Regiospecificity carbonylation reactions

There are two methods for the introduction of a hydroxyalkyl group at position 5 of the pyrazol-3-one ring. Schmidt and Zimmer converted furanediones 258a-k into arylmethylenepyrazol-3-reaction with hydrazine hydrate or methylhydrazine (83Jmechanism proposed for the reaction involves nucleophilic attack of the hydrazine on the ketone carbonyl, followed by attack on the ester carbonyl and ring opening of the... 

Table 8.17 shows the scope of the reaction of acetylcobalt tetracarbonyl with polyenes. The reactions are regiospecific with the acetyl group adding to the terminal unsaturated carbon atom of the ir-electron system to produce the E-a,p-unsaturated ketones [9]. In the reaction with fulvenes [10], only the 1-acetyl and 1,4-diacetyl derivatives are formed, with no evidence of the 2-isomer. This is an indication of the relative stabilities of the cyclic it-allyl complexes, compared with the exocyclic complex. It has been postulated that, in the reactions of conjugated systems, the initial o-allyl adduct proceeds to the products via the it-allyl complex (cf Scheme 8.1), whereas in the case of unconjugated tt-systems, the initial o-adduct is more stable and tends to undergo a further carbonylation reaction. 

The base-catalyzed condensation of azides with activated methylene compounds is a well-established route to IJT-triazoles. In particular, it is the best route to triazoles bearing a 5-amino or hydroxy substituent and an aryl or carbonyl-containing function in the 4-position. The addition is regiospecific. The reaction is a stepwise one, since anomerism of glycosyl azides has been observed in their reaction with activated methylene compounds, indicating the presence of an intermediate. The mechanism can be envisaged as a nucleophilic attack by the car-banion on the terminal nitrogen of the azide, followed by cyclization to a... 

A-Substituted pyrroles, furans and dialkylthiophenes undergo photosensitized [2 + 2] cycloaddition reactions with carbonyl compounds to give oxetanes. This is illustrated by the addition of furan and benzophenone to give the oxetane (138). The photochemical reaction of pyrroles with aliphatic aldehydes and ketones results in the regiospecific formation of 3-(l-hydroxyalkyl)pyrroles (e.g. 139). The intermediate oxetane undergoes rearrangement under the reaction conditions (79JOC2949). 

Scheme 4 shows in a general manner cyclocondensations considered to involve reaction mechanisms in which nucleophilic heteroatoms condense with electrophilic carbonyl groups in a 1,3-relationship to each other. The standard method of preparation of pyrazoles involves such condensations (see Chapter 4.04). With hydrazine itself the question of regiospecificity in the condensation does not occur. However, with a monosubstituted hydrazine such as methylhydrazine and 4,4-dimethoxybutan-2-one (105) two products were obtained the 1,3-dimethylpyrazole (106) and the 1,5-dimethylpyrazole (107). Although Scheme 4 represents this type of reaction as a relatively straightforward process, it is considerably more complex and an appreciable effort has been expended on its study (77BSF1163). Details of these reactions and the possible variations of the procedure may be found in Chapter 4.04. 

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... 

Formal isomerization of the double bond of testosterone to the 1-position and methylation at the 2-position provides yet another anabolic/androgenic agent. Mannich condensation of the fully saturated androstane derivative 93 with formaldehyde and di-methylamine gives aminoketone 94. A/B-trans steroids normally enolize preferentially toward the 2-position, explaining the regiospecificity of this reaction. Catalytic reduction at elevated temperature affords the 2a-methyl isomer 95. It is not at all unlikely that the reaction proceeds via the 2-methylene intermediate. The observed stereochemistry is no doubt attributable to the fact that the product represents the more stable equatorial isomer. The initial product would be expected to be the p-isomer but this would experience a severe 1,3-diaxial non-bonded interaction and epimerize via the enol. Bromination of the ketone proceeds largely at the tertiary carbon adjacent to the carbonyl (96). Dehydrohalogenation... 

These reactions were proposed to proceed via electrophilic attack on the enol by the SN reagents at N followed by cyclization either via a second enol as in compound 151 or by cyclization onto the more reactive carbonyl <1997J(P1)2831>. Unsymmetrical 1,3-diketones can give a mixture of regioisomers if both carbonyls have similar reactivities however, aroylacetones react regiospecifically to afford only the 3-aroyl-4-alkyl-l,2,5-thiadiazoles 154 (R = Me). 

In a similar manner, starting from 2-methylchloride-naphtho[l,8-de][l,2,3]triazine and magnesium, via a novel sonication-promoted Barbier reaction, an a-aminomethyl carbanion equivalent is generated which reacts in situ with a variety of carbonyl compounds. Subsequent catalytic hydrogenolysis of the triazine moiety yields the corresponding amines <00TL4685>. Sterically controlled regiospecific cyclization of aldose-5-ethyl-l,2,4-... 

Oxidation Products of Sucrose. The essentially regiospecific oxidation by Agrobacterium tumefaciens, whose dehydrogenase exclusively generates 3 -ketosucrose, is the prototype of an entry reaction into modified sucroses. This ready access opened the way to manifold modifications at the 3 -carbonyl function (Scheme 2.16)." Chemical oxidation proceeds less uniformly, for... 

Regiospecific and enantioselective aldol reactions 168) were also performed with SAMP (137). Lithiated hydrazones obtained from ketones (154) as described above were alkylated with carbonyl compounds and the adducts then treated with chloro-trimethylsilane. The resulting trimethylsilylethers (155) were finally oxidatively hydrolyzed to yield the chiral (3-hydroxyketones (156) (e.e. = 31-62%)168),... 

We found that a catalytic amount of cucurbituril markedly accelerated the reaction shown and rendered it regiospecific, yielding only the 1,3-disubstituted product. This result is explained by formation of a transient ternary complex between the reactants and the receptor. Simultaneous binding of both the alkyne and the azide, with one NH3 coordinated to each set of carbonyls and with the substituents extending into the interior of cucurbituril, results in alignment of the reactive groups within the core of the receptor so as to facilitate production of the 1,3-disubstituted triazole. The proposed mechanism may be visualized with the aid of Fig. 7 (R = H). 

Because of their high reactivity, these complex salts react rapidly and regiospecifically, at low temperature, with a number of carbon and heteroatomic nucleophiles, including thiols, amines, and alcohols. Finally, exposure of the double bond takes place under particularly mild conditions so that isomerization of the (3,Y-unsaturated carbonyl system may be avoided. The present scope of reactions with these vinyl cation synthons is summarized in [able I. 

The reaction is regiospecific for substitution of an a hydrogen. None of the hydrogens farther removed from the carbonyl group are affected. 

Diels-AIder reaction with Lewis acid (MgBr2 or C2H5 A1C12) proceeds stereospecifically to give cra/o-adducts in which the phenylthio function is oriented ortho to the carbonyl group (7, 75-76). The related dienes 2 and 3 undergo cycloaddition with similar stereo- and regiospecificity. 

The regiospecificity of the reaction depends on the relative migratory ability of the substituents attached to the carbonyl. Substituents which are able to stabilize a positive charge migrate more readily, so that the order of preference is tert. alkyl > cyclohexyl > sec. alkyl > phenyl > prim, alkyl > CH3. In some cases, stereoelectronic or ring strain factors also affect the regiochemical outcome. 

---