Below I present a variety of methods for the preparation of ketones from halohydrins (principally bromohydrins), as well as the preparation of compounds of the latter class from alkenes.
As can be seen in the examples below, it is a very straightforward procedure to turn isosafrole to its bromohydrin [1-(3,4-methylenedioxyphenyl)-2-bromo-1-propanol] and from that go to 3,4-methylenedioxypropiophenone (the principal precursor for Methylone).
However, if one's goal is to prepare MDP2P, the bromohydrin with the correct configuration [1-(3,4-methylenedioxyphenyl)-3-bromo-2-propanol] will have to be derived from safrole. It's a bit trickier to do as safrole is less reactive than isosafrole, but can be done in around in 70% yield according to the J. Chem. Soc. article below, or via safrole dibromide and calcium carbonate according to the procedure in https://www.thevespiary.org/rhodium/Rhodium/chemistry/mdp2p.dibromide.html
With the bromohydrin in hand, it is transformed in high yields to the corresponding ketone with any of the procedures below, using either a palladium complex (a bit expensive, but is used in a catalytic amount), a cobolt complex (cheaper, but needs to be used in an equimolar amount) and finally with the least expensive method of all - an UV lamp and catalytic p-toluenesulfonic acid.The Action of Bromine Water on Certain Olefinic Hydrocarbons and EthersJohn Read and William Galloway ReidJ. Chem. Soc. 1487-1493 (1928)
(
https://www.thevespiary.org/rhodium/Rhodium/pdf/bromohydrins.br2-h2o.pdf)
It has become evident that wide use may be made of chlorine water and bromine water as reagents for the addition of hypochlorous and hypobromous acids to olefinic substances. The present paper describes the application of bromine water in this way to styrene and a number of related aromatic ethers.
Since the bromohydrins are not readily affected by hot water, it has been possible to adduce four further examples in which the yield of bromohydrin is increased by raising the temperature during the reaction with bromine water. Under the conditions adopted, the percentage yields of bromohydrin obtained at room temperature and at about 90°C, respectively, were as follows: styrene 77.9/96.7; anethole 47.9/76.1; safrole 65.2/69.2; isosafrole 67.0/72.8. It thus appears to be a general rule that when the halogenohydrin is stable towards hot water the ratio halogenohydrin/dihalogenide increases with rise of temperature. The yield of halogenohydrin is increased also by dilution.
A Palladium Catalyzed Conversion of Halohydrins to KetonesJiro Tsuji, Hideo Nagashima, and Koji SatoTetrahedron Letters 23(30), 3085-3088 (1982)
(
https://www.thevespiary.org/rhodium/Rhodium/pdf/halohydrin2ketone.pd.1982.pdf)
Summary Pd(OAc)
2 combined with P(o-Tol)
3 catalyzes the conversion of halohydrins to ketones in the presence of K
2CO
3. Various halohydrins, which are easily available from olefins, can be converted to ketones in high yields.
Conversion of halohydrins to ketones promoted by ethylmagnesium halide or silver nitrate has been reported by House
1. However, this method is not satisfactory due to poor yields of ketones. Halohydrins are easily available from olefins, and in some cases, regioselective preparation is possible
2. Thus, the preparation of halohydrins from olefins and the subsequent conversion of halohydrins to ketones are expected to be a useful preparative method of ketones from olefins.
In this paper, we wish to report the palladium catalyzed conversion of halohydrins to ketones. By this procedure, a useful preparative method of ketones from olefins is established. As described in our previous paper
3, reaction of 1-hepten-3-ol with BrCCl
3 or CCl
4 catalyzed by Pd(OAc)
2 combined with tri-o-tolylphosphine (P(o-Tol)
3) affords 1,1,1-trichloro-4-octanone (
8) in the presence of K
2CO
3 at 110°C.
When this reaction was carried out at 40°C otherwise under the same conditions, the halohydrins
1a and
16 were formed as the main product. This result suggests that
1a and
1b are intermediates to form
8. We found that treatment of
1a and
1b with a catalytic amount of Pd(OAc)
2 combined with P(o-Tol)
3 in the presence of K
2CO
3 at 110°C afforded
8 in 87 and 57% yields, respectively. In the absence of palladium, only a trace amount of the ketone was formed. In this reaction, choice of ligand and solvent is important. P(o-Tol)
3 as the ligand gave higher yields of
8 than PPh
3, tricyclohexylphosphine, and 1,2-bis(diphenylphosphino)ethane. Use of polar solvents such as t-butyl alcohol, acetonitrile, and THF decreased the yield of
8. In all cases, a small amount of 1-(2,2,2-trichloroethyl)-2-butyloxirane was detected. This epoxide formation is considered to take place with the aid of K
2CO
3.
As shown in the Table, other halohydrins were also converted to the corresponding ketones by using Pd(OAc)2/P(o-Tol)
3 catalyst in the presence of K
2CO
3 in benzene or toluene at 80-110°C. ln the reaction of bromohydrins,
2,
3, and
4, which possess secondary bromide, and
5, which possesses tertiary bromide, the corresponding ketones were obtained in reasonable yields. Only trace amounts of the corresponding epoxides were detected. On the other hand, halohydrins having primary halide such as
6 and
7 were converted to the corresponding ketones in lower than 50% yields. In these cases, considerable amounts of the corresponding epoxides were also formed.
In a typical example, in a flask fitted with a reflux condenser were placed Pd(OAc)
2 (2 mg, 9.01 mmol), P(o-Tol)
3 (6 mg, 0.02 mmol), and K
2CO
3 (138 mg, 1 mmol) and the atmosphere was replaced by argon. The bromohydrin
2 (215 mg, 1 mmol) dissolved in benzene was added, and the suspension was refluxed for 5 h under argon atmosphere. The potassium salts were filtered off, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica-gel, hexane-ether) to give propiophenone (
9) in 87% yield.
As noted above, preparation of halohydrins from olefins and subsequent conversion of the halohydrins to ketones provide a preparative method of ketones from olefins. As a typical example, we carried out the reaction of isosafrole (
15). Treatment of
15 with N-bromosuccinimide in aqueous DMSO afforded the bromohydrin
16 in quantitative yield as a sole product. No regioisomeric bromohydrin was detected. Then,
16 was treated with Pd(OAc)
2 (5 mol%)/P(o-Tol)
3 (10 mol%) catalyst in the presence of K
2CO
3 (100 mol%) in benzene at 80°C for 3 h to give the ethyl ketone
17 in 75% yield. It is worthwhile to point out that by other preparative methods of ketones from olefins, such as palladium mediated oxidation of olefinic bond
4, and epoxidation of olefins and subsequent Lewis acid catalyzed isomerization of the epoxides to ketones
5, isosafrole (
15) is converted to the methyl ketone
18 with high selectivity. These results imply that the preparative method of ketones from olefins via bromohydrins is useful, especially when the bromohydrins are formed from olefins with high regioselectivity.
References[1] H. O. House, J. Am. Chem. Soc., 77, 5083 (1955)
[2] D. R. Dalton, V. P. Dutta, and D C. Jones,
J. Am. Chem. Soc., 90, 5498 (1968)
(
https://www.thevespiary.org/rhodium/Rhodium/pdf/halohydrins.dmso.pdf)
[3] H. Nagashima, K. Sato, and J. Tsuji, Chem. Lett., 1605 (1981)
[4] J. Tsuji, I. Shimizu, and K. Yamamoto, Tetrahedron Lett., 2975 (1976)
[5] For example, D. R. Reif and H. O. House,
Org. Syn., Coll. Vol. 4, 375 (1963)
(
http://www.orgsyn.org/orgsyn/prep.asp?prep=CV4P0375)
Palladium-Catalysed Oxidation of Alcohols with Carbon Tetrachloride [...] and Conversion of Halohydrins to KetonesHideo Nagashima, Koji Sato and Jiro TsujiTetrahedron 41(23), 5645-5651 (1985)
(
https://www.thevespiary.org/rhodium/Rhodium/pdf/halohydrin2ketone.pd.1985.pdf)
Abstract Pd salts catalyse oxidation of alcohols with CCl
4 in the presence of K
2CO
3. Primary alcohols are oxidised to esters, and secondary alcohols to ketones. CCl
4 is converted to CHCl
3. The reaction of allylic alcohols bearing a terminal olefinic bond with CCl
4 or BrCCl
3 in the presence of palladium catalyst at 110°C affords 4,4,4-trichloro ketones. At 40°C, simple adducts of CCl
4 or BrCCl
3 having a halohydrin structure are obtained, which are converted to the corresponding trichloro ketones by the catalysis of palladium. Various halohydrins are converted to ketones by Pd catalysis.
Oxidation of isosafroleMethod A (via bromohydrin)In a pyrex tube fitted with a screw cap were placed Pd(OAc)
2 (11.2 mg, 0.05 mmol), P(o-Tol)
3 (30.4 mg, 0.1 mmol) and K
2CO
3 (138 mg, 1 mmol) under argon. The bromohydrin (259 mg, 1 mmol) dissolved in benzene (1 ml) was added, and then the mixture was heated at 100°C for 5 hr. After the work-up as above, purification of the residue by column chromatography (silica gel, hexane-ether) afforded the desired methylenedioxypropiophenone.
Method B (via epoxide)To a soln of isosafrole (1.62 g, 10 mmol) in CH
2Cl
2 (10 ml) was added mCPBA (3.24 g, 15 mmol) dissolved in CH
2Cl
2 (10 ml). The mixture was stirred at 0°C for 30 min. Usual work-up and chromatographic purification (silica gel, hexane-ether) afforded the epoxide (190 mg) in 11% yield. The epoxide (190 mg, 1.07 mmol) was treated with BF
3·Et
2O (1 ml) in ether at room temp for 20 min. The soln was quenched with NaHCO
3 aq, and the ethereal layer was washed with brine and dried over MgSO
4. After removal of the solvent, the residue was purified by column chromatography (silica gel, hexane-ether) to give methylenedioxyphenylacetone in 69% yield (132 mg).
Method C (Wacker oxidation)In a flask fitted with a balloon filled with O
2 were placed PdCl
2 (35.5 mg, 0.2 mmol) and CuCl (79.2 mg, 0.8 mmol) in aqueous DMF (DMF-H
2O 7:1, 2 ml). The suspension was stirred under O
2 at room temp for 2 hr. Then, isosafrole (324.4 mg, 2 mmol) dissolved in the aqueous DMF (2 ml) was introduced. and the mixture was heated at 50°C for 10 hr. Usual work-up and purification by column chromatography (silica gel. hexane-ether) afforded methylenedioxypropiophenone (236 mg, 66%) and methylenedioxyphenylacetone (65 mg, 18%).
Photochemical Conversion of Bromohydrins to KetonesOlivier PivaTetrahedron Letters 33(18), 2459-2460 (1992)
(
https://www.thevespiary.org/rhodium/Rhodium/chemistry/halohydrin2ketone.html)
AbstractThe direct conversion of halohydrins to ketones can be achieved by irradiation in benzene or toluene in the presence of small amounts of p-toluenesulfonic acid. A two step conversion of terminal alkenes to methylketones is thus achieved with good yields and inexpensive reagents.
____ ___ __ _
Reaction of Bromohydrins with Chlorotris(triphenylphosphine)Cobalt(I)Den-ichi Momose and Yasuii YamadaTetrahedron Letters, Vol.24, No.26, pp 2669-2672 (1983)
(
https://www.thevespiary.org/rhodium/Rhodium/pdf/halohydrin2ketone.co.1983.pdf)
Summary Bromohydrins were converted into ketones in high yields by the reaction with chlorotris(triphenylphosphine)cobalt(I) in the presence of amine or olefin. A probable pathway for the formation of ketones from bromohydrins was also described.
