Ning doesn't know what the buzz at the hive is about making phenyl-2-propanols from allyl compounds, but as it is an important step in the revised acetaminophen synth, ning found some old papers with some information on just that.
Theoretically, it should be easy--just hydrate the allyl, and there's your alcohol. The literature gives two general ways to do this--the first involves concentrated sulphuric acid at high temperatures to actually
sulphonate the allyl, followed by hydrolysis; the second is a simple acid (or base?) catalyzed addition done cold (0-10 degrees).
While ning's books have info on this (a reversible reaction, by the way), ning isn't near the books, so these papers will have to do:
J.Chem.Soc(?), 1935, pg 684 (questionable, sorry)
"Influence of Poles and Polar Linkings on Tautomerism in the Simple Three-carbon System. Part III. Experiments with Benzyl-delta
a- and delta
b-propenylsulphones."
They allylate benzyl sulphinate with allyl bromide, then change the allyl to an alcohol. Here:
--SNIP--
The substances were unchanged when boiled with water, methyl alcohol, or pyridine. The addition of alkali hydroxide or alkoxide was rapid and led to the formation of b-substituted propylsulphones:
R=Ph,Me L=H or Alkyl
R.SO2.CH2.CH=CH2 or R.SO2.CH=CH.CH3 + NaOL ---> R.SO2.CH2.CH(OL).CH3
(ning assumes they didn't use alkoxide with water, of cours :->)
When, by using suitable concentrations of alkali hydroxide or alkoxide, addition was incomplete, no unsaturated sulphone other than the initial compound was found. The formation of a b-substituted addition compound from either of the sulphones did not appear to follow an isomeric change, since each of them yielded the same benzyl-b-iodopropylsulphone when boiled with concentrated hydriodic acid. (--ning thinks, yeah, sure...) Analogous cases of addition are provided by divinylsulphone, which when treated with sodium hydroxide, yields bb'-dihydroxydiethylsulphone (Kretov, J. Russ. Phys. Chem. Soc., 1930, 62, 1; compare also Cashmore, J., 1923, 123, 738), and by a and b-napthyl-deltab-propenylsulphones, which yield the corresponding b-hydroxy-derivatives (Troegar and Artmann; J. pr. Chem., 1896, 53, 484).
--SNIP--(blah blah they can be hydrolyzed apart blah blah)
Action of sodium carbonate solution:
(i) When either of the unsaturated sulphones was boiled under reflux with ?N-sodium carbonate (they left it out!) for 2 hours, a mixture of hydroxy and unchanged sulphone was obtained. Neither the other isomeride nor benzylmethylsulphone could be detected.
(ii) In order to discover whether there was any difference in the rates of conversion of the unsaturated sulphones into the hydroxy-sulphone, each of the former (0.5g) was boiled under reflux with 0.1N-sodium carbonate (25 cc) for 40 minutes. The product, extracted and dried (CaCl2) in chloroform and recovered, had m.p. 84.0 C (for delta-b) corresponding to a 76% conversion, and 86.5 C (for delta-a) corresponding to 81% conversion.
--SNIP--
well, there is a whole bunch of crap about how NaOH hydrolyzes the sulphones apart, but ning thinks to just ignore that for now. Interestingly, Na2CO3 works to hydrate the allyl--there could be something of interest here for the E people? More gentle conditions? Ning also bets that if they kept boiling for another 20 minutes, yield would be almost quantitative.
Next up:
ummm....gotta start writing those journal titles ON THE PAPERS...uhhh...lets say its..
JACS 1934, vol 56, pg.1968
"Synthesis of 5-b-Hydroxypropylbarbituric Acids"
Hey, the wheel turns around, from drugs to other drugs...cool, huh?
--SNIP--
The resistance of the ring in 5,5-ethylisopropylbarbituric acid to the action of sulphuric acid in the cold, prompted the author to study the effect of this reagent on 5,5-alkyl allyl substituted barbituric acids in order to introduce a hydroxyl group in the side chain.
The particular allyl compounds studied were 5,5-allylisopropyl and 5,5-allylisobutylbarbituric acids.
The addition of sulfuric acid to the allyl group takes place very rapidly and smoothly. It has been assumed that the addition of sulfuric acid follows Markownikoff's rule. This method would appear to be applicable to any 5,5-allylalkylbarbituric acid.
The hydroxy compound (I) obtained from 5,5-allylisopropylbarbituric acid was benzoylated to yield the product (II).
In order to show that the benzoyl group was introduced in the side chain, compound (II) was allylated in the 1,3 positions according to the method described in british patent 391,741. (--anyone know what this is??)
Experimental part:
Prep. of 5-isopropyl-5-(B-hydroxypropyl)-barbituric acid (I)
50 g of 5,5-allylisopropylbarbituric acid was added slowly with stirring to 100 cc of sulfuric acid (sp.grav. 1.84) and allowed to stand at room temperature for 8 hours. The solution was poured with constant stirring over 500 g of ice. The precipitate was then filtered and washed with cold water until the filtrate was neutral to congo paper. The product was recrystallized from alcohol. It is soluble in ethyl and methyl alcohols, but it is insoluble in water, ether, chloroform, acetone, or ethyl acetate; m.p. 221-222 C (uncorr.) yield 95%
Prep. of 5-isobutyl-5-(b-hydroxypropyl)-barbituric acid:
Repeated above procedure using 14 g. of 5,5-allylisobutylbarbituric acid, 50 cc of sulfuric acid, and 250 g of ice. The product is soluble in ethyl and methyl alcohols, but it is insoluble in water, ether, chloroform, acetone, or ethyl acetate; m.p. 216-217 C; yield 95%
Cold concentrated sulfuric acid has no action on 5,5-ethylisopropylbarbituric acid.
(AND, the allylation part...)
Diallylation of (II) - 11.1 grams of (II) was treated with 8.1 g of allyl bromide in the presence of finely divided copper and 10% sodium hydroxide according to the method described in british patent 391,741. The product obtained was a very heavy oil which was purified by vacuum distillation, b.p.(25mm) 260 C.
Summary: two 5-alkyl-5-b-hydroxypropylbarbituric acids have been prepared from the corresponding 5-alkyl-5-allylbarbituric acids by addition of sulfuric acid at the double bond and subsequent hydrolysis.
Well, how about that? The yields are nothing to sneeze at, although the conditions seem a *little* rough for some compounds. Luckily, ning's synth needs a soak in sulfuric acid anyway, so perhaps this step and the following MnO2 oxidation could be done in one pot. Ning certainly hopes yields would be as good in the real world.
J. Chem. Soc 1947, pg. 124
"The sulphonation of some derivatives of eugenol"
believe it or not, they were trying to get antibacterial behavior out of these. Wonder if they ever ate any themselves and decided not to report it?
--SNIP--
Treatment of eugenol with concentrated sulphuric acid at 0 C gave largely sulphonated polymers. When O-methyleugenol, however, was sulphonated by stirring with sulphuric acid at 0 C and the sulphonic acids were extracted with water, an amorphous mass was left, from which a 5% yield of the sulfone was isolated.
Hmm...not good. There's your answer for the whole E thing...suphonated polymers. But anyway, ning will try to find more refs on the whole direct hydration thing, while remarking that the indirect (sulphonate->hydrolyze) method, while harsh, seems to give not-too-shabby yields for tougher rings. Also, note that the barbituric acid should have had some steric effects from the other attached alkyl group. Perhaps 4 hours is more than enough for a single allyl group?
So anyway, one pot would be like this, eh?
To 40 mL cold sulfuric acid with stirring is added 10 grams of 2-amino-5-hydroxy-phenyl-2-propene. The mixture is allowed to stand for 4 hours, then is added slowly to 100 mL cold water and stirred for 1 hour. 40 grams of MnO2 (washed battery gunk) are then added, and the mixture heated to 60 C and stirred for 2 hours. The mixture is then cooled and extracted with nonpolar solvent (toluene).
? grams of p-benzoquinone-propan-2-one.
The toluene extract is placed in a beaker with 30 ml aqueous HCl/HBr and stirred at room temp. for 2 hours, then 100ml water is added, the solution basified with Na2CO3 and the toluene removed.
? grams 2,5 dihydroxy 4-chloro/bromo phenyl-2-propanone
The solution with water is boiled dry and 20 g dimethyl oxalate is added. Flask is fitted with reflux condensor/stink pipe and temperature is increased to 150 degrees. After 4 hours the mixture is allowed to cool to 50 degrees and toluene added. After cooling is complete, the toluene is removed and evaporated.
? grams 2,5 dimethoxy 4-halo-phenyl-2-propanone.
So there's your ketone. Whatcha gonna do with it?
Naturally, all the aforementioned was a mere seat of the pants guess, but hey, who knows? The road seems wide open.
