Phenethylamines, synthesis

Synthesis of Alkviamines. General Procedures. Method (A). The synthesis of p-phenethylamine is representative. A flame dried, nitrogen-flushed, 100 ml flask, equipped with a septum inlet, magnetic stirring bar and reflux condenser ivas cooled to 0°C. Sodium borohydride (9.5 mmol, 0.36 g) was placed in the flask followed by sequential addition of THF (13-15 ml) and BF3-Et20 (12 mmol, 1.5 ml) at 0°C. After the addition, the ice bath was removed and the contents were stirred at room temperature for 15 min. The solution... 

BISCHLER NAPIERALSKI Isoquinoline synthesis Isoqutnoline synthesis Irom amides of phenethylamines... 

Isequinoline synthesis Irom aromatic aldehydes and an aminoacetal (Pomeranz-Frttsch) or from phenethylamines and glyonal acetal (Schlitter-Muller). 

Model studies directed toward the synthesis of Ecteinascidin 743 employed an elegant Pictet-Spengler cyclization of phenethylamine 54 and the 1,2-dicarbonyl compound 55 to assemble the spiro tetrahydroisoquinoline 56 in a stereospecific fashion. " The silica-catalyzed condensation reaction provided 56 in excellent yield. 

Evaluation of the above route against our initial target objectives for the synthesis of taranabant indicated a high level of success, not just for the primary objectives of removing the tin chemistry and chiral chromatography, but for a number of other process improvements (Table 9.2). Of particular note was that the three crystalline intermediates were key for purification, first the phenethylamine salt 12 for the classical resolution, secondly the HC1 salt of amine 2 allowed for upgrade of diastereomeric purity, and finally the API allowed for upgrade of enantiomeric purity via initial removal of racemic material. 

The scheme used to prepare the direct 8-aza-analogue 21 of estrone bears at least formal similarity to the Torgov-Smith steroid total synthesis sequence. Acylation of the phenethylamine 9 with acryloyl chloride gives amide 16. Michael addition of dimethylamine followed by Bischler-Napieralski cyclodehydration gives the dihydroisoquinoline, 17. 

The intramolecular photoelimination of HC1 from JV-chloroacetyl derivatives of suitable amines is a useful and versatile approach to the synthesis of azaheterocycles. The iV-chloroacetyl derivative 357 has been converted in this way to 7-oxodesethylcatharanthine (358) in 55% yield.300 Investigations in this area have been particularly concerned with the A-chloroacetyl derivatives of benzylamines and phenethylamines the N-chloroacetyl-benzylamine 359 on irradiation affords the two 3-oxo-l,2,3,4-tetrahydroiso-quinolines 360 and 361.301 Competing photocyclizations have been observed in the case of l-[3-(chloroacetylamino)propyl]-3-methylindole (362) which is converted into three photoproducts, 363, 364, and 365.302... 

Amino acid synthesis (cf. 12,15). The reaction of 1 with chiral a-imino esters provides an enantio- and diastereoselective synthesis of amino acid derivatives. The imine (2), prepared from (S)-phenethylamine, reacts with 1 to give 3, which... 

Sasha had recently published his critically acclaimed PIHKAL, a Chemical Love Story ( Phenethylamines I Have Known and Loved. ). A lengthy book, the first part deals with his personal history and love affair with Ann. The second part is a technical compendium of the various psychedelic compounds he had developed. It includes structures, methods of synthesis and subjective effects as recorded by a group of special friends, who visited periodically to evaluate personally the latest of his psychoactive molecules. 

An analogous strategy, using a chiral phenethylamine derivative, was followed by Leg-seir et al. 133) in a synthesis of tubotaiwin. 

In addition to his extensive freelance work on psychedelic compounds, Shulgin has also served as a member of the faculty at San Francisco State University and the University of California at Berkeley. He is perhaps best known to the general public as the author, with his wife Ann, of two books on psychedelic drugs, PiHKAL Phenethylamines I Have Known and Loved A Chemical Love Story), and TiHKAL [Tryptamines I Have Known and Loved The Chemistry Continues). The two books provide not only a fascinating autobiographical sketch of the authors lives and works but a detailed introduction to the chemical synthesis, characterization, and properties of the chemicals belonging to major psychedelicfamilies, the phenylethylamines and the tryptamines. 

Amphetamine (1) is a very simple phenethylamine, described in the chemical literature as early as 1887 (Edeleano, 1887). Smith, Kline and French (now GSK) filed a patent on the synthesis and use of amphetamine in 1930 (Nabenhauer, 1930), and the enantiomers were assigned in 1932 (Leithe, 1932 V-Braun and Friehmelt, 1933). Not surprisingly, early access to chiral material relied on classical crystallization-based resolutions (Gillingham, 1962 Nabenhaur, 1942). The early, racemic syntheses of amphetamine fall into four major classifications according to the method used to make the C-N bond ... 

Among the most commonly applied chiral moiety for nitrones (2) is the N-a-methylbenzyl substituent (Scheme 12.6) (18-25). The nitrones 8 with this substituent are available from 1 -phenethylamine, and the substituent has the advantage that it can be removed from the resulting isoxazolidine products 9 by hydrogeno-lysis. This type of 1,3-dipole has been applied in numerous 1,3-dipolar cycloadditions with alkenes such as styrenes (21,23), allyl alcohol (24), vinyl acetate (20), crotonates (22,25), and in a recent report with ketene acetals (26) for the synthesis of natural products. Reviewing these reactions shows that the a-methylbenzyl group... 

A recent development in the synthesis of 3//-3-benzazepin-2-ones has been the photocyc-lization of A-(chloroacetyl)phenethylamines (Scheme 25). Ring closure is by homolysis of the alkyl halide followed by intramolecular coupling of the alkyl radical with an aromatic radical cation. Yields are good, especially with a stabilizing electron-donating group (MeO, NMe2) at the position meta to the ethylamino function (i.e. ortho or para to the site of cyclization). Isomeric benzazepinones are normally obtained (Scheme 25) with meta-substituted phenethylamines (80H(14)ll). 

Scheme 34 shows the synthesis of the bc portion (336), which possessed three of the nine asymmetric centers present in cobyric acid. Retrosynthesis determined that (336) could be obtained, via sulfide contraction, from the two intermediates (337) and (338). Ring c was synthesized from (+)-camphor quinone (not shown). Ring b (337) was obtained from 8-methyl-j8-acetylacrylic acid (339), the two adjacent chiral centers being generated in the required relative orientation by a Diels-Alder cycloaddition with butadiene in the presence of tin(IV) chloride. Fractional crystallization served to resolve the diastereomeric a-phenethylamine salts derived from them, eventually affording the compound (340). Oxidation with chromic acid cleaved the double bond in (340) and one of the newly generated... 

Although there are many interesting psychedelic drugs with sulfur atoms in them (the TOM s, the TOET s, the ALEPH s and all of the 2C-T s), there just aren t many that contain two sulfur atoms. BIS-TOM bombed out, and 2C-BIS-TOM remains untried, but will probably also fail, as the phenethylamines are rarely more potent than the corresponding amphetamines. This leaves 2C-T-14 as the remaining hope, and its synthesis is still underway. 

As with the phenethylamine counterpart, G-4 has a structure that lies intermediate between G-3 and G-5, both potent compounds. It is axiomatic that it too will be a potent thing, and all that now needs be done is to complete its synthesis and taste it. 

The preparation of silyl derivatives with a Si—C bond between the silicon atom and the drug is not so easy to realize as compared with Si—O and Si—N systems. In most cases the Si-C bond must be constructed at the beginning of synthesis. This is shown for the triethylsilyl derivative (4) of phenethylamine (3) in Scheme 1 ... 

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