Alkylation of a-Haloketones

The condensation of a-haloketones with monosubstituted alkyl or aryl-selenoureas (25) leads to 2-alkylamino- (26. 27) or 2-arylaminOselana-zoles (28) while disubstituted selenoureas give 2-(dialkylamino) selenazoles (26. 27) (Table X-3a). 

Dicarbonyl compounds can be converted into furans by methods other than the classical Feist- Benary method, the essential feature of which is alkylation by a haloketone or similar species. A curious variation is provided by the use of trichloronitroethene, Cl2C=CCIN02, which condenses with two moles of a 1,3-dicarbonyl compound by Michael addition followed by elimination of two chloride ions the third chloride is lost at the aroma-tization step so that, for example, methyl 3-oxobenzenepropanoate is converted into the nitrofuran 38."... 

Researchers at Sepracor later disclosed the use of a new class of chiral oxazaborolidines derived from r/. v-aminoindanol in the enantioselective borane reduction of a-haloketones.6,7 The 5-hydrogen oxazaborolidine ligand 10 was prepared in situ from d,v-aminoindanol 1 and BH3 THF.8 Stock solutions of 5-methyl oxazaborolidine 11-16 were obtained by reaction of the corresponding N-alkyl aminoindanol with trimethyl boroxine.6,7 5-Methyl catalyst 11 was found to be more selective (94% ee at 0°C) than the 5-hydrogen catalyst 10 (89% ee at 0°C), and enantioselectivities with 11 increased at lower temperatures (96% ee at -20°C). The catalyst structure was modified by introduction of A-a I kyI substituents. As a general trend, reactivities and selectivities decreased as the steric bulk or the chelating ability of the A -alkyl substituent increased (Scheme 17.4). 

Trimethylindolenine can also be N-alkylated by a-haloketones such as bromoacetone (58% yield). For a series of l -acetonylBIPS, the thermal fade rate constant was several times larger than for the corresponding l -methylBIPS. The absorption spectra exhibited bathochromic shifts in ethanol, but negligible shifts in... 

Phenylethynylcopper and phenacyl bromide afford intractable tars upon long reflux in DMF. However, at higher temperatures ( 240°C) a-haloketones can be converted in one step to furan derivatives [Eqs. (68a), (68b)] uncyclized acetylenic ketones are not isolated. The cycliza-tion is catalyzed by copper(I) through the copper-coordinated enol 128). Reaction of a,a -dibromoketones with an excess of a diorganocuprate is a new method for the a-alkylation of a ketone 231a). Only the monoalkyl derivative is isolated. The evidence points to the formation of a cyclopropanone intermediate which reacts with more of the cuprate to give an a-alkylated metal enolate. 

A major route to 2-amino-6/f-l,3,4-thiadiazines is by the condensation of a-haloketones with thiosemicarbazides (Section 6.17.7.2.2(ii)). Replacement of the thiosemicarbazide by a thiocarbamic acid or by a thiocarbazide results in formation of 3,6-dihydro-2//-l,3,4-thiadiazin-2-ones. Likewise, replacement with an A -arylthiohydrazide yields a 4//-l,3,4-thiadiazin-5(6/f)-one (Section 6.17.7.2.2(ii)). 3,6-Dihydro-27/-thiadiazin-2-ones are also available by the condensation of alkyl-hydrazines with a-(methoxycarbonylsulfenyl)alkylaryl ketones (Section 6.17.7.2.2(vi)), while the ring closure of (arylhydrazonoalkylthio)acetic acids with dicyclohexylcarbodiimide provides an alternative route to 4 -l,3,4-thiadiazin-5(677)-ones (Section 6.17.7.1.2). 2-Phenylimino-3-aryl-2,3-dihydro-l,3,5-thiadiazin-6-ones result from treatment of a-hydrazono-j8-ketoesters with aryl-isothiocyanates (Section 6.17.7.2.2(iv)). 

It is important to distinguish this synthesis from the alkylation of a 1,3-dicarbonyl enolate with an 2-haloketone, with displacement of halide, producing a 1,4-dicarbonyl unit for subsequent ring closure presumably the difference lies in the greater reactivity of the aldehyde group in the Feist-Benary sequence. 

Thus, treatment of the resin bound (cyanoacetyl)piperazine 160 with aliphatic or aromatic isothiocyanates in the presence of DBU, followed by S-alkylation with a-haloketones under slightly acidic or neutral conditions resulted in the formation of the intermediates 161 and 162 (which one being the predominant form was determined by the electronic properties of the substituents R -R ). The treatment of these intermediates 161/162 with DBU in DMF following acidolytic cleavage of the resin with TFA yielded 3-aminothiophene derivatives 163 as trifluoroacetates. This synthetic sequence towards 163 encountered however some limitations. For instance, complex mixtures of products were obtained in those cases, where strongly electron-donating isothiocyanates or a-haloketones were used, and in general, no thiophenes resulted from aliphatic haloketones, except for 3-bromo-l,l,l-trifluoro-2-propanone. 

Enamines readily undergo Sj 2 reactions with methyl and primary alkyl halides, a-haloketones, and a-haloesters. Enamines are superior to enolate anions for these reactions because they are less basic and consequently give higher ratios of substitution to elimination products. In addition, they also give more alkylation on carbon than do enolate anions. 

Alkylation of an Enamine Followed by Hydrolysis (Section 19.5A) Enamines are reactive nucleophiles with methyl and primary alkyl halides, a-haloketones, and a-haloesters. 

There are two good routes for the S5mthesis of unsymmetricaUy substituted 1,4-diketones. The classical route involves the alkylation of a p-keto-ester (1,3-keto-ester) with a 2-haloketone followed by hydrolysis and thence decarboxylation of the resulting p-keto-carboxylate (for some typical modem examples see... 

Scheme 10 Alkylation of a 1,3-keto-ester with a 2-haloketone then hydrolysis and decarboxylation to form a 1,4-diketone for thiophene ring synthesis [20]. N.B. The original method for enolate formation is shown - an alternative method would be used nowadays...

Nucleophilic reactivity of the sulfur atom has received most attention. When neutral or very acidic medium is used, the nucleophilic reactivity occurs through the exocyclic sulfur atom. Kinetic studies (110) measure this nucleophilicity- towards methyl iodide for various 3-methyl-A-4-thiazoline-2-thiones. Rate constants are 200 times greater for these compounds than for the isomeric 2-(methylthio)thiazole. Thus 3-(2-pyridyl)-A-4-thiazoline-2-thione reacts at sulfur with methyl iodide (111). Methyl substitution on the ring doubles the rate constant. This high reactivity at sulfur means that, even when an amino (112, 113) or imino group (114) occupies the 5-position of the ring, alkylation takes place on sulfiu. For the same reason, 2-acetonyi derivatives are sometimes observed as by-products in the heterocyclization reaction of dithiocarba-mates with a-haloketones (115, 116). 

The two major methods of preparation are the cycloaddition of nitrile oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamines. Additional methods include reaction of /3-haloketones and hydroxylamine, the reaction of ylides with nitrile oxides by activation of alkyl nitro compounds from isoxazoline AT-oxides (methoxides, etc.) and miscellaneous syntheses (62HC(i7)i). 

Alkylation of fert-butylacetoacetate with a-haloketones followed by treatment of the intermediate with TFA leads to substituted 2-hydroxy-3-acetylfurans 69 in high yields. A second alkylation of the intermediate followed by treatment with TFA affords trisubstituted furans 70 . 

The thiophene synthesis described herein is related to the synthesis in solution reported by Laliberte, and Medawar4 but differs in some aspects from the procedure in homogeneous phase. Laliberte and Medawar succeeded in obtaining aminothio-phenes in a one-pot reaction from acceptor-substituted acetonitriles, isothiocyanates, a-haloketones, and sodium ethoxide. In contrast to their procedure, solid-phase S-alkylation of the intermediate thioamides under basic conditions led to the formation of product mixtures. We obtained pure aminothio-phenes only when conducting the S-alkylation under neutral or slightly acidic conditions. 

The products from the N-alkylation of (anilinomethylene)malonodinitriles with a-haloacetic esters and a-haloketones spontaneously cyclize to produce pyrroles (Scheme 5.3) [21]. When the A -acylated product of the reaction of the dinitrile with ethyl chloroformate is treated with an arylamine, 5-cyanopyrimidones are obtained [21]. 

Alkylation of enamines requires relatively reactive alkylating agents for good results. Methyl iodide, allylic and benzylic halides, a-haloesters, a-haloethers, and a-haloketones are the most successful alkylating agents. Some typical examples of enamine alkylation reactions are shown in Scheme 1.10. 

A series of 3-alkyl- and 3-aryl-7/7-furo[3,2- ]-l-benzopyran-7-ones 78 (linear furocoumarins) was synthesized and evaluated for their photochemical and nonphotochemical crosslink formation with DNA as well as for their spectro-photometric and fluorescent properties, lipophilicity, and ability to photobleach A, A -dimethyl-/)-nitrosoaniline (RNO) after irradiation with UVA light <2002AP187>. The synthesis of the linear furocoumarins (Scheme 10) was a modification of a previously published method in which 7-hydroxy-2//-l-benzopyran-2-ones 76 were converted into / -ketoethers 77 by alkylation with haloketones under phase-transfer catalysis conditions. Base-catalyzed intramolecular condensation and subsequent acidification gave the corresponding 78. A molecular complex between each one of these fluorescent furocoumarins and DNA was observed, but only compounds with a 3-Me or 3-Ph group showed UVA irradiation-induced crosslink formation. 

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