spiro[cyclohexane-1,1'-isoindoline] by Asch

Query Query

1. Query

Results

Date

97 reactions in Reaxys

2017-08-01 00h:49m:04s (EST)

97 reactions in Reaxys

2017-08-01 01h:21m:04s (EST)

Search as: Substructure: on all atoms, No mixtures 2. Query

LAST_RESULT AND itemno in (2,1,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,2 5,26,27,28,29,30)

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Cl O

Rx-ID: 2978062 View in Reaxys 1/97 Yield

Conditions & References With zinc in acetic acid, Yield given Robinson, Ralph P.; Donahue, Kathleen M.; Saccomano, Nicholas A.; Tetrahedron Letters; vol. 30; nb. 39; (1989); p. 5203 - 5206 View in Reaxys

H 2N

Rx-ID: 20909440 View in Reaxys 2/97 Yield

Conditions & References Reaction Steps: 3 1: DMAP / CH2Cl2 2: HBr / CH2Cl2 / 0 °C 3: Zn / acetic acid With dmap, hydrogen bromide, zinc in dichloromethane, acetic acid Robinson, Ralph P.; Donahue, Kathleen M.; Saccomano, Nicholas A.; Tetrahedron Letters; vol. 30; nb. 39; (1989); p. 5203 - 5206 View in Reaxys O

Rx-ID: 20911736 View in Reaxys 3/97 Yield

Conditions & References Reaction Steps: 5 1: 1.) n-BuLi, TMEDA/EtO2; 2.) THF 2: HCl / H2O; tetrahydrofuran 3: DMAP / CH2Cl2 4: HBr / CH2Cl2 / 0 °C 5: Zn / acetic acid With hydrogenchloride, dmap, hydrogen bromide, zinc in tetrahydrofuran, dichloromethane, water, acetic acid Robinson, Ralph P.; Donahue, Kathleen M.; Saccomano, Nicholas A.; Tetrahedron Letters; vol. 30; nb. 39; (1989); p. 5203 - 5206 View in Reaxys

H N

Cl O

Rx-ID: 20932471 View in Reaxys 4/97 Yield

Conditions & References Reaction Steps: 2 1: HBr / CH2Cl2 / 0 °C 2: Zn / acetic acid

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With hydrogen bromide, zinc in dichloromethane, acetic acid Robinson, Ralph P.; Donahue, Kathleen M.; Saccomano, Nicholas A.; Tetrahedron Letters; vol. 30; nb. 39; (1989); p. 5203 - 5206 View in Reaxys

Rx-ID: 20933109 View in Reaxys 5/97 Yield

Conditions & References Reaction Steps: 4 1: HCl / H2O; tetrahydrofuran 2: DMAP / CH2Cl2 3: HBr / CH2Cl2 / 0 °C 4: Zn / acetic acid With hydrogenchloride, dmap, hydrogen bromide, zinc in tetrahydrofuran, dichloromethane, water, acetic acid Robinson, Ralph P.; Donahue, Kathleen M.; Saccomano, Nicholas A.; Tetrahedron Letters; vol. 30; nb. 39; (1989); p. 5203 - 5206 View in Reaxys

N H

Rx-ID: 20937348 View in Reaxys 6/97 Yield

Rx-ID: 6596449 View in Reaxys 7/97 Yield

Conditions & References Spiro<cyclohexan-1,1'-isoindolin>-3',4'-dion, Wasserstoffperoxid Patent; AB Kabi; US3947451; (1976); ; vol. 90; nb. 72076k View in Reaxys 24.b : b. b. Spiro(cyclohexane-1,3'-isoindoline)-1'-one

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The product from example 24 (a) (11.5 g; 0.05 moles) is dissolved in hot ethanol (100 ml.) A solution of sodium hydroxide (10 ml), 40 percent, is added, followed under agitation by 30 percent hydrogenperoxide (50 ml) in portions for about 20 minutes. The light yellow solution is heated and stirred for another 20 minutes and allowed to cool, after which the crystalline product is filtered off and recrystallized from ethanol. Yield 4.0 g, m.p. 232° - 234°C. Patent; AB Kabi; US3947451; (1976); (A1) English View in Reaxys O

O N H

Rx-ID: 40659650 View in Reaxys 8/97 Yield

Conditions & References Reaction Steps: 2 1: 3-chloro-benzenecarboperoxoic acid; 2-iodobiphenyl / water / 0.25 h / 25 °C 2: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 120 °C With 2-iodobiphenyl, sodium hydride, 3-chloro-benzenecarboperoxoic acid in water, N,N-dimethyl-formamide, mineral oil Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys O

O HN

Rx-ID: 40659655 View in Reaxys 9/97 Yield

Conditions & References

85 %

With sodium hydride in N,N-dimethyl-formamide, mineral oil, Time= 1h, T= 120 °C Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys

O HN

Rx-ID: 40659660 View in Reaxys 10/97 Yield

Conditions & References Reaction Steps: 4 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C / |Inert atmosphere 2: potassium carbonate / ethyl acetate; water / 0 - 20 °C 3: 3-chloro-benzenecarboperoxoic acid; 2-iodobiphenyl / water / 0.25 h / 25 °C 4: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 120 °C With oxalyl dichloride, 2-iodobiphenyl, sodium hydride, potassium carbonate, N,N-dimethyl-formamide, 3-chlorobenzenecarboperoxoic acid in dichloromethane, water, ethyl acetate, N,N-dimethyl-formamide, mineral oil Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys

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Rx-ID: 40659665 View in Reaxys 11/97 Yield

Conditions & References Reaction Steps: 3 1: potassium carbonate / ethyl acetate; water / 0 - 20 °C 2: 3-chloro-benzenecarboperoxoic acid; 2-iodobiphenyl / water / 0.25 h / 25 °C 3: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 120 °C With 2-iodobiphenyl, sodium hydride, potassium carbonate, 3-chloro-benzenecarboperoxoic acid in water, ethyl acetate, N,N-dimethyl-formamide, mineral oil Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys Br

N H

Rx-ID: 19317002 View in Reaxys 12/97 Yield

Conditions & References Reaction Steps: 2 1: p-TsOH / toluene / 72 h / Heating 2: Bu3SnH, azobis(isobutyronitrile) / toluene / 3 h / 80 °C With 2,2'-azo-bisisobutyronitrile, tri-n-butyl-tin hydride, toluene-4-sulfonic acid in toluene Glover, Stephen A.; Warkentin, John; Journal of Organic Chemistry; vol. 58; nb. 8; (1993); p. 2115 - 2121 View in Reaxys

hydrogen

Rx-ID: 19319701 View in Reaxys 13/97 Yield

Rx-ID: 19351049 View in Reaxys 14/97 Yield

Conditions & References Reaction Steps: 3 1: ethanol; H2O 2: p-TsOH / toluene / 72 h / Heating 3: Bu3SnH, azobis(isobutyronitrile) / toluene / 3 h / 80 °C With 2,2'-azo-bisisobutyronitrile, tri-n-butyl-tin hydride, toluene-4-sulfonic acid in ethanol, water, toluene Glover, Stephen A.; Warkentin, John; Journal of Organic Chemistry; vol. 58; nb. 8; (1993); p. 2115 - 2121

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View in Reaxys

N N

racemate

Rx-ID: 3454539 View in Reaxys 15/97 Yield

Conditions & References With 2,2'-azo-bisisobutyronitrile, tri-n-butyl-tin hydride in toluene, Time= 3h, T= 80 °C , Yield given. Yields of byproduct given Glover, Stephen A.; Warkentin, John; Journal of Organic Chemistry; vol. 58; nb. 8; (1993); p. 2115 - 2121 View in Reaxys

O HN

HN O

Rx-ID: 22976162 View in Reaxys 16/97 Yield

Conditions & References

88 %

8 : EXAMPLE 8Spiro[cyclohexane-1,1'-[1H]isoindole]-3',4(2'H)-dione [00092] Crude Spiro-[(cyclohexan-1,3'-isoindolin)-1'-one]-one (1.3 g, 5.0 mmol) was added to ice cold perchloric acid (30 mL) and stirred for 2 hours. The reaction was made basic by careful addition of sodium hydroxide pellets (added slowly to keep the temperature low). The basic mixture was extracted with ethyl acetate (3?60 mL) and the combined extracts were washed with water and brine, dried over MgSO4 and concentrated onto silica gel. Purification by silica gel flash chromatography using 50percent ethyl acetate/hexane gave (0.95 g, 88percent) of the desired spirocyclohexanone-benzolactam product, spiro[cyclohexane-1,1'-[1H]isoindole]-3',4(2'H)-dione, as a foamy white solid. [00093] Mp 55-65 C. 1H NMR DMSO d6 8.45 (br s, 1H), 7.88 (d, 7.4 Hz, 1H), 7.61 (d, J=3.8 Hz, 2H), 7.58-7.44 (m, 1H), 2.76 (dt, J1=13.8 Hz, J2=6.0 Hz, 2H), 2.57-2.44 (m, 2H), 2.35-2.28 (m, 2H), 1.97-1.89 (m, 2H). Stage 1: With perchloric acid, Time= 2h Stage 2: With sodium hydroxide Patent; Pfizer Inc; US6664258; (2003); (B1) English View in Reaxys

O O

O N

O HN

Rx-ID: 28118202 View in Reaxys 17/97 Yield 97 %

Conditions & References 17 : EXAMPLE 17Spiro-[(cyclohexan-1,3'-isoindolin)-1'-one]-4-one [00110] A solution of 2-bromobenzonitrile (2.00 g, 10.99 mmol) in tetrahydrofuran (50 mL) was cooled to -78 C. and n-butyllithium (2.5M, 4.6 mL, 11.5 mmol) was added slowly. The resulting orange-brown solution was stirred for 10 min., then a solution of 1,4-cyclohexanedione mono-ethylene ketal (1.70 g, 10.88 mmol) in tetrahydrofuran (25 mL) was added dropwise over 5 minutes. The reaction was stirred an additional 15 min, quenched with water (25 mL) and immediately extracted into chloroform (100 mL). This extract was dried over magnesium sulfate and concentrated to give the crude spiroimidate as a waxy yellow solid (2.74 g, 97percent). [00111] Mp 178-179 C.41. 1H NMR CDCl3 d 7.81 (d, J=7.4 Hz, 1H), 7.54 (dt, J1=7.3 Hz, J2=1.1 Hz, 1H), 7.45 (dt, J1=7.4 Hz, J2=1.0 Hz, 1H), 7.33 (d, J=7.4 Hz, 1H), 4.05-3.98 (m, 2H), 2.45-2.05 (m, 4H), 1.79 (br d, J=10.0 Hz, 4H). Analysis calculated for C15H17NO3; C, 69.46; H, 6.61; N, 5.40. Found: C, 69.33; H, 6.62; N, 5.01. Stage 1: With n-butyllithium in tetrahydrofuran, Time= 0.166667h, T= -78 °C Stage 2: in tetrahydrofuran, Time= 0.333333h

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Patent; Pfizer Inc; US6664258; (2003); (B1) English View in Reaxys O

OH HN

Rx-ID: 29825731 View in Reaxys 18/97 Yield

Conditions & References 39.A :Example 39; 4-Oxo-1-phenyl-cyclohexanecarboxylic acid (Aldrich, 2.00 g, 9.17 mmol) was treated with DPPA (Aldrich, 18.3 mmol) and TEA (2.56 mL, 18.3 mmol) in toluene (10 mL) at reflux for 4 hours. After the reaction was cooled down to room temperature, 1 N HCl aqueous solution (5 mL) and THF (5 mL) were added and the reaction was stirred overnight. The reaction was partitioned between saturated sodium bicarbonate and DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give yellow solid, which was then purified by silica gel column on a CombiFlash.(R). system using hexanes and ethyl acetate (from 10percent ethyl acetate to 100percent ethyl acetate) to afford the product compound as white solid.1H NMR (400 MHz, CDCl3) δ 7.30 (m, 4H), 6.56 (s, br, 1H), 2.98 (m, 2H), 2.80 (m, 2H), 2.64 (m, 2H), 2.45 (m, 2H). With diphenyl phosphoryl azide, triethylamine in toluene, Time= 4h, Reflux Patent; Zhang, Xuqing; Hufnagel, Heather Rae; Sui, Zhihua; US2010/267668; (2010); (A1) English View in Reaxys O N

Rx-ID: 6658994 View in Reaxys 19/97 Yield

Conditions & References 2'-Methylspiro<cyclohexane-1,3'-phthalimidine>-4-one, Ethanethiol, Raney-Ni Bailey,D.M.; De Grazia,C.G.; Journal of Organic Chemistry; vol. 35; (1970); p. 4093 - 4096 View in Reaxys 2-(1-Hydroxy-cyclohexyl)-benzoesaeure-methylamid 1. 70percentig. Perchlorsaeure 2. (Rkprod.), wss. Natronlauge Chung-Ling Mao et al.; Journal of Heterocyclic Chemistry; vol. 6; (1969); p. 475,479 View in Reaxys O

Br O

N N

N O

Rx-ID: 36932183 View in Reaxys 20/97 Yield 13 %, 38 %

Conditions & References With phen, sodium t-butanolate in 1,4-dioxane, Time= 15h, T= 145 °C , Glovebox, Sealed tube, Catalytic behavior, Reagent/catalyst, Solvent Wertjes, William C.; Wolfe, Lydia C.; Waller, Peter J.; Kalyani, Dipannita; Organic Letters; vol. 15; nb. 23; (2013); p. 5986 - 5989 View in Reaxys

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O N

Rx-ID: 36932186 View in Reaxys 21/97 Yield

Conditions & References

45 %

C−H Arylation; General Procedure General procedure: To an oven-dried 20 mL scintillation vial containing a magnetic stirbar and substrate, was added Ni(cod)2, t-BuOK, and anhydrous THF in a glove box. The vial was sealed with a Teflon-lined cap, taken out of the glove box, and the reaction mixture was stirred at r.t. for the indicated time. The reaction mixture was filtered through a 3.8 cm plug of silica gel, eluting with EtOAc (100 mL). The filtrate was concentrated and purified by chromatography on a silicagel column to afford the product With bis(1,5-cyclooctadiene)nickel (0), potassium tert-butylate in tetrahydrofuran, Time= 21h, T= 20 °C , Sealed tube Wertjes, William C.; Waller, Peter J.; Shelton, Kyle E.; Kalyani, Dipannita; Synthesis (Germany); vol. 46; nb. 22; (2014); p. 3033 - 3040; Art.No: SS-2014-C0299-OP View in Reaxys

41 %

With 1,10-phenanthroline, sodium t-butanolate in 1,4-dioxane, Time= 15h, T= 145 °C , Glovebox, Sealed tube, Catalytic behavior, Reagent/catalyst Wertjes, William C.; Wolfe, Lydia C.; Waller, Peter J.; Kalyani, Dipannita; Organic Letters; vol. 15; nb. 23; (2013); p. 5986 - 5989 View in Reaxys

Rx-ID: 37734386 View in Reaxys 22/97 Yield 94 %

Conditions & References With potassium tert-butylate, Tocopherol in dimethyl sulfoxide, Time= 3h, T= 100 °C , Inert atmosphere Kumar, Sangit; Bhakuni, Bhagat Singh; Yadav, Abhimanyu; Kumar, Shailesh; Patel, Saket; Sharma, Shubham; Journal of Organic Chemistry; vol. 79; nb. 7; (2014); p. 2944 - 2954 View in Reaxys

52 %

I HN

Rx-ID: 37734496 View in Reaxys 23/97

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Yield

Conditions & References Reaction Steps: 2 1: triethylamine / dichloromethane / 5 h / 0 °C 2: Tocopherol; potassium tert-butylate / dimethyl sulfoxide / 3 h / 100 °C / |Inert atmosphere With potassium tert-butylate, triethylamine, Tocopherol in dichloromethane, dimethyl sulfoxide Kumar, Sangit; Bhakuni, Bhagat Singh; Yadav, Abhimanyu; Kumar, Shailesh; Patel, Saket; Sharma, Shubham; Journal of Organic Chemistry; vol. 79; nb. 7; (2014); p. 2944 - 2954 View in Reaxys O

O HO

Rx-ID: 37734587 View in Reaxys 24/97 Yield

Conditions & References Reaction Steps: 3 1: thionyl chloride 2: triethylamine / dichloromethane / 5 h / 0 °C 3: Tocopherol; potassium tert-butylate / dimethyl sulfoxide / 3 h / 100 °C / |Inert atmosphere With thionyl chloride, potassium tert-butylate, triethylamine, Tocopherol in dichloromethane, dimethyl sulfoxide Kumar, Sangit; Bhakuni, Bhagat Singh; Yadav, Abhimanyu; Kumar, Shailesh; Patel, Saket; Sharma, Shubham; Journal of Organic Chemistry; vol. 79; nb. 7; (2014); p. 2944 - 2954 View in Reaxys

N H

Rx-ID: 19317008 View in Reaxys 25/97 Yield

Conditions & References Reaction Steps: 2 1: p-TsOH / toluene / 72 h / Heating 2: Bu3SnH, azobis(isobutyronitrile) / toluene / 2.5 h / 80 °C With 2,2'-azo-bisisobutyronitrile, tri-n-butyl-tin hydride, toluene-4-sulfonic acid in toluene Glover, Stephen A.; Warkentin, John; Journal of Organic Chemistry; vol. 58; nb. 8; (1993); p. 2115 - 2121 View in Reaxys

O N

hydrogen

Rx-ID: 19319707 View in Reaxys 26/97 Yield

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Rx-ID: 19351052 View in Reaxys 27/97 Yield

Conditions & References Reaction Steps: 3 1: ethanol; H2O 2: p-TsOH / toluene / 72 h / Heating 3: Bu3SnH, azobis(isobutyronitrile) / toluene / 2.5 h / 80 °C With 2,2'-azo-bisisobutyronitrile, tri-n-butyl-tin hydride, toluene-4-sulfonic acid in ethanol, water, toluene Glover, Stephen A.; Warkentin, John; Journal of Organic Chemistry; vol. 58; nb. 8; (1993); p. 2115 - 2121 View in Reaxys

H N

racemate

Rx-ID: 3455066 View in Reaxys 28/97 Yield

Conditions & References With 2,2'-azo-bisisobutyronitrile, tri-n-butyl-tin hydride in toluene, Time= 2.5h, T= 80 °C , Yield given. Further byproducts given. Yields of byproduct given Glover, Stephen A.; Warkentin, John; Journal of Organic Chemistry; vol. 58; nb. 8; (1993); p. 2115 - 2121 View in Reaxys Br O

N O

Rx-ID: 10082671 View in Reaxys 29/97 Yield

Conditions & References

71 %

With palladium diacetate, 1,8-diazabicyclo[5.4.0]undec-7-ene, T= 140 °C Kim, Guncheol; Kim, Jin Hee; Lee, Ki Youn; Journal of Organic Chemistry; vol. 71; nb. 5; (2006); p. 2185 - 2187 View in Reaxys

O N O

Rx-ID: 6660078 View in Reaxys 30/97 Yield

Conditions & References 2-Methyl-isoindolin-1-spiro-cyclohexadien-(2',5')-dion-(3,4'), H2, Pd/C Collington et al.; Journal of the Chemical Society [Section] C: Organic; (1968); p. 1017 View in Reaxys

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O N HO

Rx-ID: 6606055 View in Reaxys 31/97 Yield

Conditions & References 2-Methyl-isoindolin-1-spiro-cyclohexandion-(3,4'), NaBH4, in Methanol Collington et al.; Journal of the Chemical Society [Section] C: Organic; (1968); p. 1017 View in Reaxys (yield)90percent Collington et al.; Journal of the Chemical Society [Section] C: Organic; (1968); p. 1017 View in Reaxys O

O N H

Rx-ID: 40659651 View in Reaxys 32/97 Yield

Conditions & References

95 %

With 2-iodobiphenyl, 3-chloro-benzenecarboperoxoic acid in water, Time= 0.25h, T= 25 °C , Catalytic behavior, Reagent/catalyst, Solvent, Temperature Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys

62 %

With 9,10-dicyanoanthracene in acetonitrile, Time= 20h, Irradiation, regioselective reaction Pandey, Ganesh; Laha, Ramkrishna; Angewandte Chemie - International Edition; vol. 54; nb. 49; (2015); p. 14875 - 14879 View in Reaxys

OH O

O N

Rx-ID: 40659662 View in Reaxys 33/97 Yield

Conditions & References Reaction Steps: 3 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C / |Inert atmosphere 2: potassium carbonate / ethyl acetate; water / 0 - 20 °C 3: 3-chloro-benzenecarboperoxoic acid; 2-iodobiphenyl / water / 0.25 h / 25 °C With oxalyl dichloride, 2-iodobiphenyl, potassium carbonate, N,N-dimethyl-formamide, 3-chloro-benzenecarboperoxoic acid in dichloromethane, water, ethyl acetate Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys

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Cl O

Rx-ID: 40659666 View in Reaxys 34/97 Yield

Conditions & References Reaction Steps: 2 1: potassium carbonate / ethyl acetate; water / 0 - 20 °C 2: 3-chloro-benzenecarboperoxoic acid; 2-iodobiphenyl / water / 0.25 h / 25 °C With 2-iodobiphenyl, potassium carbonate, 3-chloro-benzenecarboperoxoic acid in water, ethyl acetate Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys

NH NH

O HO

Rx-ID: 45388514 View in Reaxys 35/97 Yield

Conditions & References Reaction Steps: 3 1.1: ammonium sulfate / toluene / |Reflux 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 2.2: 1 h / -78 - 20 °C 3.1: boron tribromide / dichloromethane / 16 h / -78 - 20 °C With ammonium sulfate, n-butyllithium, boron tribromide in tetrahydrofuran, hexane, dichloromethane, toluene Patent; EFFECTOR THERAPEUTICS, INC.; Sprengeler, Paul A.; Reich, Siegfried H.; Ernst, Justin T.; Webber, Stephen E.; (55 pag.); US2017/121339; (2017); (A1) English View in Reaxys O NH

Rx-ID: 45388526 View in Reaxys 36/97 Yield

Conditions & References 37 : Synthesis of 6′-methoxy-4′-methylspiro[cyclohexane-1,1′-isoindoline] (2) To a solution of 6′-methoxy-4′-methylspiro[cyclohexane-1,1′-isoindolin]-3′-one (1, 1.00 g, 4.08 mmol) in tetrahydrofuran (20 mL) is added dropwise borane dimethyl sulfide complex (12.24 mL, 24.48 mmol, 2 M in tetrahydrofuran). The reaction is stirred at 65° C. for 7 h, then stirred at room temperature overnight. 0.5 M hydrochloric acid (8 mL) is added dropwise and the mixture is refluxed for 2 h. The mixture is cooled to room temperature, basified with 1 M aqueous sodium hydroxide solution to pH=8 and extracted with ethyl acetate. The combined organics is dried over magnesium sulfate, filtered and concentrated. The crude is purified via column chromatography to afford methyl 6′methoxy-4′-methylspiro[cyclohexane-1,1′-isoindoline] (2). Stage 1: With dimethylsulfide borane complex in tetrahydrofuran, T= 20 - 65 °C Stage 2: With hydrogenchloride in tetrahydrofuran, water, Time= 2h, Reflux Patent; EFFECTOR THERAPEUTICS, INC.; Sprengeler, Paul A.; Reich, Siegfried H.; Ernst, Justin T.; Webber, Stephen E.; (55 pag.); US2017/121339; (2017); (A1) English View in Reaxys

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O NH

Rx-ID: 45388529 View in Reaxys 37/97 Yield

Conditions & References Reaction Steps: 4 1.1: dimethylsulfide borane complex / tetrahydrofuran / 20 - 65 °C 1.2: 2 h / |Reflux 2.1: ammonium sulfate / toluene / |Reflux 3.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 3.2: 1 h / -78 - 20 °C 4.1: boron tribromide / dichloromethane / 16 h / -78 - 20 °C With ammonium sulfate, n-butyllithium, dimethylsulfide borane complex, boron tribromide in tetrahydrofuran, hexane, dichloromethane, toluene Patent; EFFECTOR THERAPEUTICS, INC.; Sprengeler, Paul A.; Reich, Siegfried H.; Ernst, Justin T.; Webber, Stephen E.; (55 pag.); US2017/121339; (2017); (A1) English View in Reaxys

Rx-ID: 45388540 View in Reaxys 38/97 Yield

Conditions & References Reaction Steps: 2 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 1.2: 1 h / -78 - 20 °C 2.1: boron tribromide / dichloromethane / 16 h / -78 - 20 °C With n-butyllithium, boron tribromide in tetrahydrofuran, hexane, dichloromethane Patent; EFFECTOR THERAPEUTICS, INC.; Sprengeler, Paul A.; Reich, Siegfried H.; Ernst, Justin T.; Webber, Stephen E.; (55 pag.); US2017/121339; (2017); (A1) English View in Reaxys

Rx-ID: 45388551 View in Reaxys 39/97 Yield

Conditions & References 37 : Synthesis of 3′,4′-dimethylspiro[cyclohexane-1,1′-isoindolin]-6′-ol (6) To a solution of N-tert-butyl-1-(6′-methoxy-3′,4′-dimethylspiro[cyclohexane-1,1′-isoindolin]-2′-yl)methanimine (5, 1.00 g, 3.04 mmol) in dichloromethane (20 mL) at −78° C. is added slowly boron tribromide (0.59 mL, 6.08 mmol). The reaction is stirred at room temperature for 16 h. After completion, the reaction mixture is quenched with saturated aqueous sodium bicarbonate solution to adjust to pH 8. The mixture is extracted with dichloromethane (2×30 mL). The combined organics is dried over sodium sulfate, filtered and concentrated. The crude is then purified via column chromatography to afford 3′,4′-dimethylspiro[cyclohexane-1,1′-isoindolin]-6′-ol (6). With boron tribromide in dichloromethane, Time= 16h, T= -78 - 20 °C Patent; EFFECTOR THERAPEUTICS, INC.; Sprengeler, Paul A.; Reich, Siegfried H.; Ernst, Justin T.; Webber, Stephen E.; (55 pag.); US2017/121339; (2017); (A1) English

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View in Reaxys

Rx-ID: 24932161 View in Reaxys 40/97 Yield

Conditions & References 1 : Spiro[1,3-dihydroisoindole-1,1'-(1,2,3,4-tetrahydronaphthalene)] formula Ie, n=2) EXAMPLE 1 Spiro[1,3-dihydroisoindole-1,1'-(1,2,3,4-tetrahydronaphthalene)] formula Ie, n=2) To a cold (ice bath) stirred suspension of the lactam spiro[1,3-dihydroisoindole-1,1'-(1,2,3,4-tetrahydronaphthalene)]-3-one (0.61 g, 2.4 mM) in tetrahydrofuran (15 mL) under a nitrogen atmosphere was added lithium aluminum hydride (0.37 g, 9.8 mM). After stirring 5 min, the cooling bath was removed and the reaction mixture was refluxed for 18 hr and then cooled using an ice bath. To this cooled mixture was added dropwise in successive portions 0.37 mL of water, 0.37 mL of 15percent aqueous hydroxide and 1.1 mL of water. The resulting mixture was filtered and the collected solids were washed several times with tetrahydrofuran. The filtrate and washes were combined, dried (sodium sulfate), filtered and concentrated to leave a yellow oil. This oil was chromatographed over silica gel (eluant: 1:2 ethyl acetate/hexane) to separate the title spiroisoindoline (0.43 g, 77percent) as a pale yellow oil. A portion (0.30 g, 1.3 mM) of the above chromatographed oil in 2 mL of ethanol was treated with ethereal hydrogen chloride. The resulting precipitate was collected and recrystallized from ethanol/diethyl ether (1:1) to given the hydrochloride salt of the spiroisondoline (0.24 g, 69percent) as an off-white crystalline solid, mp 250°-251° C. Analysis: C, 74.14; H, 6.73; N, 5.09 Calculated: C, 74.14; H, 6.73; N, 5.09 Found: C, 74.17; H, 6.72; N, 5.10 Patent; ICI Americas Inc.; US5098925; (1992); (A1) English View in Reaxys

O N O

Rx-ID: 6605667 View in Reaxys 41/97 Yield

Conditions & References 2-Ethylisoindolin-1-spiro-1'-cyclohexadien-3,4'-dion, H2, in A., Adams Katalys. Hey et al.; Journal of the Chemical Society; (1961); p. 232,235 View in Reaxys

H H O N OH

O H

Rx-ID: 40659610 View in Reaxys 42/97 Yield

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With pyridine, 1,1'-bis-(diphenylphosphino)ferrocene, oxalyl dichloride, 2-iodobiphenyl, potassium acetate, palladium diacetate, potassium carbonate, N,N-dimethyl-formamide, 3-chloro-benzenecarboperoxoic acid in dichloromethane, water, dimethyl sulfoxide, ethyl acetate Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys

H O N O H

Rx-ID: 40659616 View in Reaxys 43/97 Yield

Conditions & References Reaction Steps: 6 1: Re2(CO)10 / toluene / 24 h / 150 °C 2: pyridine / dichloromethane / 5 h / 0 - 20 °C / |Inert atmosphere 3: palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene; potassium acetate / dimethyl sulfoxide / 60 °C / 760.05 Torr 4: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C / |Inert atmosphere 5: potassium carbonate / ethyl acetate; water / 0 - 20 °C 6: 3-chloro-benzenecarboperoxoic acid; 2-iodobiphenyl / water / 0.25 h / 25 °C With pyridine, 1,1'-bis-(diphenylphosphino)ferrocene, oxalyl dichloride, Re2(CO)10, 2-iodobiphenyl, potassium acetate, palladium diacetate, potassium carbonate, N,N-dimethyl-formamide, 3-chloro-benzenecarboperoxoic acid in dichloromethane, water, dimethyl sulfoxide, ethyl acetate, toluene Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys

H H

F F

H O N

O H

Rx-ID: 40659621 View in Reaxys 44/97 Yield

Conditions & References Reaction Steps: 4 1: palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene; potassium acetate / dimethyl sulfoxide / 60 °C / 760.05 Torr 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C / |Inert atmosphere 3: potassium carbonate / ethyl acetate; water / 0 - 20 °C 4: 3-chloro-benzenecarboperoxoic acid; 2-iodobiphenyl / water / 0.25 h / 25 °C With 1,1'-bis-(diphenylphosphino)ferrocene, oxalyl dichloride, 2-iodobiphenyl, potassium acetate, palladium diacetate, potassium carbonate, N,N-dimethyl-formamide, 3-chloro-benzenecarboperoxoic acid in dichloromethane, water, dimethyl sulfoxide, ethyl acetate Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys

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N HO

Rx-ID: 40659625 View in Reaxys 45/97 Yield

N Cl

Rx-ID: 40659627 View in Reaxys 46/97 Yield

H H HN

H O N

Rx-ID: 40659658 View in Reaxys 47/97 Yield 72 %

Conditions & References With 2-iodobiphenyl, 3-chloro-benzenecarboperoxoic acid in water, Time= 0.25h, T= 25 °C , stereospecific reaction Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys

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H O

O N O H

Rx-ID: 40659678 View in Reaxys 48/97 Yield

O Br

Rx-ID: 39050917 View in Reaxys 49/97 Yield

Conditions & References C−H Arylation; General Procedure General procedure: To an oven-dried 20 mL scintillation vial containing a magnetic stirbar and substrate, was added Ni(cod)2, t-BuOK, and anhydrous THF in a glove box. The vial was sealed with a Teflon-lined cap, taken out of the glove box, and the reaction mixture was stirred at r.t. for the indicated time. The reaction mixture was filtered through a 3.8 cm plug of silica gel, eluting with EtOAc (100 mL). The filtrate was concentrated and purified by chromatography on a silicagel column to afford the product With bis(1,5-cyclooctadiene)nickel (0), potassium tert-butylate in tetrahydrofuran, Time= 21h, T= 20 °C , Sealed tube, Overall yield = 84 percent; Overall yield = 102.1 mg Wertjes, William C.; Waller, Peter J.; Shelton, Kyle E.; Kalyani, Dipannita; Synthesis (Germany); vol. 46; nb. 22; (2014); p. 3033 - 3040; Art.No: SS-2014-C0299-OP View in Reaxys O

H N

Br O

Rx-ID: 39050930 View in Reaxys 50/97 Yield

Conditions & References Reaction Steps: 2 1: N-ethyl-N,N-diisopropylamine / diethyl ether / 1 h / 0 - 20 °C / |Schlenk technique; |Inert atmosphere 2: bis(1,5-cyclooctadiene)nickel (0); potassium tert-butylate / tetrahydrofuran / 21 h / 20 °C / |Sealed tube With bis(1,5-cyclooctadiene)nickel (0), potassium tert-butylate, N-ethyl-N,N-diisopropylamine in tetrahydrofuran, diethyl ether

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Wertjes, William C.; Waller, Peter J.; Shelton, Kyle E.; Kalyani, Dipannita; Synthesis (Germany); vol. 46; nb. 22; (2014); p. 3033 - 3040; Art.No: SS-2014-C0299-OP View in Reaxys

O N

hydrogen

Rx-ID: 19319711 View in Reaxys 51/97 Yield

Conditions & References Reaction Steps: 2 1: p-TsOH / toluene / 120 h / Heating 2: Bu3SnH, azobis(isobutyronitrile) / toluene / 2.5 h / 80 °C With 2,2'-azo-bisisobutyronitrile, tri-n-butyl-tin hydride, toluene-4-sulfonic acid in toluene Glover, Stephen A.; Warkentin, John; Journal of Organic Chemistry; vol. 58; nb. 8; (1993); p. 2115 - 2121 View in Reaxys Reaction Steps: 2 1: p-TsOH / toluene / 120 h / Heating 2: Bu3SnH, azobis(isobutyronitrile) / toluene / 2.5 h / 80 °C With 2,2'-azo-bisisobutyronitrile, tri-n-butyl-tin hydride, toluene-4-sulfonic acid in toluene Glover, Stephen A.; Warkentin, John; Journal of Organic Chemistry; vol. 58; nb. 8; (1993); p. 2115 - 2121 View in Reaxys

N H

Rx-ID: 19326563 View in Reaxys 52/97 Yield

Br N

Rx-ID: 19351058 View in Reaxys 53/97 Yield

Conditions & References Reaction Steps: 3 1: 92 percent / benzene / Heating 2: p-TsOH / toluene / 120 h / Heating

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3: Bu3SnH, azobis(isobutyronitrile) / toluene / 2.5 h / 80 °C With 2,2'-azo-bisisobutyronitrile, tri-n-butyl-tin hydride, toluene-4-sulfonic acid in toluene, benzene Glover, Stephen A.; Warkentin, John; Journal of Organic Chemistry; vol. 58; nb. 8; (1993); p. 2115 - 2121 View in Reaxys Reaction Steps: 3 1: 92 percent / benzene / Heating 2: p-TsOH / toluene / 120 h / Heating 3: Bu3SnH, azobis(isobutyronitrile) / toluene / 2.5 h / 80 °C With 2,2'-azo-bisisobutyronitrile, tri-n-butyl-tin hydride, toluene-4-sulfonic acid in toluene, benzene Glover, Stephen A.; Warkentin, John; Journal of Organic Chemistry; vol. 58; nb. 8; (1993); p. 2115 - 2121 View in Reaxys O

Rx-ID: 40659417 View in Reaxys 54/97 Yield

Conditions & References Reaction Steps: 5 1: pyridine / dichloromethane / 5 h / 0 - 20 °C / |Inert atmosphere 2: palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene; potassium acetate / dimethyl sulfoxide / 60 °C / 760.05 Torr 3: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C / |Inert atmosphere 4: potassium carbonate / ethyl acetate; water / 0 - 20 °C 5: 3-chloro-benzenecarboperoxoic acid; 2-iodobiphenyl / water / 0.25 h / 25 °C With pyridine, 1,1'-bis-(diphenylphosphino)ferrocene, oxalyl dichloride, 2-iodobiphenyl, potassium acetate, palladium diacetate, potassium carbonate, N,N-dimethyl-formamide, 3-chloro-benzenecarboperoxoic acid in dichloromethane, water, dimethyl sulfoxide, ethyl acetate Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys

O N

O F F

O O

Rx-ID: 40659420 View in Reaxys 55/97 Yield

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Rx-ID: 40659424 View in Reaxys 56/97 Yield

Rx-ID: 40659426 View in Reaxys 57/97 Yield

O N H

Rx-ID: 40659657 View in Reaxys 58/97 Yield

Conditions & References

74 %

With 2-iodobiphenyl, 3-chloro-benzenecarboperoxoic acid in water, Time= 0.25h, T= 25 °C Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys O N

Rx-ID: 40659709 View in Reaxys 59/97 Yield

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3: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C / |Inert atmosphere 4: potassium carbonate / ethyl acetate; water / 0 - 20 °C 5: 3-chloro-benzenecarboperoxoic acid; 2-iodobiphenyl / water / 0.25 h / 25 °C With pyridine, 1,1'-bis-(diphenylphosphino)ferrocene, oxalyl dichloride, 2-iodobiphenyl, potassium acetate, palladium diacetate, potassium carbonate, N,N-dimethyl-formamide, 3-chloro-benzenecarboperoxoic acid in dichloromethane, water, dimethyl sulfoxide, ethyl acetate Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys

O O

S O

O N

Rx-ID: 40659714 View in Reaxys 60/97 Yield

Rx-ID: 40659717 View in Reaxys 61/97 Yield

Rx-ID: 40659720 View in Reaxys 62/97

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Yield

O N H

Rx-ID: 40659825 View in Reaxys 63/97 Yield

Conditions & References

75 %

NH NH

O HO

Rx-ID: 45388520 View in Reaxys 64/97 Yield

Conditions & References Reaction Steps: 4 1.1: ammonium sulfate / toluene / |Reflux 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 2.2: 1 h / -78 - 20 °C 3.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 3.2: 1 h / -78 - 20 °C 4.1: boron tribromide / dichloromethane / 16 h / -78 - 20 °C With ammonium sulfate, n-butyllithium, boron tribromide in tetrahydrofuran, hexane, dichloromethane, toluene Patent; EFFECTOR THERAPEUTICS, INC.; Sprengeler, Paul A.; Reich, Siegfried H.; Ernst, Justin T.; Webber, Stephen E.; (55 pag.); US2017/121339; (2017); (A1) English View in Reaxys O NH

Rx-ID: 45388535 View in Reaxys 65/97 Yield

Conditions & References Reaction Steps: 5 1.1: dimethylsulfide borane complex / tetrahydrofuran / 20 - 65 °C 1.2: 2 h / |Reflux 2.1: ammonium sulfate / toluene / |Reflux 3.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 3.2: 1 h / -78 - 20 °C 4.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 4.2: 1 h / -78 - 20 °C

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5.1: boron tribromide / dichloromethane / 16 h / -78 - 20 °C With ammonium sulfate, n-butyllithium, dimethylsulfide borane complex, boron tribromide in tetrahydrofuran, hexane, dichloromethane, toluene Patent; EFFECTOR THERAPEUTICS, INC.; Sprengeler, Paul A.; Reich, Siegfried H.; Ernst, Justin T.; Webber, Stephen E.; (55 pag.); US2017/121339; (2017); (A1) English View in Reaxys

Rx-ID: 45388546 View in Reaxys 66/97 Yield

Conditions & References Reaction Steps: 3 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 1.2: 1 h / -78 - 20 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 2.2: 1 h / -78 - 20 °C 3.1: boron tribromide / dichloromethane / 16 h / -78 - 20 °C With n-butyllithium, boron tribromide in tetrahydrofuran, hexane, dichloromethane Patent; EFFECTOR THERAPEUTICS, INC.; Sprengeler, Paul A.; Reich, Siegfried H.; Ernst, Justin T.; Webber, Stephen E.; (55 pag.); US2017/121339; (2017); (A1) English View in Reaxys

Rx-ID: 45388556 View in Reaxys 67/97 Yield

Rx-ID: 45388568 View in Reaxys 68/97 Yield

Conditions & References 38 : Synthesis of 3′,3′,4′-trimethylspiro[cyclohexane-1,1′-isoindolin]-6′-ol (3) To a solution of N-tert-butyl-1-(6′-methoxy-3′,4′-dimethylspiro[cyclohexane-1,1′-isoindolin]-2′-yl)methanimine (2, 1.00 g, 2.92 mmol) in dichloromethane (20 mL) at −78° C. is added slowly boron tribromide (0.56 mL, 5.84 mmol). The reaction is stirred at room temperature for 16 h. After completion, the reaction mixture is quenched with saturated aqueous sodium bicarbonate solution to adjust to pH 8. The mixture is extracted with dichloromethane (2×30 mL).

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The combined organics is dried over sodium sulfate, filtered and concentrated. The crude is then purified via column chromatography to afford 3′,3′,4′-trimethylspiro[cyclohexane-1,1′-isoindolin]-6′-ol (3). With boron tribromide in dichloromethane, Time= 16h, T= -78 - 20 °C Patent; EFFECTOR THERAPEUTICS, INC.; Sprengeler, Paul A.; Reich, Siegfried H.; Ernst, Justin T.; Webber, Stephen E.; (55 pag.); US2017/121339; (2017); (A1) English View in Reaxys

N H

racemate

Rx-ID: 3457158 View in Reaxys 69/97 Yield

N H

racemate

Rx-ID: 3457159 View in Reaxys 70/97 Yield

Conditions & References With 2,2'-azo-bisisobutyronitrile, tri-n-butyl-tin hydride in toluene, Time= 2.5h, T= 80 °C , kendo, kexo (rel. rates); variation of Bu3SnH concentration, Rate constant, Product distribution Glover, Stephen A.; Warkentin, John; Journal of Organic Chemistry; vol. 58; nb. 8; (1993); p. 2115 - 2121 View in Reaxys

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racemate

Rx-ID: 3457160 View in Reaxys 71/97 Yield

HN O

Rx-ID: 3480212 View in Reaxys 72/97 Yield

Conditions & References

44 %

With hydrogen, platinum(IV) oxide in acetic acid, p= 2585.7Torr , Ambient temperature Houlihan; Uike; Parrino; Journal of Organic Chemistry; vol. 46; nb. 22; (1981); p. 4515 - 4517 View in Reaxys O

N H

O N

Rx-ID: 40659664 View in Reaxys 73/97 Yield

Conditions & References

73 %

Rx-ID: 40659721 View in Reaxys 74/97 Yield

Conditions & References Reaction Steps: 6 1: phosphoric acid / 16 h / 100 °C 2: pyridine / dichloromethane / 5 h / 0 - 20 °C / |Inert atmosphere 3: palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene; potassium acetate / dimethyl sulfoxide / 60 °C / 760.05 Torr 4: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C / |Inert atmosphere 5: potassium carbonate / ethyl acetate; water / 0 - 20 °C 6: 3-chloro-benzenecarboperoxoic acid; 2-iodobiphenyl / water / 0.25 h / 25 °C With pyridine, 1,1'-bis-(diphenylphosphino)ferrocene, oxalyl dichloride, phosphoric acid, 2-iodobiphenyl, potassium acetate, palladium diacetate, potassium carbonate, N,N-dimethyl-formamide, 3-chloro-benzenecarboperoxoic acid in dichloromethane, water, dimethyl sulfoxide, ethyl acetate

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Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys O

Rx-ID: 40659726 View in Reaxys 75/97 Yield

F S

O N

Rx-ID: 40659730 View in Reaxys 76/97 Yield

OH F

Rx-ID: 40659733 View in Reaxys 77/97 Yield

Conditions & References Reaction Steps: 3 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C / |Inert atmosphere 2: potassium carbonate / ethyl acetate; water / 0 - 20 °C

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3: 3-chloro-benzenecarboperoxoic acid; 2-iodobiphenyl / water / 0.25 h / 25 °C With oxalyl dichloride, 2-iodobiphenyl, potassium carbonate, N,N-dimethyl-formamide, 3-chloro-benzenecarboperoxoic acid in dichloromethane, water, ethyl acetate Zhu, Chendan; Liang, Yong; Hong, Xin; Sun, Heqing; Sun, Wei-Yin; Houk; Shi, Zhuangzhi; Journal of the American Chemical Society; vol. 137; nb. 24; (2015); p. 7564 - 7567 View in Reaxys O

Rx-ID: 40659736 View in Reaxys 78/97 Yield

Rx-ID: 40659737 View in Reaxys 79/97 Yield

O O

(+-)-1-<4-methoxy-phenyl>-propan-2-ol

O NH

Rx-ID: 17626141 View in Reaxys 80/97 Yield

Conditions & References Reaction Steps: 3 1: 66 percent / 4 h / 140 °C 2: 1.) Mg / 1.) THF, 2.) 0 deg C, 4 h 3: 51 percent / TFA / 50 h / Heating With magnesium, trifluoroacetic acid

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Bahajaj, Abood A.; Vernon, John M.; Journal of the Chemical Society - Perkin Transactions 1; nb. 10; (1996); p. 1041 - 1046 View in Reaxys

O O

Rx-ID: 17631597 View in Reaxys 81/97 Yield

Conditions & References Reaction Steps: 2 1: 1.) Mg / 1.) THF, 2.) 0 deg C, 4 h 2: 51 percent / TFA / 50 h / Heating With magnesium, trifluoroacetic acid Bahajaj, Abood A.; Vernon, John M.; Journal of the Chemical Society - Perkin Transactions 1; nb. 10; (1996); p. 1041 - 1046 View in Reaxys

Rx-ID: 24932162 View in Reaxys 82/97 Yield

Conditions & References

75%

2 : 2-Methylspiro[1,3-dihydroisoindole-1,1'-(1,2,3,4-tetrahydronaphthalene)] (formula Ie; n=2; R=CH3) The combined extracts were dried (sodium sulfate), filtered and concentrated to leave 0.35 g of a colorless oil. Flash chromatography of this oil over silica gel (eluant: 3:1 hexane: diethyl ether) gave a solution of the title spiroisoindoline which was treated with exess ethereal oxalic acid followed by enough ethanol to provide a free flowing crystalline solid. The solid was collected, washed with diethyl ether and air dried to give the oxalate salt of the title spiroisoindoline as a white solid. Recrystallization of this material from ethanol/diethyl ether provided the oxalate salt (0.35 g, 75percent) as a white solid, mp 180°-182° (dec). Analysis for C18H19N.(HO2C)2.0.2 H2 O: Calculated: C, 70.04; H, 6.29; N, 4.08. Found: C, 70.18; H, 6.29; N, 3.94. Patent; ICI Americas Inc.; US5098925; (1992); (A1) English View in Reaxys

Cl I O

N O

Rx-ID: 37734389 View in Reaxys 83/97 Yield 93 %

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Cl Cl O N

Rx-ID: 37734562 View in Reaxys 84/97 Yield

N O

Rx-ID: 37734579 View in Reaxys 85/97 Yield

Rx-ID: 24932164 View in Reaxys 86/97 Yield

Conditions & References 5 : Spiro[1,3-dihydroisoindole-1,1'-(1,2,3,4-tetrahydronaphthalene)]-6-ol (formula Ie; n=2; Y3 =OH) A portion of this material was crystallized from diethyl ether/ethyl acetate to give an analytical sample of the compound as a white solid, mp 158°-159° C. Analysis for C17 H17 NO.0.10 (C2 H5)2 O: Calculated: C, 80.77; H, 7.01; N, 5.41. Found: C, 80.40; H, 7.01; N, 5.29. Patent; ICI Americas Inc.; US5098925; (1992); (A1) English View in Reaxys HO

N O

Rx-ID: 2512247 View in Reaxys 87/97 Yield 34 %

Conditions & References With PPA, Time= 0.333333h, T= 130 °C Fleming, Ian; Moses, Roger C.; Tercel, Moana; Ziv, Joseph; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); nb. 3; (1991); p. 617 - 626

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View in Reaxys O

O HN

Rx-ID: 21606519 View in Reaxys 88/97 Yield

Conditions & References Reaction Steps: 3 1: 40.1 percent / SeO2 / acetic anhydride / 12 h / 90 °C 2: 80 percent / NH2OH 3: 34 percent / polyphosphoric acid / 0.33 h / 130 °C With selenium(IV) oxide, PPA, hydroxylamine in acetic anhydride Fleming, Ian; Moses, Roger C.; Tercel, Moana; Ziv, Joseph; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); nb. 3; (1991); p. 617 - 626 View in Reaxys O

Rx-ID: 21607256 View in Reaxys 89/97 Yield

Conditions & References Reaction Steps: 2 1: 80 percent / NH2OH 2: 34 percent / polyphosphoric acid / 0.33 h / 130 °C With PPA, hydroxylamine Fleming, Ian; Moses, Roger C.; Tercel, Moana; Ziv, Joseph; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); nb. 3; (1991); p. 617 - 626 View in Reaxys

O HN

O O

Rx-ID: 21607591 View in Reaxys 90/97 Yield

Conditions & References Reaction Steps: 4 1: 93 percent / polyphosphoric acid / 5 h / 100 °C 2: 40.1 percent / SeO2 / acetic anhydride / 12 h / 90 °C 3: 80 percent / NH2OH 4: 34 percent / polyphosphoric acid / 0.33 h / 130 °C With selenium(IV) oxide, PPA, hydroxylamine in acetic anhydride Fleming, Ian; Moses, Roger C.; Tercel, Moana; Ziv, Joseph; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); nb. 3; (1991); p. 617 - 626 View in Reaxys

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O HN

O O O

Rx-ID: 21610315 View in Reaxys 91/97 Yield

Conditions & References Reaction Steps: 5 1: 93 percent / Cu / pyridine / 9 h / 100 °C 2: 93 percent / polyphosphoric acid / 5 h / 100 °C 3: 40.1 percent / SeO2 / acetic anhydride / 12 h / 90 °C 4: 80 percent / NH2OH 5: 34 percent / polyphosphoric acid / 0.33 h / 130 °C With selenium(IV) oxide, PPA, hydroxylamine, copper in pyridine, acetic anhydride Fleming, Ian; Moses, Roger C.; Tercel, Moana; Ziv, Joseph; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); nb. 3; (1991); p. 617 - 626 View in Reaxys O HN

Br–+Mg

Rx-ID: 21626926 View in Reaxys 92/97 Yield

Conditions & References Reaction Steps: 6 1: 87 percent / Cu(I)Br / diethyl ether / 1) 0 deg C to r.t., 20 min, 2) 40 deg C, 6h 2: 93 percent / Cu / pyridine / 9 h / 100 °C 3: 93 percent / polyphosphoric acid / 5 h / 100 °C 4: 40.1 percent / SeO2 / acetic anhydride / 12 h / 90 °C 5: 80 percent / NH2OH 6: 34 percent / polyphosphoric acid / 0.33 h / 130 °C With selenium(IV) oxide, PPA, hydroxylamine, copper, copper(I) bromide in pyridine, diethyl ether, acetic anhydride Fleming, Ian; Moses, Roger C.; Tercel, Moana; Ziv, Joseph; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); nb. 3; (1991); p. 617 - 626 View in Reaxys

N Br

O O

racemate

Rx-ID: 8718065 View in Reaxys 93/97 Yield 41 %

Conditions & References With 2,2'-azo-bisisobutyronitrile, tri-n-butyl-tin hydride in toluene, Time= 3h, Heating Parsons, Andrew F; Williams, David A.J; Tetrahedron; vol. 56; nb. 37; (2000); p. 7217 - 7228 View in Reaxys

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O O

CHCl2C(O)Hal

N O

Rx-ID: 15641749 View in Reaxys 94/97 Yield

Conditions & References Reaction Steps: 2 1.1: 3 h / Heating 1.2: 51 percent / 20 °C 2.1: 41 percent / tributyltin hydride; azobis(isobutyronitrile) / toluene / 3 h / Heating With 2,2'-azo-bisisobutyronitrile, tri-n-butyl-tin hydride in toluene Parsons, Andrew F; Williams, David A.J; Tetrahedron; vol. 56; nb. 37; (2000); p. 7217 - 7228 View in Reaxys

O N

Cl O

Rx-ID: 15641836 View in Reaxys 95/97 Yield

O N

racemate

Rx-ID: 4543141 View in Reaxys 96/97 Yield

Conditions & References

51 %

With trifluoroacetic acid, Time= 50h, Heating, Yields of byproduct given Bahajaj, Abood A.; Vernon, John M.; Journal of the Chemical Society - Perkin Transactions 1; nb. 10; (1996); p. 1041 - 1046 View in Reaxys

51 %

With trifluoroacetic acid, Time= 50h, Heating, Yield given. Title compound not separated from byproducts Bahajaj, Abood A.; Vernon, John M.; Journal of the Chemical Society - Perkin Transactions 1; nb. 10; (1996); p. 1041 - 1046 View in Reaxys

O O O

H H O

H O S

Rx-ID: 24912496 View in Reaxys 97/97

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Yield

Conditions & References 1.b : b. b. Spiro[1,3-dihydroisoindole-1,1'-(1,2,3,4-tetrahydronaphthalene)]-3-one A solution of the spirolactone produced in Example 1a (3.68 g, 14.7 mM) in 93 mL of ethanol was added to a solution of ammonium chloride (3.93 g, 73.5 mM) in 289 mL of 28percent aqueous ammonium hydroxide. The resulting mixture was cooled in an ice bath, saturated with ammonia gas, placed in a stainless steel pressure vessel and heated to 232°-240° C. (1200 psi) for 20 hr. After cooling to room temperature, the contents of the pressure vessel were removed and concentrated. The residue was suspended in an ethyl acetate/water mixture, filtered and the filtrate extracted three times with ethyl acetate. The combined extracts were dried (sodium sulfate), filtered to remove some insoluble material and concentrated to give an amber oil. The oil was chromatographed over silica gel (eluant: diethyl ether) to give 1.77 g of a foam which was a mixture of 2(5,6-dihydronaphthalen-8-yl)benzamide and the desired spirolactam, and 0.18 g of pure spirolactam which crystallized from diethyl ether as an off-white crystalline solid, mp 236.5°-240° C. Analysis for C17H15NO.: Calculated: C, 81.9; H, 6.06; N, 5.62. Found: C, 81.86; H, 6.15; N, 5.22. Patent; ICI Americas Inc.; US5098925; (1992); (A1) English View in Reaxys

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