Halo ketones formation

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... 

The possible ambiguities that may arise in ring syntheses based upon nueleophilic reaetions with a-halo ketones are also exemplified by the reactions with a-lithioaldimines leading to pyrrole formation, as shown in Scheme 73a 73TL3517). A simitar problem could well arise in the related carbazole synthesis indicated in Scheme 73b if a less symmetrical substrate was employed 81TL1475). 

The optical rotatory dispersion curves of steroidal ketones permit a distinction to be made between the conformations, and assignment of configuration is possible without resorting to chemical methods (see, e.g. ref. 36) which are often tedious. The axial halo ketone rule and, in the more general form, the octant rule summarize this principle and have revealed examples inconsistent with the theory of invariable axial attack in ketone bromination. 2-Methyl-3-ketones have been subjected to a particularly detailed analysis. There are a considerable number of examples where the products isolated from kinetically controlled brominations have the equatorial orientation. These results have been interpreted in terms of direct equatorial attack rather than initial formation of the axial boat form. 

In the absence of steric factors e.g. 5 ), the attack is antiparallel (A) (to the adjacent axial bond) and gives the axially substituted chair form (12). In the presence of steric hindrance to attack in the preferred fashion, approach is parallel (P), from the opposite side, and the true kinetic product is the axially substituted boat form (13). This normally undergoes an immediate conformational flip to the equatorial chair form (14) which is isolated as the kinetic product. The effect of such factors is exemplified in the behavior of 3-ketones. Thus, kinetically controlled bromination of 5a-cholestan-3-one (enol acetate) yields the 2a-epimer, (15), which is also the stable form. The presence of a 5a-substituent counteracts the steric effect of the 10-methyl group and results in the formation of the unstable 2l5-(axial)halo ketone... 

The formation of derivatives of this type by free-radical attack has been mentioned previously (see section E above). The most common route to vinylogous halo ketones is by halogenation of dienol acetates or ethers. Both free halogen and A -halo compounds may be employed, and this approach has frequently been used to obtain 6 (axial) halo compounds ... 

Until recently, pyridine-type bases have been commonly used to produce conjugated enones from 2-halo ketones yields are usually poor °° and these reactions are frequently accompanied by rearrangement, reduction and salt formation. Thus, Warnhoff found that dehydrobromination of (28) with 2,4-lutidine gave a mixture of (29), (30) and (31) in the ratio 55 25 20. Collidine gave a ratio of 38 25 37, whereas pyridine gave mainly the salt (32). 

Formation of oxiranes on the sterically more hindered side of the steroid ring system is usually carried out via /raw -halohydrins which afford oxiranes on treatment with base (c -Halohydrins yield ketones on exposure to base). Two general methods are available for the synthesis of tm s-halohydrins (1) the reduction of a-halo ketones and (2) the addition of a hypohalous acid to unsaturated steroids. 

Alkylation of enamines requires relatively reactive alkylating agents for good results. Methyl iodide, allyl and benzyl halides, a-halo esters, a-halo ethers, and a-halo ketones are the most successful alkylating agents. The use of enamines for selective alkylation has largely been supplanted by the methods for kinetic enolate formation described in Section 1.2. 

The reaction of a-halo ketone oximes 204 with isocyanides leads to formation of 5-aminoisoxazole derivatives 205. The reaction involves formation of nitrosoalkenes as intermediates (equation 89) ". ... 

In addition to solvolysis and nitrenium ion formation, Af-aLkoxy-A-chloroamides (2) also undergo bimolecular reactions with nucleophiles at nitrogen. Not only is the configuration destabilized by the anomeric effect, it also parallels that of a-halo ketones, where halogen on an sp carbon is activated towards reactions by the adjacent carbonyl. This rate-enhancing effect on 8 /2 processes at carbon is well-known, and has been attributed to conjugation of the p-orbital on carbon with the carbonyl jr-bond in the S 2 transition state stabilization of ionic character at the central carbon as outlined by Pross as weU as electrostatic attraction to the carbonyl carbon. The transition states are also affected by the nature of the nucleophile. ... 

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 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). " ... 

Fig. 13.2. Illustration of the basic concept of Basis Products, (a) The PGVL reaction scheme of VRXN-2-00051 (formation of the H-imidazo[1,2-a]pyridine ring system using aminoheterocycles and alpha-halo ketones) is used for the illustration (b) The Basis Products of A are formed by all A reactants with one constant reactant (B CAP, 1 -bromopropan-2-one). The Basis products of are formed by all reactants with a constant A reactant (A CAP, 2-amino pyridine). The blue triangle and yellow hexagon represent two such basis products. The red star represents a product molecule which is related to those two corresponding basis products.

For a-halo ketones, bisphosphonium salt formation can also take place by vinylation or arylation of the phosphine (reaction 90). Bisphosphonium salts can also be obtained, in moderate yield, by the introduction of two phosphines on the same aromatic or heterocyclic ring, at high temperature358 (reaction 91). For pyridine, activation by triflic anhydride allows successive additions of two phosphonio groups in the 2,4-positions247 (reaction 92). 

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... 

Two possible mechanisms can be envisaged for this reduction, both involving the formation and protonation of Sm(III) enolates. Molander proposed that a-halo ketones react with Sml2 to give a ketyl radical 32 that is then quenched by the cosolvent.29 A second reduction then gives carbanion 33 that undergoes (3-elimination to produce the enol tautomer of the product ketone (Scheme 4.20). 

Electrooxidation of halide salts is quite useful for the generation of reactive species of halogen atoms under mild conditions. Functionalization of alkenes involving the formation of halohydrins, 1,2-halides, a-halo ketones, epoxides, allylic halides and others has been achieved by electrochemical reactions and is well documented in the literature. On the other hand, electrogenerated carbenium ions can be captured by nucleophilic halide anions, providing a new route to halogenated compounds... 

The formation of cyano ketones by this method is illustrated by the conversion of phenacyl halides to the corresponding nitriles. Ring closure to cyclopropane derivatives is a side reaction which has been encountered with y-halo ketones. Benzalacetophenone dibromide is converted by alcoholic potassium cyanide to the fi-cyaao ketone, the a-halogen atom being reduced. Several a-chloro ketones have been found to yield a-cyano epoxides. ... 

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. "... 

In 1913, Kishner observed in one instance that under standard Wolff-Kishner reduction conditions, 2-hydroxy-2,6-dimethyloctan-3-one underwent eliminative reduction upon treatment with hydrazine hydrate and base at elevated temperatures to afford 2,6-dimethyloctan-2-ene (Scheme 7). This same reaction was later found to occur in the case of a-methoxy ketones and has since been referred to as the Kishner eliminative reduction. The reaction entails initial formation of the hydrazone and elimination of the a-substituent to afford the intermediate alkenyldiazene, which subsequently collapses to the desired alkene. Given the facile transformation of ketones into a-halo ketones, these conditions have been used to introduce alkenes regioselectively in the 2a-halocholestan-3-one series as shown in Scheme 8. Yields of 2-cholestene parallel the resistance of the a-halogen to undergo competitive elimination reactions. 

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