Phenylacetones

Our trusted friend Osmium has been stressing this following recipe as a breakthrough P2P synthesis for speed from a very unlikely precursor. It is apparently a novel rearrangement of a

thoroughly unwatched chemical called 2-phenylpropanal (a.k.a. methyl-phenyl-acetaldehyde, a.k.a. hydratropic aldehyde). Osmium was kind enough to translate the German article from which it comes [87], The following is all Osmium's translations and comments:

2-Phenylpropanal

" With H2S04:

9g 2-phenylpropanal (called Methyl-phenyl-acetaldehyd in the ref) are added during 40 minutes to 40ml cone. H2S04 which is cooled to -16°C. Let react for further 15 mins at -15°C. The mixture is poured on ice. An oily liquid arid a gummy/rubbery/sticky mess are evident. All is extracted with ether and distilled (91-96°C/11 torr) Yield: 5.6g P2P (62%).

With HgCI2:

3g 2-phenylpropanal are heated with a solution of HgCI2 (6g, equimolar amount) in 45ml 75% EtOH in a sealed glass container for 4.5 hours. Temp 10(fC. A precipitate is formed, which dissolves in the following steam-distillation. The oily layer resulting from this steam-distillation is separated and fractionated. Yield more than 80%.

They isolated their products after conversion into the solid semi-carbazone, which included recrystallizations (more losses). This and the fact that they distilled those tiny amounts make me believe that yield will be even higher (at least with the HgCl2 route).

I also found a patent dealing with phenylpropanal rearrangement: - 187-

USPat. 4,694,107 They react 2-phenylpropanal in the gas phase at 300-400°C with zeolithes (silicate) to yield 86% P2P. Quite hot, yes, but otherwise not too difficult, I think."

Strike found this next thing doing an all-nighter Chemical Abstracts search. Strike does not even want to try to explain it. Just read it. If you understand it, great! If not, don't sweat it. Hell if Strike will ever try the damn thing [88] (Note the P2Pol production):

" 113: 151836e Preparation of ketones by oxidation of olefins using cobalt diketone catalysts. Mukoyama, Mitsuaki: Isayama, Shigeru: Kato, Koji: Inoki, Satoru: Yamada, Toru: Takai, Toshiniro (Mitsui Petrochemical Industries, Ltd.) Jpn. Kokai Tokkyo Koho JP 02,121,944 [90,121,944] (CI. C07C49/04) 09 May 1990, Appl. 88/272,450, 28 Oct 1988; 19pp. R1COCH2R2 and R1CH2COF? [I ; R1 = (un)substituted (cyclo)alkyl or aryl(alkyl); R2 = H, (un)substituted, alkyl or aryl(alkyl)] are prepd. By reaction of R1CH:CHR2 with O-contg. Gas in the presence of a secondary ale. And a Co (II) catalyst [II; R3, R5, Rs, Ra = H, straight-chain, branched or cyclic ¿1-10 alkyl, (un)substituted aryl or CONH2 , etc.; R4, R7 = H, alkyl, halo, C02H, alkoxycarbonyl: excluding R3 =

R5 = R6 = R8 = CF3 and R4 = R7 = H]. II may be prepd. By reaction of diketone ligands R3C0CHR4C0R5 with CoCI2 in the presence of KOH in H20. Thus, 2 mmol PhCH2CH2CH:CH2 was oxidized 2 h at 76° and atom O in the presence of 20 mol% II (R3 = R5 = R6 = R8 = tert-Bu, R4 =R7 = H) in 10 mL Me2CHOH to give 29% PhCH2CH2COMe and 71% PhCH2CH2CH(OH)Me. Addnl. 39 catalysts were evaluated for the above oxidn. And 18 other olefins were oxidized; ales, were obtained as byproducts."

This next method for making P2Ps was posted anonymously on the a.d.c. quite awhile ago. Strike is sure most everyone knows who did this, but Strike doesn't to this day. So whoever you are-Thanks! Although Strike has an original paper copy of this post, Strike had no copy on disc. So Strike snagged the text from an archived example saved on Rhodium's home page. So if you want to see more about this method go and visit the site where it rests among many other chemical goodies.

"Subject: Phenyl acetones by electrolytic oxidation From: "guest" <[email protected]> Date: 1997/11/08

Appendix - Phenyl acetones by electrolytic oxidation. Process for 3,4-dlmethoxyphenyl-acetone preparation. European Patent Application 0247526, Filed: 02.12.87; to LARK S.p.a. Milan.

Example 1.

6.27 g of NaBr is dissolved in 25 ml of H20 and 125 ml of CH3CN, the mixture is then strongly stirred by means of magnetic stirring, and to it 3.76 g of isoeugenol-methylether (I) is then added. The obtained mixture is then electrolysed in a 250-ml not-partitioned electro chemical cell, with a constant current of 850 mA, with two graphite anodes with a total surface of about 17 cm2, and a central stainless-steel cathode having a surface of about 25 cm2 being used, with a distance between electrodes of about 1 cm. 5,200 Coulombs are passed, with the reaction mixture being kept at a temperature of 20° C.From the reaction mixture, discharged from the electrochemical cell, two phases, i.e., the aqueous phase, containing Br- ions, and the organic phase, containing acetonitrile and the reaction product, are separated. From the organic phase acetonitrile is evaporated off under reduced pressure, and to the resulting reaction product 40 ml of ethyl acetate is added. The gas-chromatographic analysis of the organic phase shows the presence of epoxide (II) with a >90% purity.

The reaction mixture in ethyl acetate is then transferred to a 100-ml reactor, purged under a nitrogen atmosphere, 340 mg of Lil is added, and the whole mass is then heated, with mechanical stirring, on an oil bath, up to ethyl acetate reflux temperature. The heating is continued for 5 hours, until the disappearance of the epoxide (II), as evidenced by the thin-layer chromatography.

The reaction product is cooled to room temperature, is washed with 10 ml of H20 to the purpose of removing lithium iodide and is then dehydrated over Na2S04. 3.57 g is obtained of dimethoxy-phenylacetone (III), as determined by gas-chromatographic analysis with an inner standard of 4,4'-dimethoxybenzophenone. The yield of ketone (III) relative to the olefin (I) used as the starting material is of 87.1%.

Example 2

Example 1 is repeated in exactly the same way, with the exception that in the isomerization step 250 mg of LiBr instead of 340 mg of Lil is used, and that the reaction time results to be of 10 hours,

instead of 5 hours. In this way, a yield of ketone (III) of 86% relatively to the olefin (I) used as the starting material is obtained.

Example 3

To a 250-ml not-partitioned electro chemical cell, 125 ml of CH3CN, 25 ml ofH20, 6.47 g of NaBr and 2.78 g of isoeugenol-methylether (I) is added. The mixture is electrolysed at a constant current of 350 mA, with a titanium anode coated with a mixed Ru-Ti oxide (50:50 by weight), with a total surface of about 7 errr2, and a central stainless-steel cathode having a surface of about 15 cm2 being used, with a distance between electrodes ofabout 1 cm. Through the cell 4,000 Coulombs are passed, with the reaction mixture being kept at the temperature of 20° C. The reaction mixture is then processed according to such modalities as reported in Example 1, until the solution of the reaction product in ethylace-tate is obtained; to such solution, 337 mg of Lil is added. The mixture is then refluxed (at ethyl acetate refluxing temperature) for 5 hours, and the process is continued as described in Example 1, until 2.795g is obtained of ketone (III), with a yield of 92.2% relatively to the olefin (I) used as the starting material.

Example 4

To a 250-ml not-partitioned electrochemical cell, 125 ml of CH3CN, 25 ml 0fH2O, 6.40 g of NaBr and 2.675 g of isoeugenol-methylether (I) is added. The mixture, kept at 20° C, is electrolysed, with the same constant current density and the same set of electrodes as of Example 1 being used, through the cell 3,625 Coulombs, equalling 2.5 Faradays/mol, being passed. The reaction mixture is then transferred to a rotary evaporator, for CH3CN tobe stripped under vacuum. The resulting reaction product is then extracted three times with 30 ml of ethyl acetate, and is then dried over Na2S04. The organic extract, concentrated to a volume of 25 ml, and with 160 mg of added Lil, is refluxed (at ethyl acetate re-fluxing temperature) for 6 hours. The process is continued as described in Example 1, and 2.54 g is obtained of ketone (III), with a yield of 86.5% relatively to the olefin (I) used as the starting material.

Example 5

To a 250-ml not-partitioned electrochemical cell, 135 ml of CH3CN, 15 ml ofH20, 6.20 g of NaBr and 2.82 g of olefin (I) is added. The mixture, kept at 20° C, is electrolysed by using the same electrodes as of Example 1, but with a constant current density of 1.7 A being used, until through the cell 4,000 Coulombs have been passed. The reaction mixture is then processed as described in Example 4.2.56 g is obtained of ketone (III), with a yield of 83.2%, as computed relatively to the olefin (I) used as the starting material.

Examples 6-9

To a 250-ml not-partitioned electrochemical cell, 100 ml of DMF, 50 ml of H20, 6.72 g of NaBr and 4.25 g of isoeugenol-methylether (I) is charged. The mixture is then electrolysed under the same conditions, and by using the same set of electrodes as used in Example 1, with a total of 5,670 Coulombs being passed. At reaction end, the mixture is discharged, to it 250 ml is added of 20% aqueous NaCI solution, and it is then extracted four times with 50 ml of ethyl acetate. The extract is washed twice with 50 ml of 20% aqueous NaCI solution, and is then dried.The organic extract is concentrated to a volume of 100 ml by the solvent being evaporated off. On three aliquots, of 20 ml each, of said extract, the isomerization reactions are carried out at the ethyl acetate reflux temperature, by using the same lithium salts and reaction times as shown in Table 1. From the fourth aliquot of 20 ml of above said extract, ethyl acetate is evaporated off and replaced with the same amount of acetonitrile. The isomerization of the reaction product is then carried out at acetonitrile refluxing temperature, with the lithium salt and the reaction time being used as shown in Table 1 (Table not shown)."

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