Halo ketones alkylation

Alkyl Halides, Polyhalides, a-Halo Ketones and Esters... 

Analyzing the target molecule in this way reveals that the required alkyl halide IS an a halo ketone Thus a suitable starting material would be bromomethyl phenyl ketone... 

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... 

Various alkylating agents are used for the preparation of pyridazinyl alkyl sulfides. Methyl and ethyl iodides, dimethyl and diethyl sulfate, a-halo acids and esters, /3-halo acids and their derivatives, a-halo ketones, benzyl halides and substituted benzyl halides and other alkyl and heteroarylmethyl halides are most commonly used for this purpose. Another method is the addition of pyridazinethiones and pyridazinethiols to unsaturated compounds, such as 2,3(4//)-dihydropyran or 2,3(4//)-dihydrothiopyran, and to compounds with activated double bonds, such as acrylonitrile, acrylates and quinones. 

In general the Stork reaction gives moderate yields with simple alkyl halides better yields of alkylated product are obtained with more electrophilic reactants such like allylic, benzylic or propargylic halides or an a-halo ether, a-halo ester or a-halo ketone. An example is the reaction of 1-pyrrolidino-l-cyclohexene 6 with allyl bromide, followed by aqueous acidic workup, to yield 2-allylcyclohexanone ... 

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... 

Alkenylboranes (R2C=CHBZ2 Z — various groups) couple in high yields with vinylic, alkynyl, aryl, benzylic, and allylic halides in the presence of tetra-kis(triphenylphosphine)palladium, Pd(PPh3)4, and a base to give R C CHR. 9-Alkyl-9-BBN compounds (p. 1013) also couple with vinylic and aryl halides " as well as with a-halo ketones, nitriles, and esters.Aryl halides couple with ArB(IR2 ) species with a palladium catalyst. ... 

Among other methods for the preparation of alkylated ketones are (1) the Stork enamine reaction (12-18), (2) the acetoacetic ester synthesis (10-104), (3) alkylation of p-keto sulfones or sulfoxides (10-104), (4) acylation of CH3SOCH2 followed by reductive cleavage (10-119), (5) treatment of a-halo ketones with lithium dialkyl-copper reagents (10-94), and (6) treatment of a-halo ketones with trialkylboranes (10-109). 

Trialkylboranes react rapidly and in high yields with a-halo ketones,a-halo esters, a-halo nitriles, and a-halo sulfonyl derivatives (sulfones, sulfonic esters, sulfonamides) in the presence of a base to give, respectively, alkylated ketones, esters, nitriles, and sulfonyl derivatives. Potassium tert-butoxide is often a suitable base, but potassium 2,6-di-tert-butylphenoxide at 0°C in THF gives better results in most cases, possibly because the large bulk of the two tert-buXy groups prevents the base from coordinating with the R3B. The trialkylboranes are prepared by treatment of 3 mol of an alkene with 1 mol of BH3 (15-16). With appropriate boranes, the R group transferred to a-halo ketones, nitriles, and esters can be vinylic, or (for a-halo ketones and esters) aryl. " °... 

Reaction of halo ketones or diazo ketones with boranes 10-112 Carbonylation of alkyl halides... 

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. 

A number of these alkylation reactions are illustrated in Scheme 9.2. Entries 1 and 2 are typical examples of a-halo ester reactions. Entry 3 is a modification in which the highly hindered base potassium 2,6-di-f-butylphenoxide is used. Similar reaction conditions can be used with a-halo ketones (Entries 4 and 5) and nitriles (Entry 6). Entries 7 to 9 illustrate the use of diazo esters and diazo ketones. Entry 10 shows an application of the reaction to the synthesis of an amide. 

In these reactions, the cydization mode is also determined by the substitution patterns of the aryl ring. If one or both ortho-positions are occupied by a methoxy group, the reaction affords spiro-endo mode cydization products 411 (Scheme 10.159) [185]. The formation of a 408-type intermediate was supported by the fact that 2-halo-l-alkyl ketones 412 were formed in some cases [184, 185]. 

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). 

Alkylation of oxazolones with a-halo ketones under phase-transfer catalysis generated an enolate 155 from initial alkylation at C-4 that immediately translac-tonized to produce an enol lactone 156 (Scheme 7.46)." Selected examples of 5(47/)-oxazolones prepared via alkylation are shown in Table 7.17 (Fig. 7.19). 

Reaction of halo ketones or diazo ketones with boranes 0-102 Carbonylation of alkyl halides 0-104 Reaction between acyl halides and organometallic compounds 0-105 Reaction between other acid derivatives and organometallic compounds... 

A recent procedure which utilizes the pivaloyl derivative of o-bromoaniline as one of the fragments is also a type llac approach. The compound is converted to its dilithio derivative at -78 °C. Reaction with a-halo ketones then affords indole hydrates by N-alkylation and reaction of the o-lithiated position with the carbonyl group dehydration subsequently yields indoles (equation 108) (81TL1475). The (V-trifluoroacetyl and N-t-butoxycarbonyl derivatives of o-bromoaniline exhibit similar reactivity. 

Direct alkylation of indoles under neutral conditions has been observed for especially reactive alkyl halides. 3-Methylbutenyl bromide gives the 3-substituted indole in acetic acid-sodium acetate at room temperature (equation 170) (69TL2485). At higher temperature in acidic solution, 1,2-dimethylindole undergoes bisallylation (equation 171) (67CJC2628). a-Halo ketones including bromoacetone, 3-bromo-2-butanone and 2-chlorocyclohexanone can alkylate 2-substituted indoles in aqueous acetic acid, but the acidic conditions used in these reactions would probably be destructive of indole itself (72JOC2010). 

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]. 

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