4-benzylcyclohexan-1-one

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2 g of 4-benzylcyclohexanone, the product of Example 1, Step 3, 16 g of ammonium acetate, 100 mL of methanol and 2.5 g of sodium cyanoborohydride was stirred for 5 days at room temperature. After cooling in an ice bath, the reaction was carefully quenched in an efficient fume hood by dropwise addition of 25 mL of 1N HCl. After stirring for 10 min, sodium hydroxide pellets were added to the cold solution until the pH (indicator paper) was about 10. The mixture was concentrated under reduced pressure, diluted with 100 mL of water, made basic by addition of more sodium hydroxide pellets and extracted into 4×100 mL portions of chloroform. After drying over magnesium sulfate, the extracts were concentrated under reduced pressure and then dried under vacuum overnight. Analysis by TLC (silica gel, elution with 90:10:1 chloroform:methanol:conc. ammonium hydroxide) indicated no 4-benzylcyclohexanone or 4-benzylcyclohexanol was present, only 2 new bands which correspond to a mixture of cis- and trans 4-benzyl-cyclohexylamine, which was an oil. After cooling in an ice bath the reaction was carefully quenched in an efficient fume hood by dropwise addition of 25 mL of 1N HCl sodium hydroxide pellets were added to the cold solution until the pH (indicator paper) The mixture was concentrated under reduced pressure diluted with 100 mL of water made basic by addition of more sodium hydroxide pellets extracted into 4×100 mL portions of chloroform After drying over magnesium sulfate the extracts were concentrated under reduced pressure dried under vacuum overnight Analysis by TLC (silica gel, elution with 90:10:1 chloroform:methanol:conc. ammonium hydroxide) only 2 new bands which correspond to a mixture of cis- and trans 4-benzyl-cyclohexylamine, which

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 28 g of 8-benzyl-1,4-dioxa-spiro[4.5]decane, 100 mL of water, 10 mL of methanol and 20 g of Amberlite™ IR-120+ was heated to reflux for 5 h. After cooling, removal of solvents under reduced pressure gave 24 g of 4-benzyl-cyclohexanone as an oil. was heated to reflux for 5 h After cooling removal of solvents under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5 g of 4-benzyl-cyclohexanone, 3.5 g of pyrrolidine, 500 mL of benzene and 10 mg of p-toluenesulfonic acid monohydrate was heated under a water separator apparatus for 48 h, removing the distillate periodically until there was about 50 mL remaining. The solution was cooled and concentrated to 8 g of an amber liquid. The NMR was consistent with complete conversion to the enamine. was heated under a water separator apparatus for 48 h removing the distillate periodically until there The solution was cooled concentrated to 8 g of an amber liquid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 28 g of 8-benzyl-1,4-dioxa-spiro[4.5]decane, 100 mL of water, 10 mL of methanol and 20 g of Amberlite® IR-120+ was heated to reflux for 5 h. After cooling, removal of solvents under reduced pressure gave 24 g of 4-benzyl-cyclohexanone as an oil. was heated to reflux for 5 h After cooling removal of solvents under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 28 g of 8-benzyl-1,4-dioxa-spiro[4.5]decane, 100 mL of water, 10 mL of methanol and 20 g of Amberlite® IR-120+ was heated to reflux for 5 h. After cooling, removal of solvents under reduced pressure gave 24 g of 4-benzyl-cyclohexanone as an oil. was heated to reflux for 5 h After cooling removal of solvents under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In an alternate method, when n is the bridging group --CH2 --, the 8-phenylmethylene-1,4-dioxaspiro[4.5]decane is treated with acetic acid and water as previously described, yielding the corresponding 4-phenylmethylenecyclohexanone. The cyclohexanone is then reduced with hydrogen gas in the presence of 10% palladium on charcoal (Degussa type), yielding the corresponding 4-phenylmethylcyclohexanol, which is in turn treated with sodium dichromate and sulfudc acid in water, affording the 4-phenylmethylcyclohexanone. The 4-phenylmethylcyclohexanone is then reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-phenylmethyl-5,6,7,8-tetrahydroquinazoline. Example 3 provides a detailed description of how this reaction is conducted.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: For example, when n is the bridging group --CH2 --, an appropriately substituted or unsubstituted phenylmethyl bromide, for example, 2-chlorophenylmethyl bromide, is reacted with triphenylphosphine in toluene, affording the corresponding phenylmethyltriphenylphosphonium bromide. The so-prepared phosphonium bromide is then treated with n-butyllithium, and reacted with 1,4-cyclohexanedione mono-ethylene ketal, yielding the appropriate 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane. The 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane is in turn reduced with hydrogen gas in the presence of 10% palladium on charcoal, giving the corresponding 8-phenylmethyl-1,4-dioxaspiro[4.5]-decane. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 4-phenylmethylcyclohexanone. The 4-phenylmethylcyclohexanone is then reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-phenylmethyl-5,6,7,8-tetrahydroquinazoline. Example 2 provides a detailed description of how this reaction is conducted.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-benzylcyclohexanone (4.40 g, 0.023 mole), 3.67 g of potassium cyanide, 5.50 g of dimethylamine hydrochloride and 3 ml of methanol in 30 ml of saturated aqueous dimethylamine was stirred at room temperature for 3 days. The mixture was then extracted thoroughly with CH2Cl2, and the organic layer was concentrated in vacuo. The residue was dissolved in diethyl ether, and the basic material was precipitated with 2 N HCl in diethyl ether. This solid was recrystallized from methylene chloride:ethyl acetate to give 3.91 g (61%) of 4-benzyl-1-cyano-1-(dimethylamino)cyclohexane hydrochloride, m.p. 150°-154° C. The mixture was then extracted thoroughly with CH2Cl2 the organic layer was concentrated in vacuo The residue was dissolved in diethyl ether the basic material was precipitated with 2 N HCl in diethyl ether This solid was recrystallized from methylene chloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7.15 g (0.031 mole) of 4-benzylidenecyclohexanone, ethylene ketal and 0.35 g of 10% palladium on carbon in 150 ml of ethyl acetate was shaken under hydrogen until the theoretical gas uptake had been observed (1 hour). The catalyst was then removed on a filter and the filtrate was concentrated in vacuo to give 4-benzylcyclohexanone, ethylene ketal as an oil, the nmr spectrum of which agreed with the structure. (1 hour) The catalyst was then removed on a filter the filtrate was concentrated in vacuo