Halo carbonyl compounds

Synthesis Since a-halo-carbonyl compounds are very reactive electrophiles, we can use a short cut ... 

The behaviour of /S-oxovinylazides is quite similar to those above. The Z isomer (556), formed from the /S-halo carbonyl compound and sodium azide, is unstable losing N2 and forming the isoxazole (557) in an anchimerically assisted concerted reaction (75AG(E)775, 78H(9)1207). At moderate temperatures (50-80 °C) the E isomer formed acylazirines which at higher temperatures rearranged to oxazoles and isoxazoles. 

The condensation of 3-amino-1,2,4-benzotriazine 1-oxides 29 with a-halo-carbonyl compounds results in imidazo[2,l-c]-l,2,4-benzotiiazine 1-oxides 30 (82JHC61, 86MI). 

Mannich bases (see 16-15) and p-halo carbonyl compounds can also be used as substrates these are converted to the C=C—Z compounds in situ by the base (16-15, 17-12). Substrates of this kind are especially useful in cases where the C=C—Z compound is unstable. The reaction of C=C—Z compounds with enamines (12-18) can also be considered a Michael reaction. Michael reactions are reversible. 

Reaction of imines with a-halo carbonyl compounds... 

Halo Acids, Esters, Aldehydes, Ketones see Halo Carbonyl Compounds) Haloamines... 

Organoboranes can also be used to construct carbon-carbon bonds by several other types of reactions that involve migration of a boron substituent to carbon. One such reaction involves a-halo carbonyl compounds.20 For example, ethyl bromoac-etate reacts with trialkylboranes in the presence of base to give alkylated acetic acid derivatives in excellent yield. The reaction is most efficiently carried out with a 9-BBN derivative. These reactions can also be effected with (3-alkenyl derivatives of 9-BBN to give (3,y-unsaturated esters.21... 

The reaction of an a-halo carbonyl compound with zinc, tin, or indium together with an aldehyde in water gave a direct cross-aldol reaction product (Eq. 8.90).226,227 A direct Reformatsky-type reaction occurred when an aromatic aldehyde reacted with an a-bromo ester in water mediated by zinc in low yields. Recently, it was found that such a reaction mediated by indium was successful and was promoted by son-ication (Eq. 8.91).228 The combination of BiCl3-Al,229 CdCl2-Sm,230 and Zn-Et3B-Eb0231 is also an effective mediator. Bismuth metal, upon activation by zinc fluoride, effected the crossed aldol reaction between a-bromo carbonyl compounds and aldehydes in aqueous media. The reaction was found to be regiospecific and syn-diastereoselective (Eq. 8.92).232... 

Reaction of /V,/V-unsubstituted selenoureas 332 with methyl vinyl ketone in the presence of ferric chloride in refluxing ethanol gives 2-amino-5-(l -ethoxy)-1,3-selenazoles 335 <06H(68)2145>. This approach obviates the use of lachrymatory halo carbonyl compounds frequently utilized in the synthesis of 1,3-selenazoles. 

A lot of methods are available for the synthesis of this heterocycle, and most of them rely on the formation of the five-membered ring. In this section, only the methodologies of reasonable scope will be reported. The most classical method involves the cyclocondensation of 2-aminopyridine with an a-halo carbonyl compound. Due to the broad availability of the required substrates and the efficiency of this cyclocondensation, it continues to be the method of choice to prepare this heterocycle. New examples highlighting the generality of this reaction are collected in Table 14. 

Dehalogenation.1 DMBI effects dehalogenation of a-halo carbonyl compounds in a variety of ethereal solvents with formation of DMBI+X in generally high yield. The order of relative reactivity is Br > Cl > F (halides) and primary > secondary > tertiary (for the a-substituted position). In combination with HO Ac (1 equiv.) the reagent also reduces acyl chlorides to aldehydes (70-90% yield). 

Oshima [30] reported a radical alkenylation of a-halo carbonyl compounds under mild conditions by utilizing alkenylindium reagents. Using 0.5 equivalent of triethylborane as a radical initiator at ambient temperature, we demonstrated that this process affords the alkenylation products in high yield (Scheme 10, Eq. 10a). Styrylation reaction showed retention of the stereochemistry from starting alkenylindium (Eq. 10b). 

Alkylation of enolates with a-halo carbonyl compounds. (Formation of 1,4-dicarbonyl compounds)... 

Iron-acyl enolates, such as 2, prepared by x-deprotonation of the corresponding acyl complexes with lithium amides or alkyllithiums, are nearly always generated as fs-enolates which suffer stereoselective alkylation while existing as the crmt-conformer which places the carbon monoxide oxygen anti to the enolate oxygen (see Section 1.1.1.3.4.1.). These enolates react readily with strong electrophiles, such as primary iodoalkanes, primary alkyl sulfonates, 3-bromopropenes, (bromomethyl)benzenes and 3-bromopropynes, a-halo ethers and a-halo carbonyl compounds (Houben-Weyl, Volume 13/9 a, p 413) (see Table 6 for examples). 

More reactive electrophiles, such as benzyl and allyl halides, as well as a- or 3-halo-carbonyl compounds, react smoothly with amines, often even at room temperature. Support-bound chloro- and bromoacetamides, for instance, react cleanly with a wide range of aliphatic and aromatic amines to yield glycine derivatives (Entries 1-4, Table 10.2 [22-32]). This reaction is usually conducted in DMSO at room temperature (2-12 h), but for sensitive amines DMF or NMP might offer milder reaction conditions (Entry 3, Table 10.2). Higher yields can often be obtained by increasing the reaction temperature and the concentration of the amine. 

Other methods to form carboxylic acids Cyanotrimethylsilane, 87 a-Substituted carboxylic acids (see also Amino acids, Halo carbonyl compounds, Hydroxy acids) Camphor-10-sulfonic acid, 62 Chiral compounds Alcohols... 

Dimethyl sulfate, 239 Halo carbonyl compounds Camphor-10-sulfonic acid, 62 Dimethyl tartrate, 124 Halohydrins... 

Lithium diisopropylamide, 163 Phenyl azide-Aluminum chloride, 240 Halo carbonyl compounds (see also Unsaturated carbonyl compounds) a-Chloro acids Sodium nitrite, 282 a-Halo aldehydes and ketones... 

Methylthiomethyl p-tolyl sulfone, 192 Potassium ruthenate, 259 Trimethylsilyl chlorochromate, 327 a-Substituted ketones (see also Halo carbonyl compounds, Hydroxy aldehydes and ketones) a-Acetoxy ketones Benzeneselenenyl chloride-Silver acetate, 27... 

This synthesis, originally devised by Tschitschibabin,8 is still the most widely used because it can easily be modified to yield substituted indolizines. The synthesis involves the quaternization of a 2-substituted pyridine, normally using an a-halo carbonyl compound, followed by intramolecular cyclization of the quaternary salt with a mild base, usually aqueous sodium bicarbonate (Scheme 1). 

The disconnection 47 gives a different synthon 48 at the carbonyl oxidation level and the best reagents are the a-halo carbonyl compounds 49. At first this looks like a one-group disconnection but there are two reasons why it isn t. The presence of the carbonyl group makes the Sn2 displacement of halide enormously faster and the a-halo carbonyl compounds 49 are made from the ketone 51 by acid-catalysed halogenation of the enol 50. 

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