Phenacyl acetates

Lobinine, CjgHggOgN. First isolated by Wieland, Ishimasa and Koschara who, on the evidence then available, regarded it as 2-phenacyl-l-methyl-7-)3-hydroxypropylhexamethyleneimine, CjgHjjOjN (XXI), which was modified to (XX) in 1989. It furnishes an oxime (B. HCl, m.p. 182°) and a benzoyl derivative (B. HCl, m.p. 146-7°). On reduction by sodium in acetic acid it is converted into the unsaturated dihydric alcohol for which th original name lobinol has been changed to /3-lobinanidine,... 

To the best of our knowledge, the hrst paper which mentioned an A-(l-haloalkyl)pyridinium compound appeared 66 years ago in the Chemische Berichte (Krohnke 33CB1386). Tlie author described the reaction of phenacyl pyridinium derivatives 1 with bromine in acetic acid to give the halides 2 (36CB2006 37CB864). Tire addition of bromine to the double bonds of A-vinylpyridinium salts 3 and 4 giving the adducts 5 and 6 has also been reported (51CB399) (Scheme 1). 

A carboxylic acid (not the salt) can be the nucleophile if F is present. Mesylates are readily displaced, for example, by benzoic acid/CsF. Dihalides have been converted to diesters by this method. A COOH group can be conveniently protected by reaction of its ion with a phenacyl bromide (ArCOCH2Br). The resulting ester is easily cleaved when desired with zinc and acetic acid. Dialkyl carbonates can be prepared without phosgene (see 10-21) by phase-transfer catalyzed treatment of primary alkyl halides with dry KHCO3 and K2C03- ... 

Alternatively, 232 was obtained by cyclocondensation of 233 with phenacyl halides in the presence of acetic acid and subsequent reaction of the formed triazinophthalazine with alkoxides or sec-amines (89FES29). 

Alkylation of 694 with phenacyl bromides, followed by cyclization with acetic anhydride gave (87H2183) thiazolo[2,3-c]pyrido[2,l-/][ 1,2,4]-triazine 695. 

It appears that treatment of phenacyl bromides 1239 with methylhydrazine in refluxing acetic acid leads also to 1,4-disubstituted triazoles 1244. Fivefold excess of methylhydrazine is used in these reactions. According to the proposed mechanism, structures 1240-1243, methylhydrazine has a double role, as a condensing agent and an oxidant. In the final account, three molecules of methylhydrazine have to be used to produce one molecule of triazole 1244, two molecules of methylamine and one molecule of ammonia. The basic triazole 1244 (X = Y = H) is separated in 59% yield. The reactions go well with electron-donating substituents (for X = OH, the yield is 81%), but electron-withdrawing substituents can lower the yield dramatically (11% for X = N02) (Scheme 206) <2003JCM96>. 

Phenacyl chloride, c31 Phenazone, a299 1,2,4-Phenenyl triacetate, tl 93 Phenethyl acetate, pill Phenethyl alcohol, pi 10 sec-Phenethyl alcohol, ml49 Phenethylamine, pi 12 Phenethyl bromide, b334 Phenethyl chloride, cl28 Phenetole, e36... 

Synthetic approaches to representatives of this ring system have been discussed in CHEC-II(1996) <1996CHEC-II(8)496>. Research activity in this area has been considerably extended during the past years. Thus, the basic starting material is a 6,6-disubstituted tetrahydro[l,2,4,5]tetrazin-3-thione 52, which has been converted in three different ways reaction with phenacyl bromides led to 3,3-disubstituted 3,4-dihydro-6-phenyl-2//-thiazolo[3,2-4]-[l,2,4,5]tetrazines 53, reaction of 52 with 1,2-dibromoethane gave 3,4,6,7-tetrahydro-2//-thiazolo[3,2-7][l,2,4,5]tetra-zines 54, whereas transformation of 52 with chloroacetic acid in the presence of sodium acetate yields substituted 3,4-di hydro-1-2//-thiazolo[3,2- 1 [ 1,2,4,5]tctrazin-6(7//)-oncs 55 <2001IJB584> (Scheme 17). Details are shown in Table 2. 

Most of the now synthetically used quantitative cascade reactions involve an initial substitution step. That is quite clear for the reactions of acyl hahdes with thioureas to give 2-aminothiazoliiun salts. The 3-cascade consists of substitution to form the thiuronium salt, specific cychzation with the more nucleophihc of the amino groups, and elimination of water. In all reported cases, the water of reaction is taken up by the product crystal and it can be removed by heating to about 80 °C in a vacuiun. For example, if the thioureas 162 and phenacyl bromide 217 are stoichiometrically ball-milled at room temperature for 30 min, quantitative yields of the pure products 428 are obtained in all cases after drying at 0.01 bar at 80 °C [ 10] (Scheme 67). The free bases 429 can be obtained by trituration of 428 with NaHCOj solution. Furthermore, the thioureido-acet-amides 275 react correspondingly with 217 to give quantitative yields of the salts 430 from which the free bases can be obtained by NaHCOj trituration [96]. 

The first fully aromatic 2-azaquinolizinium salts were prepared by Krohnke et al. (64CB3566), who examined three approaches to the l-hydroxy-3-phenyI-2-azaquinoIizinium ion (262 Scheme 130). The first involved the reaction of picolinamide (261) with phenacyl bromide which produced (262) in unspecified yield. Most effective was refluxing 2-cyanopyridine (263) in moist acetonitrile with phenacyl bromide. Finally, it was shown that 2-ethoxycarbonyl-l-phenacylpyridinium ion (265) could serve as a starting material if ammonium acetate were present in the solvent. 

A novel approach to the synthesis of a 1,5-naphthyridine starts from quinuclidin-3-one (143), which is first converted to the 2-arylidene derivative and then reacted with phenacyl-pyridinium bromides and ammonium acetate to give l,4-ethano-3,4-dihydro-2//-l,5-naph-thyridines (144) (82S27). 

A primary or a secondary amine can be protected by reaction with phenacyl-sulfonyl chloride (PhC0CH2S02Cl) to give a sulfonamide RNHS02CH2C0Ph or R2NS02CH2C0Ph.1741 The protecting group can be removed when desired with zinc and acetic acid. Sulfonyl chlorides react with azide ion to give sulfonyl azides RSO-.N3.1742 OS IV, 34, 943 V, 39, 179, 1055 VI, 78, 652 VII, 501 69, 158. See also OS VI, 788. 

On standing at 25°C, the spiro-3//-pyrazole 57 is converted via an isolable 3-azopyrazole to a pyrazolotriazine.96 Pyridazines have been prepared both from a 4-vinyl-3//-pyrazole by heating in acetic acid92 and from a 3-phenacyl-3//-pyrazole in strong base.114... 

Hydrazino-l,3-dimethyluracil (185) reacts with phenacyl bromides in DMF to give the corresponding 3-aryl-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7-diones (186). 6-Benzyl-idenehydrazino-l,3-dimethyluracils are also known to react with DMF dimethyl acetal to give pyrimido[4,5-c]pyridazines (78JHC781). 

In the following sections we have attempted to classify the methods available for the synthesis of benzo[6]thiophenes. (Arylthio)acetalde-hyde dialky] acetals, (arylthio)acetones, aryl phenacyl sulfides, and S-arylthioglycolic acids are the most common starting materials. A number of the syntheses, which we have included in Section IV, A, may become general methods in the future, e.g., cyclohexanone and a number of substituted cyclohexanones have been used recently as starting materials. 

Wibberley formulated as 23 the intermediate they isolated from the treatment of the phenacyl quaternary salt with benzoyl chloride on the grounds that both 20 and 21 were formed when it was treated with acetic anhydride. However, Krock and Krohnke prepared the same intermediate by treating the quaternary salt of 2-picoline and dibenzoyl-methyl bromide with potassium carbonate thus establishing its structure as 22, and this was confirmed by infrared and NMR spectroscopy. 

A mixture of phenacyl chloride 1 (0.46 g, 3 mmol), aldehyde 2 (0.64 g, 6 mmol), ammonium acetate (1.55 g, 20 mmol) and glacial acetic acid (10 ml) in w-PrOH (20 ml) in the presence of molecular sieves (4 A) was irradiated for 5-10 min in a self-tunable CEM microwave synthesizer at 90 °C (Scheme A.7). After the reaction had been cooled to room temperature, the solvent was removed under vacuum and the residue was crystallized from ethanol to give 2,4,6-triphenyl-3,5-diazabicyclo[3.1.0]hex-2-ene 3 as colorless crystals. Melting point 155-156°C. 

To obtain more information on the nature of the quasiphosphonium intermediates involved in these systems we have studied the reactions gf sterically hindered neopentyl esters by means of 1P nmr spectroscopy. Trineopentyl phosphite and a-bromoacetophenone gave rise to a peak at +41 ppm due to the ketophosphonium intermediate 3 (R = Me.CCH, R = Ph X = Br ) within half an hour of mixingJthe reactants in acetone-dfi at 27 °C ( p nmr shifts are relative to 85% H-PO. down-field positive). Peaks due to the ketophospnonate 4 +19 ppm and the vinyl phosphate 7 (-7 ppm) were also observed (compound 4 and 7 have satisfactory elemental analysis and spectroscopic data ). The concentration of the intermediate reached a maximum after about two hours when it was precipitated from acetone solution by the addition of anhydrous ether to give white crystals of trineopentyloxy (phenacyl)phosphonium bromide, identified by elemental analysis and nmr spectroscopy ( XP 6+41, in CDCl ). When redissolved in acetone-dg, deuterochloroform, acetic acid, or acetic acid-acetone mixtures, the intermediate decomposed to yield keto-phosphonate 4 but none of the vinyl phosphate 6 (Perkow product). Nor was the course of reaction affected by the addition of chloride ion or of a-chloro-acetophenone in acetonitrile. 

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