Halo ketones, amination

Among compounds other than simple alkyl halides a halo ketones and a halo esters have been employed as substrates m the Gabriel synthesis Alkyl p toluenesul fonate esters have also been used Because phthalimide can undergo only a single alkyl ation the formation of secondary and tertiary amines does not occur and the Gabriel synthesis is a valuable procedure for the laboratory preparation of primary amines... 

Mattox and Kendall have suggested that loss of bromide from the initially formed hydrazone of the a-halo ketone is facilitated by participation of the electron pair on the amine nitrogen atom. The same group has shown that semicarbazones are often superior to 2,4-dinitro-phenylhydra-zones since they can be obtained in higher yields and undergo cleavage more... 

Primary amines can be prepared from alkyl halides by the use of hexamethylenetetramine followed by cleavage of the resulting salt with ethanolic HCl. The method, called the Delepine reaction, is most successful for active halides such as allylic and benzylic halides and a-halo ketones, and for primary... 

Cf. Gabriel synthesis, where the product is also amine and Sommelet reaction, where the product is aldehyde. The Delepine works well for active halides such as benzyl, allyl halides, and a-halo-ketones. 

Aqueous solutions of vanadous chloride (vanadium dichloride) are prepared by reduction of vanadium pentoxide with amalgamated zinc in hydrochloric acid [213], Reductions are carried out in solution in tetrahydrofuran at room temperature or under reflux. Vanadiiun dichloride reduces a-halo ketones to ketones [214], a-diketones to acyloins [215], quinones to hydroquinones [215], sulfoxides to sulfides [216] and azides to amines [217] (Procedure 40, p. 215). 

The 2(3//)-oxazolones may be synthesized by the direct condensation of three components. Thus, a mixmre of a-halo ketones 123, carbon dioxide, and primary amines can be heated at 80-100 °C under gas pressure of 50 kg/cm to result in the direct formation of 3-substituted 2-oxazolones 124 in 4-25% yield (Fig. 5.30). " ... 

The reaction of a-halo ketones (chloro, bromo, or iodo) with alkoxide ions143 to give rearranged esters is called the Favorskii rearrangement.144 The use of hydroxide ions or amines... 

Addition of alcohols or other car-bocation sources to nitriles (Ritter) 6-65 Addition of water to isocyanides 8-7 Rearrangement of ot-halo ketones in the presence of amines (Favorskii) 8-8 Rearrangement of diazo ketones in the presence of amines (Arndt-Eis-tert)... 

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... 

Various approaches have been used to prepare pyrroles on insoluble supports (Figure 15.1). These include the condensation of a-halo ketones or nitroalkenes with enamines (Hantzsch pyrrole synthesis) and the decarboxylative condensation of N-acyl a-amino acids with alkynes (Table 15.3). The enamines required for the Hanztsch pyrrole synthesis are obtained by treating support-bound acetoacetamides with primary aliphatic amines. Unfortunately, 3-keto amides other than acetoacetamides are not readily accessible this imposes some limitations on the range of substituents that may be incorporated into the products. Pyrroles have also been prepared by the treatment of polystyrene-bound vinylsulfones with isonitriles such as Tosmic [28] and by the reaction of resin-bound sulfonic esters of a-hydroxy ketones with enamines [29]. 

Support-bound alkylating agents have been used to N-alkylate pyridines and dihydropyridines (Entries 7 and 8, Table 15.21). Similarly, resin-bound pyridines can be N-alkylated by treatment with a-halo ketones (DMF, 45 °C, 1 h [267]) or other alkylating agents [246]. Polystyrene-bound l-[(alkoxycarbonyl)methyl]pyridinium salts can be prepared by N-alkylating pyridine with immobilized haloacetates (Entry 8, Table 15.21). These pyridinium salts react with acceptor-substituted alkenes to yield cyclopropanes (Section 5.1.3.6). Pyridinium salts have also been prepared by reaction of resin-bound primary amines with /V-(2,4-dinitrophenyl)pyridinium salts [268,269]. 

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). 

Next, a nucleophilic substitution reaction at saturated carbon. a-Halo ketones are excellent electrophiles and react rapidly with nucleophiles, such as this secondary amine, by the S 2 mechanism (Chapter 17). All that remains is to reduce the ketone and the acid to alcohols and remove the benzyl protecting group (both discussed in Chapter 24). 

The interaction of alkyl halides, preferably iodides or bromides, with hexamine in chloroform or alcohol solution forms quaternary ammonium salts which on heating with hydrochloric acid are readily converted to primary amines. The procedure has been employed successfully in the reaction of primary, but not secondary or tertiary, aliphatic halides, certain benzyl halides, halo ketones, halo acids, and halo esters. The yields range from 40% to 85%. 

Aliphatic and aryl aliphatic amino ketones are made by the amination of the halogenated carbonyl compounds, - e.g., dimethylaminoacetone (74%), l-diethylamino-2-pentanone (79%), and a-methylaminopropio-phenone (57%). It is noteworthy that this system may undergo a rearrangement, viz., ArCOCH,Br+ (C,H,),NH— ArCHjCON(C,H5)a (45%). The reaction of a-halo ketones with arylamines is even more complex. Examples of the formation of a-aminoaldehydes by this method are few. However, the same results may be achieved by the amination of the halo acetals with subsequent hydrolysis. "... 

Palladium complexes also catalyze the carbonylation of halides. " Aryl (see 13-15), vinylic, benzylic, and allylic halides (especially iodides) can be converted to carboxylic esters with CO, an alcohol or alkoxide, and a palladium complex.Similar reactivity was reported with vinyl triflates. a-Halo ketones are converted to (3-keto esters with CO, an alcohol, NBU3 and a palladium catalyst at 110°C. Use of an amine instead of the alcohol or alkoxide leads to an amide. 

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