160 C.) to give 2-ethyl-6-isobutyl-2,3-dihydro-1H-inden-1-one as colourless oil (2.60 g, 48.6% yield).

(45) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.52 (s, 1H), 7.34-7.40 (m, 2H), 3.28 (dd, J=17.1, 7.8 Hz, 1H), 2.78 (dd, J=17.1, 3.9 Hz, 1H), 2.58-2.65 (m, 1H), 2.52 (d, J=7.2 Hz, 2H), 1.80-2.04 (m, 2H), 1.46-1.60 (m, 1H), 1.01 (t, J=7.5 Hz, 3H), 0.90 (d, J=6.6 Hz, 6H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3): 209.2 (s), 151.5 (s), 141.1 (s), 137.0 (s), 136.0 (d), 126.1 (d), 123.8 (d), 49.2 (d), 44.9 (t), 32.0 (t), 30.2 (d), 24.5 (t), 22.3 (2q), 11.7 (q) ppm; GC/MS (EI): m/z (%): 216 (7) [M.sup.+], 188 (100), 173 (33), 145 (36), 131 (20), 91 (7), 77 (7).

Example 11: Preparation of 2-Isopropyl-6-methyl-2,3-dihydro-1H-inden-1-oneOne-Pot Synthesis Using Methanesulfonamide (MeSO2NH2)

(46) ##STR00026##

(47) To a solution of (E)-3-methyl-2-(4-methylbenzylidene)butanal (3.00 g, 15.9 mmol) in toluene (100 ml) was added methanesulfonamide (2.27 g, 23.9 mmol) and iron(III) chloride (0.388 g, 2.39 mmol). The mixture was stirred and heated to 80 C. After the aldehyde was completely consumed (monitored by TLC), the reaction was cooled down and added methanol (30.0 ml) and sodium hydroxide (1.27 g, 31.9 mmol) in water (10.0 ml), the mixture was stirred for 2 h at rt. Further methanol (30 ml) and hydrogen chloride (3.78 ml, 39.8 mmol) was added, the mixture was heated to 70 C. and stirred overnight. Water (200 ml) was added and the solution was extracted with MTBE (1503 ml). The combined organic layers were washed with brine, dried with MgSO.sub.4, filtered and concentrated to give the crude product. The residue was purified by silica gel chromatography (hexane/MTBE=50:1) to give 0.8 g of product as light yellow oil. The oil was distilled via Kugelrohr (0.12 mbar, 140 C.) to give 0.500 g of product as colourless oil (26.7% yield).

(48) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.53 (s, 1H), 7.31-7.44 (m, 2H), 3.09 (dd, J=17.1, 9.0 Hz, 1H), 2.83-2.90 (m, 1H), 2.64-2.68 (m, 1H), 2.36-2.42 (m, 3H), 1.04 (d, J=6.9 Hz, 3H), 0.78 (d, J=6.6 Hz, 3H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3): 209.0 (s), 151.6 (s), 137.8 (s), 137.1 (s), 135.8 (d), 126.2 (d), 123.5 (d), 53.4 (d), 29.1 (d), 27.8 (t), 21.0 (q), 20.9 (q), 17.3 (q) ppm; GC/MS (EI): m/z (%): 188 (2) [M.sup.+], 173 (3), 146 (100), 131 (21), 115 (12), 91 (5), 77 (4).

Example 12: Preparation of 6-Ethyl-2-methyl-2,3-dihydro-1H-inden-1-oneOne-Pot Synthesis Using Methanesulfonamide (MeSO2NH2)

(49) ##STR00027##

(50) Prepared according to general procedure in Example 11, reaction of (E)-3-(4-ethylphenyl)-2-methylacrylaldehyde (5.0 g, 28.7 mmol), methanesulfonamide (4.09 g, 43.0 mmol) and iron(III) chloride (0.931 g, 5.74 mmol) followed by distillation through Kugelrohr (150 C./0.12 mbar) to give 6-ethyl-2-methyl-2,3-dihydro-1H-inden-1-one as a colorless oil (1.30 g, 26.0% yield).

(51) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.58 (s, 1H), 7.34-7.44 (m, 2H), 3.35 (dd, J=18.0, 8.7 Hz, 1H), 2.65-2.73 (m, 1H), 2.64-2.68 (m, 4H), 1.22-1.31 (m, 6H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3): 209.6 (s), 151.1 (s), 143.7 (s), 136.5 (s), 135.0 (d), 126.3 (d), 122.6 (d), 42.3 (d), 34.6 (t), 28.5 (t), 16.3 (q), 15.6 (q) ppm; GC/MS (EI): m/z (%): 174 (60) [M.sup.+], 159 (100), 145 (23), 131 (32), 115 (22), 91 (13), 77 (7).

Example 13: Preparation of 6-(sec-Butyl)-2-methyl-2,3-dihydro-1H-inden-1-oneOne-Pot Synthesis Using Methanesulfonamide (MeSO2NH2)

(52) ##STR00028##

(53) Prepared according to general procedure in Example 11, reaction of (E)-3-(4-(sec-butyl)phenyl)-2-methylacrylaldehyde (5.00 g, 14.8 mmol), methanesulfonamide (1.69 g, 17.8 mmol) and iron(III) chloride (0.481 g, 2.97 mmol) followed by distillation through Kugelrohr (150 C./0.08 mbar) to give 6-ethyl-2-methyl-2,3-dihydro-1H-inden-1-one as a colorless oil (1.00 g, 33.3% yield). (mixture of two isomers).sup.1H NMR (300 MHz, CDCl.sub.3): 7.59 (s, 1H), 7.38-7.44 (m, 2H), 3.32-3.41 (m, 1H), 2.66-2.73 (m, 3H), 1.58-1.63 (m, 2H), 1.31 (d, J=7.2 Hz, 3H), 1.25 (d, J=6.9 Hz, 3H), 0.81 ppm (t, J=7.2 Hz, 3H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3): 209.8 (s), 151.3 (s), 147.2 (s), 136.5 (s), 134.4 (d), 134.3 (d), 126.3 (d), 121.9 (d), 121.9 (d), 42.4 (d), 41.4 (d), 34.6 (t), 31.1 (t), 21.9 (q), 16.3 (q), 12.2 (q) ppm; GC/MS (EI): m/z (%): 202 (30) [M.sup.+], 187 (5), 173 (100), 159 (7), 117 (27), 91 (8), 77 (4).

Example 14: Preparation of 6-Isopentyl-2-methyl-2,3-dihydro-1H-inden-1-oneOne-Pot Synthesis Using Methanesulfonamide (MeSO2NH2)

(54) ##STR00029##

(55) Prepared according to general procedure in Example 11, reaction of (E)-3-(4-isopentylphenyl)-2-methylacrylaldehyde (5.00 g, 18.5 mmol), methanesulfonamide (2.11 g, 22.2 mmol) and iron(III) chloride (0.600 g, 3.70 mmol) followed by distillation through Kugelrohr (162 C./0.10 mbar) to give 6-isopentyl-2-methyl-2,3-dihydro-1H-inden-1-one as a colorless oil (1.30 g, 32.5% yield).

(56) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.57 (s, 1H), 7.32-7.42 (m, 2H), 3.34 (dd, J=18.0, 8.7 Hz, 1H), 2.62-2.70 (m, 4H), 1.46-1.62 (m, 3H), 1.29 (d, J=7.2 Hz, 3H), 0.93 (d, J=6.9 Hz, 6H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3): 209.5 (s), 151.0 (s), 142.5 (s), 136.5 (s), 135.4 (q), 126.3 (q), 123.1 (q), 42.3 (d), 40.8 (t), 34.6 (t), 33.3 (t), 27.5 (d), 22.5 (2q), 16.3 (q) ppm; GC/MS (EI): m/z (%): 216 (80) [M.sup.+], 201 (30), 187 (1), 159 (98), 132 (100), 118 (55), 104 (55), 91 (23), 77 (8).