Halo acid chlorides

An interesting C-S bond formation mediated by benzyltriethylammonium tetrathiomolybdate converts -halo acid chlorides into thiolactones [64] (Scheme 4.16). 

In contrast to thiomiinchnones, thioisomiinchnones (5) (l,3-thiazolium-4-olates) have received considerable attention over the past three decades, and a rich array of 1,3-dipolar cycloaddition chemistry is described in Section 10.2.5. These heterocycles were initially constructed by Potts (1,53,57) from thioamides and a-halo acid chlorides, an example of which is shown in Scheme 10.17 (58). 

The same reagent (/ )-(+) -pantolactone 112 gives good results with a-halo acids that are good precursors for many other compounds such as a-amino acids by nucleophilic displacement. The a-halo acid chlorides 115 are prepared directly from the simple acids 114 and treated with the same tertiary amine EtNMe2 used above to give the unstable ketenes 116 and hence the esters 117 by reaction with (R)-(+) -pantolactone22112. 

Pivaloylindole gives high yields of 6-substituted ketones on reaction with a-halo-acid-chlorides and aluminium chloride simple acid chlorides react only at 0-3. The sequence below shows how a 1-pivaloyl-3-(indol-3-yl)propanoic acid undergoes Friedel-Crafts cyclisation to C-4, away from the deactivated heterocyclic ring. °... 

Dihydro-l//-l,4-benzodiazepin-2-ones 21 are obtained from o-aminobenzophenones by a cyclocondensation with amino esters under base catalysis or by A -acylation with halo acid chlorides followed by cyclization with ammonia ... 

In contrast with the photochemical cycloaddition reaction of two alkenes, the [2+2] cycloaddition of a ketene and an alkene occurs under thermal conditions. The ketene is formed typically from an acid chloride and a mild base such as EtsN, or from an a-halo-acid chloride and zinc. Cycloaddition with an alkene occurs stereospecifically, such that the geometry of the alkene is maintained in the cyclobutanone product. The regioselectivity is governed by the polarization of the alkene, with the more electron-rich end of the alkene forming a bond to the electron-deficient central carbon atom of the ketene. Thus, the product from cycloaddition of dimethylketene with the enol ether Z-171 is the cyclobutanone m-172, whereas with -171, the isomer trans-lll is formed (3.116). ... 

Iminium salts, generated in situ from the amides and lactams, react with 1 to produce the corresponding thioamides and thio-lactams, respectively, in good yields (eq T)P- The advantages of this methodology are the easy work-up and chemoselectively amides are thionated in the presence of ketones, aldehydes, and esters (eq 8). ra-Halo acid chlorides react with 1 and the corresponding thiolactones are obtained in moderate yields under mild reaction conditions (eq 9). This reaction works well for the synthesis of small and medium ring thiolactones, but is not useful for the synthesis of macrocyclic thiolactones. ... 

Acid chlorides and bromides, allyl halides, a-halo-ketones, esters, amides and nitriles react at 25° within 3 minutes. Vinyl and aryl halides are inert. 

Cyanohydrins react with hydrogen haUdes or PCl to give a-halo nitriles which can be further hydrolyzed to the a-halo carboxyUc acids. The a-hydroxy group of cyanohydrins can be esterified with an acid or acid chloride. Dehydration of cyanohydrins with phosphoms pentoxide gives >80% yields of alkylacrylonitriles (8). 

Oxidation of benzene to phenol. This was attempted in the former U.S.S.R. and Japan on a pilot-plant scale. High yields were reported, but full-scale operation apparently was discontinued because of destruction of product by irradiation and the possibility of explosion in the reaction vessel. The latter danger can be controlled in the oxidation of halo-genated hydrocarbons such as trichloro- or tetrachloroethylenes, where a chain reaction leads to the formation of dichloro- or trichloro-acetic acid chlorides through the respective oxides. 

The acid chlorides have served as useful synthetic intermediates leading to ketones via the malonic acid synthesis and Friedel rafts reaction, thiadiazole acetic acid derivatives, and halo ketones via the Arndt Eistert synthesis and carbinols by hydride reduction <68AHC(9)107>. The dialkylcadmium conversion of acid chlorides into ketones fails in the 1,2,5-thiadiazole series. The major product is either a tertiary carbinol or the corresponding dehydration product, by virtue of the high reactivity of the intermediate ketone. 

Aminoethanethiol reacts with ot, 3-unsaturated or (3-halo ketones to give (355). Similarly, reaction with a, (3-unsaturated acids, esters or acid chlorides, and with 3-halopropionyl halides, yields 5-oxo derivatives such as (356). Thioglycollic acid (HSCH2C02H) with 3-bromopropylamine gives (357). 

The ring may be cleaved hydrogenolytically. Halo acids afford 4-halobutanols or 1,4-dihalobutanes, depending on the reaction conditions. Acid chlorides in the presence of zinc chloride afford esters of 4-chlorobutanol, and LAH and aluminum chloride give butanol. Reaction with carbon monoxide and nickel tetracarbonyl affords adipic acid. 

Scheme 2 shows a similar mechanistic pathway for a Heck reaction taking place on a Pd octahedral comer. This mechanism is based on that established for soluble Pd catalysts (ref. 5). Adsorption of the aryl halide (or aryl acid chloride after decarbonylation) gives the aryl Pd halide, 15, by way of the adsorbed intermediate, 14. Vinyl ether adsorption, as in 16, takes place as described in Scheme 1. Aryl insertion gives the halometalalkyl, 17, which on f) elimination to the available 4dxy orbital gives the aryl enol ether, 2 (or 1 depending on which hydrogen is eliminated in 17). The resulting halo palladium hydride, 18, then reacts with the tertiary amine to give the amine hydrochloride and regenerates the octahedral comer for further reaction.

---