Semidirect Am I Nation Of Safrole

The dream of every X chemist is to get that amine function directly on the safrole molecule without having to go thru any intermediate such as the ketone of MD-P2P or the bromine of bromosafrole. But Strike can tell you right now that that is very, very tough (that is why there ain't no methods for it). About the only article Strike has ever found for the actual placement of an amine directly on a terminal alkene (a.k.a. safrole) is the following [79]:

"Amination of propylene: The conversion of ammonia and propylene to isopropylamine and diisopropylamine was shown to take place over a sodium catalyst at ca. 25CPC and 850-1000 atm pressure (ref. 7). In contrast, we have found that these reagents - 183 -

can react in the presence of cesium amide containing catalysts, under far milder reaction conditions to give mostly isopropylamine. In a specific example, NH3 (112 mmol) and C3He (142 mmol) were reacted in a reactor of 40 cm3 total capacity containing CsNH2 (18.5 mmol) and NaNH2 (6.4 mmol), for 17.5 hours at 139°C. Isopropylamine (13 mmol), n-propylamine (0.7 mmol) as well as propane (2 mmol) and non-condensible gasses (0.8 mmol) were produced."

Man, that recipe is WEAK! But hey! That's 10% final product in one pot. Yeesh! Why bother? Don't take this first method seriously folks. It was just Strike's way of illustrating the futility of easy answers. All the rest of the stuff in this section is much, much better.

So without direct amination we are confined to 'semi-direct' ami-nation (Strike's terminology). In Strike's opinion, the direct addition of an azide (N3) counts. Once on the beta carbon, that azide is as good as an amine. But can we get an azide directly onto safrole without having to go thru the bromosafrole intermediate as was discussed earlier? Maybe we can!

This following article was sent to Strike by Osmium and Feck (are they the same person?). It involves the direct addition of azide to a terminal alkene (you-know-who) by the in situ production of the reactant mercury (II) azide from mercuric acetate and sodium azide (please don't ask) [80], hydrofuran is added 0.1 mol of alkene. After stirring at 50 to 9(fC for an appropriate period (17-24 h), the two-phase mixture is diluted with 100 ml of 15% aqueous potassium hydroxide and treated with a solution of 2 g sodium borohydride in 100 ml of 15% potassium hydroxide solution. The alkyl azide is isolated by ether extraction followed by distillation at reduced pressure."(% yield for the representative terminal alkenes 1-heptene and 1-octene were 88% and 55% respectively)

That looks simple and direct don't it?! If safrole was used as the alkene one would get safrole-azide as product. Just one teensy little reduction away from MDA. Strike also found some azide papers that, with a little work, will get safrole-azide in a totally different way. Strike came across a lot of work where groups were using dinucleophilic addition to get an azide and a halogen added across a double bond. The azide would always go to the 'beta' secondary carbon and the halogen to the primary carbon (just what one would want if safrole was the substrate).


The first was from a CA article [81]. Various alkenes, styrene and cycloalkenes were tried. But a more followable method is the following [82], The 'supported salt' of NaN3-AI203 was made by mixing the NaN3 with the alumina in water then evaporating the mixture under vacuum in a water bath until dry:

"General Procedure - To a solution of 0.3 moles of sodium azide and 0.1 mole of mercuric acetate in 200mL of 50% aqueous tetra-- 184-

"Reaction with l2 (1.5 mmol) [or Br2], supported salt (1.5 mmol), alkene (0.625 mmol), in 5 ml of ethanol-free CHCI3 at room tem-

perature for 30-48 h. Work up with aq. Na2S203 wash, CH2CI2 extraction, drying (MgS04) and solvent evaporation."

So, theoretically, one would have a safrole with an azide in the right place and a halogen sticking out the end. So what?! Well, Strike was thinking that since the easiest Grignard reagent to make is the one at a primary carbon (which the I or Br will be in this species), one could just make the Grignard reagent out of the intermediate then destroy it by pouring water into the solution which would immediately remove the halogen. Just a thought.

The next method Strike has for semi-direct amination is really weird. Strike is really exposing Strike's ignorance of chemistry with this dog. But if one looks hard at the articles cited, the potential is there. The authors came up with this little procedure that produced vicinal diamines out of alkenes [83], Later they found that if they did a couple of things different, they would end up with a 'monoamine' with the majority product being at the 'beta' carbon. The following is a conjoining of the two paper's experimentáis:

"The addition of N-bromosuccinimide (1.1 equiv) to a dichlo-romethane solution containing the alkene (1 equiv) and cyana-mide (4 equiv). The solution was maintained at room temperature (3 days) and then washed with water, dried, and concentrated in vacuo. Treatment of the bromocyanamide [intermediate] with 1% palladium on charcoal in methanol (1h) led to reduction of the formadme. Addition of base to the reaction mixture (50% aqueous KOH, reflux 6h) followed by extraction with ether gave monoamine." (Yield is 48-64% final amine from alkenes analogous to safrole)

Continue reading here: Phenylacetones

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