  Subject: MDP2P directly from safrole
     Date: 8 Apr 1998 16:24:51 GMT
     From: Rhodium <rhodium@anon.nymserver.com>
Newsgroup: alt.drugs.chemistry

Found an interesting MDP2P synthesis the other day in this patent.
It is slightly edited for clarity, and unnecessary stuff cut out.

Have Fun in the lab!

Rhodium


    US Pat 4,731,482
    PROCESS FOR THE PREPARATION OF PHENYLPROPANONES
    Inventors: Carlo Vanturello et al.

    OTHER PUBLICATIONS
    Venturello et al, J Org Chem, 48, 3831-3833 (1983).
    Venturello et al, Chem Abst, 104, 27804z (1986).
    Rickborn et al J Am Chem Soc, 90, 4193-4194 (1968).

    ABSTRACT

    Process for the preparation of phenylpropanones having formula:

    1-(3-R1-4-R2)phenyl-2-propanones
     
    R1 and R2, equal or different, being C1-C4 alkyl groups or being
    coincident in the CH2 group of a heterocyclic ring, wherein the
    corresponding allylbenzenes are catalytically epoxidized by means of H2O2,
    in a biphase system comprising an aqueous phase containing H2O2 and an
    organic phase containing said allylbenzenes, a solvent immiscible with said
    aqueous phase and a catalyst having formula Q3XW4O24 (Q being a quaternary
    cation containing hydrocarbylic groups having on the whole from 20 to 70 C
    atoms, and X being P or As) and wherein the thus obtained epoxide are iso-
    merized by heating at 90-150øC, in the presence of catalytic amounts of LiI.
    
    BACKGROUND OF THE INVENTION

    Phenylpropanones are known to be prepared by oxidation (using peracids,
    such as performic or peracetic acid) of Phenylpropenes, to give an
    intermediate glycol (via epoxide), which is successively converted into a
    ketone by heating in the presence of mineral acids. Such a process,
    however, gives rise to many drawbacks; said process, in fact:
    
    * require the use of an internal olefin that is not commercially
      available and that has to be prepared by isomerization of the
      corresponding terminal olefin;

    * require the preparation of performic acid just at the moment of its
      use, owing to its limited stability with time (a very thorough care is
      needed for safety purposes; alternatively, the use of expensive organic
      solutions of peracetic acid is needed;

    * presents some problems connected with the recovery or with the
      disposal of considerable amounts of organic acids resulting from the
      reduction of said peracids.

    The Applicant has now found that it is possible to prepare said
    phenylpropanones by a simpler and cheaper catalytic process, free from
    danger and from the other drawbacks of the known art, which process allows,
    particularly, to avoid the use of dangerous and/or expensive oxidizing
    agents, such as performic or peracetic acids.

    DISCLOSURE OF THE INVENTION

    In its widest form the invention concerns a process comprising the
    catalytic epoxidation, by means of H2O2, of allylbenzenes (without any
    preliminary isomerization to phenylpropenes) and subsequent catalytic
    isomerization of the obtained epoxides to the corresponding phenyl-
    propanones. More in detail our process is characterized in that:

    (a) an allylbenzene is epoxidized by reaction with H2O2 under stirring,
        at 40-90øC, in system comprising an aqueous phase (containing H2O2)
        and an organic phase consisting of at least one solvent immiscible
        with the aqueous phase, of the allylbenzene, and of a catalyst having
        general formula Q3XW4O24, wherein Q is a quaternary cation (R2R3R4R5M)+,
        M being selected from the group comprising N and P and R2, R3, R4 and
        R5 (equal or different) being selected from the group comprising
        hydrogen and the hydrocarbylic groups (wherein said cation has from 1
        to 4 hydrocarbylic groups containing, on the whole, from 20 to 70
        carbon atoms and wherein X is P or As) by using H2O2:allylbenzene
        molar ratios between 1:1 and 1:2;

    (b) the organic phase coming from (a) (after removal of solvent and
        catalyst) or the epoxide isolated from said organic phase, are
        isomerized by heating, under stirring, in the presence of catalytic
        amounts of lithium iodide, at temperatures from 90-150øC.
    
    Phenylpropanones, in particular piperonylmethylketone and veratryl-
    methylketone, are obtained at a high purity level and with yields of
    50-75% with respect to the reacted allylbenzene.

    The epoxydation catalyst consists of a peroxidic complex containing
    tungsten, phosphorus (or arsenic) and a sufficiently lipophilic quaternary
    cation, obtained, according to known processes. According to a preferred
    embodiment, X is phosphorus and in the quaternary cation M is nitrogen and
    R2, R3, R4 and R5 are hydrocarbylic groups containing on the whole from 25
    to 40 C atoms, such as in the case of methyltrioctylammonium,
    dimethyldioctadecylammonium, dimethyldihexadecylammonium and mixtures
    thereof. Most preferred are the catalysts having the following formulas:
    (C25H54N)3PW4O24 and (C37H78N)3PW4O24.

    Such catalysts can be prepared, for Instance, by reacting tungstic acid
    (or an alkali metal tungstate), phosphoric acid (or an alkali metal
    phosphate) and hydrogen peroxide (in an aqueous acid phase) with a
    quaternary salt, selected from the group comprising methyltrioctylammonium
    chloride (commercially traded as ALIQUAT 336) and dimethyl[dioctadecyl(75%)
    + dihexadecyl (25%)] ammonium chloride (commercially traded as ARQUAD 2HT),
    containing in an organic phase immiscible in the aqueous one. The reaction
    between the inorganic reactants may be carried out at 20-80øC, then the
    quaternary salt, dissolved in a solvent (for instance, 1,2-dichloroethane),
    is added, preferably at room temperature, and the stirring of the biphasic
    mixture is carried on for 15-30 minutes. The aqueous acid phase has
    preferably a pH below 2 and this pH can be adjusted by means of a mineral
    acid (for instance H2SO4 or HCl). The molar ratios among the reactants
    should generally be as follows: 4 moles of W and up to 2 moles of
    quaternary salt per mole of P and from 2.5 to 6 moles of H2O2 per mole of
    W. After evaporation of the organic phase, the catalyst is obtained in an
    oily or solid form.

    Epoxydation reaction (a) is then carried out according to the double
    phase technique, the organic phase contains an allylbenzene, the catalyst
    and a solvent immiscible with the aqueous phase. Chlorinated hydrocarbons
    (for instance trichloromethane, tetrachloroethylene, dichloroethanes,
    trichloroethanes and so on) or aromatic hydrocarbons (for instance benzene,
    toluene or xylenes) can be used as immiscible solvents. Our advise is to
    work under vigorous stirring at 40-90øC, preferably between 60 and 75øC, at
    atmospheric pressure, the reaction time (depending on the used catalyst and
    its amounts, on the temperature, on the nature and on the concentration of
    the allylbenzene) generally ranges between 2 and 3 hours; the catalyst:H2O2
    molar ratio should range between 1:150 and 1:230.

    Finally a H2O2:allylbenzene molar ratio between 1:1 and 1:2 (preferably
    between 1:1.5 and 1:1.6) should be generally used. The amount of
    allylbenzene in the organic phase should generally range from 30 to 80%
    and preferably from 40 to 60% by weight. Use can be made of a concentration
    of H2O2, in the aqueous phase, between 1 and 70% and preferably between 10
    and 30% by weight; a 98-99% H2O2 conversion is thus obtained.

    The isomerization step (b) can be carried out on the organic phase as
    such, coming out from the epoxidation reaction (a), after solvent and
    catalyst have been removed. Alternatively, the epoxide can be isolated
    from said organic phase and then isomerized. Our advise is to work, under
    stirring, at 90-150øC., preferably at 130øC, and at atmospheric pressure.
    The reaction time, depending on the used catalyst, on its amount and on
    the temperature, generally ranging from 1 to 3 hours.

    The amount of lithium iodide catalyst ranges from 0.3 to 3%, preferably
    from 0.5 to 2% by weight, with respect to the organic phase to be
    isomerized. In the case of the isomerization of the isolated epoxide, a
    LiI:epoxide molar ratio frown 0.5:50 to 5:50, preferably from 1:50 to 3:50
    is used. When the reaction is over, the phenylpropanone can be isolated
    from the reaction medium by distillation, by column cromatography or by
    other usual techniques.  The hydrogen peroxide and phosphoric acid
    concentrations are expressed, in the examples, as grams per 100ml of
    solution.

    EXAMPLE 1 (MD-P2P)

    (a) Preparation of catalyst, mainly of (C25H54N)3PW4O24. The preparation
        was exactely identical to the one described by example 3 of European
        Patent Application No. 86/109120.

    (b) Piperonylmethylketone preparation.

        7 ml of H20, 6.83 ml of H2O2 at 40% (80 mmoles), 0.8 g (0.35
        mmoles) of catalyst dissolved in 20 ml of 1,2-dichloroethane, 20-30
        mg of p-tert-butylphenol and 19.9 g of 98% safrole (120 mmoles)
        were loaded into a three necked flask having a 100 ml capacity and
        equipped with mechanical stirrer, thermometer and reflux cooler.
        The biphasic mixture was brought, under vigorous stirring, up to
        60øC and kept at this temperature for 2 hours. A conversion of H2O2
        higher than 98% was obtained (determined by iodometric titration of
        the aqueous phase). The organic phase (lower one) was separated,
        diluted with ethyl ether (30-40 ml), then kept under stirring for 5
        minutes in contact with an aqueous solution (10 ml) containing 1g
        of Na2SO3 and 1g of Na2CO3 and then quickly eluted with ethyl ether
        on a small silica gel column. 400 mg of LiI were added to the light
        yellow oil obtained after the solvent evaporation and the resulting
        mixture was kept under stirring at 130øC (bath temperature) for 1
        hour; after cooling, the mixture were fractionated on a silica gel
        column (eluent: 50/50 mixture of ethyl ether and n-hexane). 8.50g
        (47.75 mmol) of piperonylmethylketone (MDP2P) was thus obtained and
        8.70g (53.7 mmol) of unreacted safrole was recovered; selectivity
        to the ketone, with respect to the converted safrole, was 72%

[End of transmission]


