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Clandestine Approach to the Synthesis of Phenyl-2-Propanone from Phenylpropenes
                       by Terry A. Dal Cason et. al.
           Journal of Forensic Sciences 29(4), 1187-1208 (1984).
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        ABSTRACT: A number of published syntheses for the manufacture of
        controlled substances appear to be impractical for the average
        clandestine laboratory. A closer inspection of these syntheses may
        reveal modifications which greatly simplify their application. An
        excellent example of this is the preparation of phenyl-2-propanone
        (P-2-P) from allylbenzene. In the prototype published method,
        oxygen is introduced into the reaction vessel by using a tank of
        compressed oxygen with a balloon for a gas reservoir. In our
        modification, oxidation is accomplished with a 30% hydrogen
        peroxide solution. P-2-P has been prepared by both methods and a
        comparison made of the reaction mixtures at various times during
        their synthesis. Additionally, propenylbenzene, a by-product of
        these reactions, can be converted to P-2-P by modification of a
        second synthesis.


Background

The investigation of clandestine drug manufacturing laboratories represents a
combined effort between the criminal investigator and the forensic chemist.
At an early point in an investigation the special agent will frequently request
a list of the chemicals and synthesis methods used to produce a controlled
substance. Providing these lists is often a very simple assignment for the
forensic chemist. A general understanding of various chemicals reactions and
techniques is a part of the forensic chemist's training, academic background,
and experience. Additionally, numerous specific and detailed drug syntheses
are also available to him from the open literature. The chemist may, none
the less, encounter problems when reviewing published procedures. If the
literature procedures do not explicitly illustrate the synthesis of the desired
compound, the chemist may erroneously assume that it is not applicable to the
clandestine laboratory. This conclusion may, in part, be due to the complicated
nature of the procedure or to the apparent requirement for specialized
equipment. It may also arise from the failure of the chemist to visualize
an application of the literature to the synthesis of the clandestine drug.
In this context, the synthesis methods are themselves clandestine; they are
"hidden" within the literature. A determined study of literature procedures,
however, often reveals that while these do not detail the synthesis of the
drug in question, they can be modified to give useful or simple methods for
its manufacture. Sometimes this requires only the substitution of appropriate
chemicals or certain changes in reaction parameters or catalysts.

Examples of this conceptual approach can be shown by the synthesis of the
nonpsychoactive controlled substance phenyl-2-propanone (P-2-P). Halting
the clandestine manufacture of P-2-P is of particular interest to enforcement
personnel since it serves as the primary precursor in a number of syntheses
for amphetamine and methamphetamine. By substitution of the chemicals and
through slight changes in procedure, two published syntheses have been modified
for P-2-P manufacture. These simple changes are illustrated below and are
of the type to be expected of a clandestine drug chemist. By procuring chemicals
and using procedures not generally recognized for the production of the
controlled substance, the clandestine chemist may improve his chances to
escape detection. Each of the two procedures investigated give fair to
excellent yields of P-2-P, and, by using the procedures consecutively, yields
are greatly increased.


Allylbenzene Procedure

The following procedure, which Tsuji et al (1) used for the preparation of
1-decanone, required only the substitution of allylbenzene (1-phenyl-2-propene)
for 1-decene. A three-neck round bottomed flask was fitted with a magnetic
stirrer and a pressure-equalized dropping funnel containing allylbenzene.

The flask was charged with a mixture of palladium chloride, cuprous chloride,
and aqueous N,N-dimethylformamide (DMF). With all outlets securely stoppered
and wired down, and an oxygen-filled balloon was placed over one neck and the
flask contents stirred at room temperature to allow oxygen uptake. After a
period of oxygenation, allylbenzene was added dropwise. The solution was
continuously stirred under the pressurized balloon. During this period of
addition, the color of the solution turned from green to black and gradually
returned to green as the reaction approached completion. The mixture was
poured into cold hydrochloric acid and extracted with methylene chloride
(CH2Cl2). The extract was washed with saturated sodium bicarbonate and dried
over anhydrous sodium sulfate. Through filtration and distillation, P-2-P and
trans-beta-methylstyrene (1-phenyl-1-propene) were recovered. The reaction
is shown in Fig. 1. Yields approximate those listed in the "modified"
procedure given below.

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                O2, CuCl2
  Allylbenzene ============> Phenyl-2-Propanone + trans-beta-Methylstyrene
                PdCl2, DMF

  Fig 1: Synthetic procedure for Phenyl-2-propanone - allylbenzene method
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Modified Allylbenzene Procedure

The procedure employed was a simple modification of the preceding reaction.
The equipment modification eliminates the oxygen filled balloon, which
requires an outside source of oxygen, such as a compressed oxygen tank, and
replaces it with a 30% hydrogen peroxide solution. The aqueous DMF solution
is thus prepared by using 30% hydrogen peroxide in place of water. The
quantity of palladium chloride catalyst was also decreased. This reaction
is shown in Fig. 2. The synthesized P-2-P (49% yield) was separated from
the reaction mixture by shaking with saturated aqueous sodium bisulfite
solution and cooling the resultant mixture. Vacuum filtration of the mixture
yielded crystalline P-2-P bisulfite addition product. The two-phase filtrate
was then separated and the organic layer containing the trans-beta-methylstyrene
(45% yield) was recovered by extraction with CH2Cl2. The recovered trans-beta-
methylstyrene still contained several grams of P-2-P and trace amounts of
allylbenzene and cis-beta-methylstyrene.

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              CuCl2, PdCl2
Allylbenzene ==============> Phenyl-2-Propanone + trans-beta-Methylstyrene
                H2O2, DMF

    Fig 2: Synthetic procedure for P-2-P - Modified allylbenzene method
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trans-Beta-Methylstyrene Procedure

By using a modification of Fujisawa and Deguchi's (2) synthesis of
3,4-methylenedioxybenzyl methyl ketone, the trans-beta-methylstyrene
by-product of the previous reaction was also converted to P-2-P. This
conversion was accomplished by dropping an acetone/trans-beta-methylstytene
solution into a stirred solution of hydrogen peroxide in formic acid [2,3].
The acidic solution was refluxed and, then, neutralized and extracted with
CH2Cl2. After Evaporating most of the CH2Cl2, the extracted mixture of
glycol and glycol esters was stirred stirred and heated in a solution of
methanol and dilute sulfuric acid. The resulting solution was neutralized
with aqueous base and extracted with CH2Cl2 to yield phenyl-2-propanone.
(93%). The sequence shown in Fig. 3 was adapted from Fujisawa and Deguchi.

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                             Acetone
trans-beta-Methylstyrene  =============> 1-Phenyl-1,2-propandiol (and esters)
                           H2O2, HCOOH

                                            CH3OH
      1-Phenyl-1,2-propandiol (and esters) =======> Phenyl-2-Propanone
                                            H2SO4

   Fig 3: Synthetic procedure for P-2-P - trans-beta-methylstyrene method    
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Conclusion

Although phenyl-2-propanone is not a sympathomimetic substance in and of
itself, it is frequently synthesized in clandestine laboratories to produce
the essential chemical for the manufacture of amphetamine or methamphetamine.
By modification and coupling of available literature procedures, a sequence
is presented for the manufacture of P-2-P. This sequence uses chemicals not
normally associated with the clandestine synthesis of P-2-P. Evaluation of
these syntheses underscores the diligence required of the forensic chemist
to provide enforcement personnel with accurate information. The investigated
reactions and procedures are easily performed and, when used consecutively,
result in an approximate total yield for P-2-P of 79%.

References:
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[1] Tsuji, J., Organic Synthesis 60, 2165 (1981)
[2] Fujisawa, T., J Pharm Soc Japan, 74(9), 975 (1954)
[3] Fujisawa, T., Chemical Abstracts  52, 11965 (1958)

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                                A Discussion of
Clandestine Approach to the Synthesis of Phenyl-2-Propanone from Phenylpropenes
                               by James B. Ellern
                  Journal of Forensic Sciences xx(x), x (198x)
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Sir:

In the title technical note [1], Dal Cason et al show that amphetamine and
methamphetamine could conceivably be ready made from phenyl-propenes via P-2-P.
It is worth noting (1) that the route described from beta-methylstyrene is known
to be the prevalent clandestine method for synthesis of 3,4-methylenedioxy-
amphetamine (MDA) via 3,4-methylenedioxy-phenyl-2-propanone [2], and (2) that a
quite simple method for converting alllybenzene to amphetamine without going
through P-2-P was published over 35 years ago [3].

With respect to Point 1, the reactions described by Frank (2) for making MDA
from isosafrole (commercially available from Eastman) are those of Dal Cason's
second reference. A further inference one can make from the title paper's
modified allylbenzene procedure is that MDA can likely be made from safrole,
3,4-methylenedioxyallylbenzene. This compound costs about one eighth as much as
allylbenzene (latest Aldrich catalog). It need not even be obtained as such, as
it is the main constituent of sassafras oil.

The methylenedioxy P-2-P obtainable from safrole or isosafrole is also the usual
intermediate for making the recently highly publicized 3,4-methylenedioxymeth-
amphetamine (MDMA, "Ecstasy"). As MDMA became a Schedule I substance on 1 July
1985, increasing clandestine manufacture is likely.

With respect to Point 2, an early example of the Ritter reaction was conversion
of allylbenzene to amphetamine by alkylation of acetonitrile in sulfuric acid [3]:

From the procedure's description, modification to a one-pot prep of amphetamine
sulfate or the freebase seems feasible. Later, French workers obtained
amphetamine by the same reaction using benzonitrile as the nitrogen source [4].
Further, MDA should be obtainable from safrole by the same reaction.

The attractiveness of the Ritter reaction for clandestine amphetamine synthesis
lies in its simplicity and the fact that one never produces a controlled
substance as an intermediate. While the reaction cannot directly produce
methamphetamine, MDMA or any other secondary amine, a way to make N-methyl-
amphetamines from amphetamines is given in the same Journal issue as the title
paper [5].

James B. Ellern, Ph. D.


References:
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[1] Dal Cason, T.A., Angelos, S.A., and Raney, J.K., "A Clandestine Approach
    to the Synthesis of Phenyl-2-Propanone from Phenylpropenes," Journal of
    Forensic Sciences, Vol. 29, No. 4, Oct. 1984, pp. 1187-1208.

[2] Frank, R.S., "The Clandestine Drug Laboratory Situation in the United
    States," Journal of Forensic Sciences, Vol. 28, No. 1, Jan. 1983, pp. 18-31.

[3] Ritter, J.J. and Kalish, J., Journal of the American Chemical Society,
    Vol. 70, Dec. 1948, pp. 4048-4050

[4] Christol, H., Laurent, A., and Mousseron, M., Chemical Abstracts, Vol. 56,
    1962, col. no. 14132.

[5] Clark, C.C., "The Identification of Methoxy-N-Methylamphetamines," Journal
    of Forensic Sciences, Vol. 29, No. 4, Oct. 1984, pp. 1065-1071.

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