Halo ketones cyclization

If cyano-haloalkanes are used instead of the halo-ketones, cyclization reactions take place under Barbier conditions to produce ketones [Eq. (22) 57]. However, the solvent and the halogen seem to have a greater effect on the product distribution. 

Protoadamantanone has been prepared by the nitrous acid deamination of 2-amino-l-adamantanol (77%), by aprotic diazo-tization of endo-7-aminomethylbicyclo[3.3.1]nonan-3-one in benzene with an equivalent amount of acetic acid (67%), and by thermolysis of 1-adamantyl hypohalites followed by base-promoted cyclization of the resulting halo ketones (32-37%)." In spite of low and erratic yields, the last reaction sequence has provided the most convenient route to the protoadamantanes, since the other two approaches require lengthy syntheses of the starting materials. 

Treatment of 2-mercaptoimidazoles 33 with a-halo ketones gives 2-(acyl-alkylthio)-imidazoles 34, which can be cyclized to substituted imidazo[2,l-fejthiazoles 35 [86HC(46)77]. A one-step synthesis from 33 with a-halo ketones is also successful. 

Russian authors investigated this important reaction type to prepare a wide range of aryl-, alkyl-, and acyl-substituted imidazo[2,l-ft]thiazoles (70KGS508, 70KGS512 71KGS389). Several 2-mercaptoimidazoles react with a-halo ketones in one step directly to the bicyclic products 35 under reflux in butanol or ethanol followed by basification. Yields vary between 52 and 99%, but the two-step cyclization route requires isolation of the intermediates 34 and subsequent heating in phosphorus oxychloride. 

Mercaptotriazoles 133, available from thiosemicarbazones, are versatile starting materials for the preparation of thiazolo[3,2-h][l,2,4]triazoles. Treatment with a-halo ketones (and esters) yields S-alkylated derivatives that are cyclized to 134 either directly or on treatment with acidic catalysts (e.g., P2O5/H3PO4). 

A variety of other reaction conditions have been examined for acylation of alkenes by acyl chlorides. With the use of Lewis acid catalysts, reaction typically occurs to give both enones and jS-halo ketones.7 The latter reaction has been most synthetically useful in intramolecular cyclizations. The following reactions are illustrative. 

A new approach to the formation of the 2-aryl thietane derivatives 124 includes Friedel-Crafts acylation to give a )9-halo ketone. Following conversion of the ketone to the chloride, cyclization is effected with thiourea ... 

The cyclodehydration method used for the synthesis of benzo[a jquinolizinium ion and its congeners (Scheme 97) requires that phenylpyridines (176) (including benzo analogs) be converted into quaternary salts (177) by the action of a -halo ketones or a -halo aldehyde derivatives. The acid-catalyzed cyclization of these salts (177) has provided access to a number of compounds containing the benzo[a]quinolizinium system (178) (Table 8). 

The thiazole-2-thione (51) with an a-halo ketone gives the intermediate (52) which is cyclized by strong acid into the thiazolo[2,3-/ thiazolium salt (53) (77HC(30-i)l). A wide variety of [5,5]-fused systems are prepared in this way. 

Several significant pyrrole syntheses involve the formal tricomponent cyclization of type III ace (equation 126). The Hantzsch pyrrole synthesis involves a dicarbonyl compound, an a -halo ketone and ammonia or an amine. The mechanistic pattern is similar to that involved in the Knorr synthesis (Section 3.06.3.4.1). In addition to a-halo ketones and a-haloal-dehydes, compounds such as 1,2-dichloroethyl acetate, 1,2-dibromoethyl acetate and 1,2-dichloroethyl ethyl ether can serve as a -haloaldehyde equivalents (equation 127) (70CJC1689, 70JCS(C)285>. It is believed that the initial step in these reactions is the formation of a stabilized enamine from the amine and the /3 -dicarbonyl compound. A structural ambiguity... 

Syn- and anti -selective halo-Prins cyclizations of 8,s-unsaturated ketones to give 1,3-halohydrins have been catalysed by Lewis acids, with syn selectivity correlating (g) with acid strength.184... 

Aminothiadiazoles also react with halo aldehydes and halo ketones in a bidentate fashion to give imidazo[2,1-b ][1,3,4]thiadiazoles (145). The NMR properties, aromatic character, basicity and crystal structure data are available (80JCS(P2)42l). Aminothiadiazoles also react with trichloromethanesulfenyl chloride to give the sulfenamide (146) which in the presence of an aromatic amine cyclizes to 3//- [1,3,4]thiadiazolo[2,3-c ][1,2,4]thiadiazole (147) (75JOC2600). 

Halo ketones react with thioacids to form 1,3-dithiolylium salts 225 which are also obtained from -dimercaptoethy-lenes 224 (Scheme 110) . A new approach to the synthesis of 1,3-dithiolylium salts 228 involves an acid-catalyzed cyclization of the corresponding dithiocarbamates 227, obtained from -bromo ketones 226 in a high yield (Scheme 111) <2001SC1271, 2003SUL155, CHEC-III(4.12.9.1)1015>. 

The condensation of active methylene compounds such as malononitrile, ethyl cyanoacetate, etc., with phenyl isocyanate followed by alkylation and cyclization gives 3-aminothiophenes 304 (Scheme 51) <2003T1557>. Dihydrothienopyrimidine-4(/7T)ones 306 are prepared by the reaction of 305 with a-halo ketones <2006HAC104>. 

Muratake et al. reported the intramolecular a-arylation of ketones [55,56]. Thus, polycyclic compounds are readily obtained from aromatic keto-bromides and keto-triflates (Eq. 16). Bromo-amides can give the corresponding cycliza-tion products (Eq. 17) [52]. Related intramolecular vinylation reactions to give aliphatic polycyclic compounds have also been reported (Eq. 18) [57,581. The intramolecular cyclization of aromatic halo-ketones under carbon monoxide, which proceeds by mechanism C, gives the corresponding a-acylated products (Eq.l9) [321. 

In contrast to the above intramolecular reactions, Yamamoto and coworkers have demonstrated that aromatic halo-ketones having an alkyl substituent at their a-position are transformed to cyclized products at the carbonyl carbon (Eq. 21) [60]. This suggests that a new mechanism, nucleophilic addition of the arylpalladium moiety in the key intermediate to the carbonyl group (Scheme 2), can occur. Addition of an alcohol such as 1-hexanol is essential for the reaction. A possible role of it might be to facilitate the reduction of Pd(II) to Pd(0). 

The total synthesis of the tricyclic sesquiterpene (+)-P-copaene was accomplished by E. Wenkert and co-workers. The required bicyclic starting material was prepared in three steps from carvacrol. In the first step, carvacrol was subjected to typical Reimer-Tiemann conditions. The abnormal Reimer-Tiemann product, 6-dichloromethyl-3-isopropyl-6-methyl-cyclohexa-2,4-dienone, was obtained, and upon treatment with sodium carbonate in DMSO, cyclization occurred to afford a bicyclic halo ketone. The double bonds were then hydrogenated in the presence of Pd(C) catalyst. 

Syntheses of tndoliztnes carrying substituents in the pyridine ring are not numerous but substituted a-picolines quatemized (review [1870]) with an a-halo ketone (review [B S]) are convenient substrates for cyclization to indolizines or related compounds the reaction is mediated by ammonia on its own at 5°C or with hydrogencarbonate, TEA or methanolic sodium hydroxide. 2-Alkylpyri-dines may be A -alkylated and cyclized in a one-pot reaction (see Chapter 104, Section I.l). 

Cyclization of the ot-bromoacetylphenol (88.2) (reviews of a-halo ketones [B-4S, 2348]) in DMF containing sodium hydrogencarbonate at 40-45X gives a low yield of the benzofuran-3-one. The bromo ether (88J) is dealkylated and cyclized with hydrobromic acid in high yield. 

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