1.3- Dicarbonyl compounds from enamines

In addition to preparation of arylhydrazones from the carbonyl compounds and an arylhydrazine, the Japp-Klingemann reaction of arenediazonium ions with enolates and enamines is an important method for preparation of arylhydrazones. This method provides a route to monoarylhydrazones of a-dicarbonyl compounds from /3-keto acids and to the hydrazones of pyruvate esters from / -keto esters. Enamines also give rise to monoarylhydrazones of a-diketones. Indolization of these arylhydrazones provides the expected 2-acyI-or 2-alkoxycarbonyl-indoles (equations 95-97). 

The Biju group discovered an NHC-catalyzed generation of chiral a,p-unsaturated acylazoliums from 2-bromoenals followed by their interception with 1,3-dicarbonyl compounds or enamines, via a formal [3 + 3] annulation reaction. The reaction results in the enantioselective synthesis of synthetically and medicinally important dihydropyranones and dihydropyridinones, and tolerates a wide range of functional groups. It is noteworthy that the... 

In most cases of formation of 1,3-dicarbonyl compounds from isoxazoles derivatives, catalytic hydrogenation has been used, and we are not aware of any cases wherein an exocyclic olefinic bond survived during the reductive cleavage. Likewise in our case, attempted hydrogenation of 9 (R = )-9-tridecenyl) using either Raney nickel or platinum resulted in both the N-0 moiety and the side chain olefinic bond being reduced at similar rates. Additionally, when considering possible alternative reduction procedures, not only must the exocyclic olefinic bond be considered as a site of unwanted reduction, but also the keto and ketol ups as well. Further, Ae selected method must avoid overreduction of the enamine in the initial product 10. 

Second, an enamine from a mowoketone can be used in the Michael addition, whereas enoJate ions only from fi-dicarbonyl compounds can be used. 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

Work from several laboratories has demonstrated the utility of this method.49-52 In addition to enamines and 1,3-dicarbonyl compounds,49... 

V-Aminopyrroles, easily prepared from the reaction of azoalkenes with enamines and /3-dicarbonyl compounds, have been shown to react with electron deficient alkynes to afford substituted benzenes (79TL2969). While the N-methoxycarbonylaminopyrrole (208) reacted with DM AD under rather vigorous conditions to afford (211) in only 13% yield, the N-unsubstituted aminopyrrole (209) prepared from (208) by NaCN treatment reacted with DMAD in CHC13 solution at room temperature to give (211) in 50% isolated yield. The formation of the aromatic system probably occurs by extrusion of the heteroatom bridge from (210) to afford a relatively stable nitrene (212 Scheme 45). 

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... 

Enamine (235) obtained from cyclic ketones and the acetal of /V-methyl-2-pyrrolidone gave a fused 2-pyrone [83IJC(B)1083]. 2//-Chromenes were obtained from of 3,5-dichlorosalicylaldehyde and enamines (94RRC183) (Scheme 42). The pyran ring is formed by a reaction of aminals of conjugated w-dimethylaminoaldehydes with cyclic /1-dicarbonyl compounds (94IZV285) (Scheme 43). 

The reaction of tnfluoromethyl-substituted N-acyl umnes toward nucleophiles in many aspects parallels that of the parent polyfluoro ketones Heteronucleophiles and carbon nucleophiles, such as enamines [37, 38], enol ethers [38, 39, 40], hydrogen cyanide [34], tnmethylsilylcarbomtnle [2,41], alkynes [42], electron-nch heterocycles [43], 1,3-dicarbonyl compounds [44], organolithium compounds [45, 46, 47, 48], and Gngnard compounds [49,50], readily undergo hydroxyalkylation with hexafluoroace-tone and amidoalkylation with acyl imines derived from hexafluoroacetone... 

Since simple ketones 22 are less reactive compared to 1,3-dicarbonyl compounds 19, improvement of the nucleophilicity of the a-carbon is required by conversion to enamines. When dinitropyridone 1 is treated with acetone 22a in the presence of amines, 2,6-disubstituted 4-nitroanilines 23a-c are produced in good yields (Table 1). In this reaction, the enamine is formed in situ, and attacks stepwise at the 4- and the 6-position of pyridone 1 to afford bicyclic intermediate from which anionic nitroacetamide is eliminated leading to nitroaniline derivative 23. It is possible to synthesize unsymmetri-cal nitroanilines having different substituents at the 2- and the 6-positions by changing ketones 22, and modification of the amino group is also achieved by using other amines [41]. 

We met enamines as specific enol equivalents in the last chapter and they are particularly good at conjugate addition. The pyrrolidine enamine from cyclohexanone 41 adds to acrylic esters 42 in conjugate fashion and the first-formed product 43 gives the enamine 44 by proton exchange.4 Acid hydrolysis via the imine salt 45 gives the 1,5-dicarbonyl compound 46. 

The enamine will normally prefer to adopt the first configuration shown in which cyclization is i not possible, and (perhaps for this reason or perhaps because it is difficult to predict which quinoline will be formed from an unsymmetrical 1,3-dicarbonyl compound) this has not proved a very important quinoline synthesis. We shall describe two more important variants on the same theme, one for quinolines and one for qui nolo lies. 

An enamine is formed from a ketone when it is necessary to synthesize a 1,5-diketone or a 1,5-dicarbonyl compound containing an aldehyde or ketone. The ketone starting material is converted to an enamine in order to increase the reactivity of the ketone and to direct the regiochemistry of addition. The process, as described in Section 23.11, is (1) conversion of a ketone to its enamine (2) Michael addition to an a,P-unsaturated carbonyl compound (3) hydrolysis of the enamine to the starting ketone. 

A route to pyrroles illustrated by the preparation of 292 involves initial treatment of the nitroketene-5, 5 -acetal 293 with an organometallic reagent, followed by conversion of the resulting alkene 294 to the enamine 295, and final annulation to the target heterocycle (Scheme 34) <1998T12973>. A related approach featuring constmction of /3-hydroxyenamines from 1,3-dicarbonyl compounds and /3-amino alcohols, and subsequent palladium-catalyzed cyclization to pyrroles, has been reported <1996TL9203>. 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

The results obtained from subsequent studies indicate that this same approach can be used to promote telomerization of butadiene with p-dicarbonyl compounds, nitroalkanes, and enamines. ... 

The reductive coupling of carbonyl compounds with formation of C-C double bonds was developed in the early seventies and is now known as McMurry reaction [38, 39]. The active metal in these reactions is titanium in a low-valent oxidation state. The reactive Ti species is usually generated from Ti(IV) or Ti(III) substrates by reduction with Zn, a Zn-Cu couple, or lithium aluminum hydride. A broad variety of dicarbonyl compounds can be cyclized by means of this reaction, unfunctionalized cycloalkenes can be synthesized from diketones, enolethers from ketone-ester substrates, enamines from ketone-amide substrates [40-42], Cycloalkanones can be synthesized from external keto esters (X = OR ) by subsequent hydrolysis of the primary formed enol ethers (Scheme 9). 

Similarly, carbanions from 1,3-dicarbonyl compounds can act as nucleophiles [153]. In a somewhat related reaction, enamines of cyclohexanone or cycloheptanone are oxidized in an iodide-mediated indirect electrochemical process leading to a Favorskii-type rearrangement. Thus, bicyclo[(n — 1).1.0] systems containing a nucleophile like a cyano or a methoxy function are formed [Eq. (27)] [154]. 

Amines and -keto carbonyl compounds form enamines in high yields. This reaction has been used to protect amino acids and amino acid esters (Scheme 17). Enamines (28) from acyclic P-dicarbonyl com-... 

Enamines behave in much the same way as enolate ions and enter into many of the same kinds of reactions. In the Stork reaction, for example, an enamine adds to an a,/3-unsaturated carbonyl acceptor in a Vlichael-like process. The initial product is then hydrolyzed by aqueous acid (Section 19.8) to yield a 1,5-dicarbonyl compound. The overall reaction is thus a three-step sequence of (1) enamine formation from a ketone, (2) Michael addition to an o ,j8-unsaturatcd carbonyl compound, and (3) enamine hydrolysis back to a ketone. 

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