1.2- Dicarbonyl compounds from imines

A synthesis of a set of 2-pyridylpyrroles has been described, involving annulation of 1,3-dicarbonyl compounds with 2-(aminomethyl)pyridine under acidic conditions, as illustrated by the construction of compound 437 (Equation 121) <20020L435>. Likewise, pyrroles have also been obtained from reactions between 1,3-diaryl-l,3-dicarbonyl compounds and imines or oximes promoted by the TiCU/Zn-system <2004SL2239>. Yet another approach involves rhodium-catalyzed reactions of isonitriles with 1,3-dicarbonyl synthons, which enables for instance preparation of fluorinated pyrroles <20010L421>. 

Scheme 14.16 Mannich reactions of 1,3-dicarbonyl compounds with imines generated in situ from a-amido sulfones catalysed by cinchonine CN.

The reaction of tnfluoromethyl-substituted A -acyl umnes toward nucleophiles in many aspects parallels that of the parent polyfluoro ketones Heteronucleophiles and carbon nucleophiles, such as enarmnes [37, 38], enol ethers [38, 39, 40], hydrogen cyanide [34], tnmethylsilylcarbomlnle [2,47], 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 denved from hexafluoroacetone... 

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 applications of ruthenium tetroxide range from the common types of oxidations, such as those of alkenes, alcohols, and aldehydes to carboxylic acids [701, 774, 939, 940] of secondary alcohols to ketones [701, 940, 941] of aldehydes to acids (in poor yields) [940] of aromatic hydrocarbons to quinones [942, 943] or acids [701, 774, 941] and of sulfides to sulfoxides and sulfones [942], to specific ones like the oxidation of acetylenes to vicinal dicarbonyl compounds [9JS], of ethers to esters [940], of cyclic imines to lactams [944], and of lactams to imides [940]. 

The experimental data do not warrant calculation of an accurate value for the molecular ratio, methylglyoxal-glyoxal. However, it is certain that the mixture of dicarbonyl compounds consists mainly of methylglyoxal. This compound must be formed from a structure in which the second and third carbon atoms are linked by a single bond. In this connection one might consider the a-pyrrolenine structure (IVa) formed from the imine structure by the shifting of a proton. 

From 2-bromobenzaldehyde, isoindolinones and 3-alkylphthalides are obtained by reaction with amines " (imines ) and 1,3-dicarbonyl compounds, respectively. Alkyl aroates are similarly accessible from aryl tosylates, but the scope is very limited, as only 4-acetylphenyl tosylate furnishes acceptable yields. ... 

Strecker [34] discovered that the reaction between amino acids (glycine, alanine, leucine) and the tricarbonyl compound alloxan yields CO2 and aldehydes. The Strecker degradation of amino acids occurs also with dicarbonyl compounds [35] including those that are formed in the course of the Maillard reaction, in particular deoxyglycosones and some of the smaller sugar fragments like 7 and diacetyl. Fig. 3.22 shows the reaction pathway that involves the formation of an imine 8, followed by decarboxylation and liberation of the resulting aminoketo compound and the Strecker aldehyde from the intermediate 10. Odour-active Strecker aldehydes which... 

The first disconnection to be considered is breaking all the C-X bonds in the ring. This is an obvious strategy for a pyrazole since one C-N bond is part of an enamine and the other is an imine 23. Both functional groups are made from amines and carbonyl compounds. Here hydrazine is the diamine that emerges from an easily made 1,3-dicarbonyl compound 24. 

Apart from phosphanes, typical systems used as chiral ligands in catalysis are alcohols, amines, amino alcohols and other N-functionalities including imines, amides and N-modificd carbonyl groups. Dicarbonyl compounds and their chirally modified equivalents such as dioximes or crown ethers, as well as sulfoxides, arsines, and cyclopentadienyl ligands with chiral side chains have been used. 

The retrosynthesis (see Fig. 6.22) of the pyrazine system is based on principles proven valid for the other azines. Bond fission at the imine function (retrosynthetic step a) leads to 1,2-dicarbonyl compounds 14 and 1,2-diaminoethenes 15 as starting materials for the direct pyrazine synthesis by cyclocondensation. The dihydropyrazines 16 and 18 (from the retroanalysis operation b and c) are alternative starting materials which are accessible from the 1,2-diaminoethanes 17 and 14 or from the ar-amino ketones 19. 

Currently, a significant body of work deals with the use of chiral cationic palladium complexes bearing ligands of the BINAP type or related bisphosphine ligands such as SEGPHOS (Fig. 3). These are based on the pioneering work from Sodeoka on the direct formation of chiral palladium enolate complexes from the palladium precursors and 1,3-dicarbonyl compounds [10, 23]. Within this context, the combination of cationic BINAP-Pd complexes and N-fluoro-bis(phenylsulfonyl)imine (NFSI) was introduced by Sodeoka for the realization of an extremely efficient a-fluorination of 3-keto esters (Scheme 5). 

The dicarbonyl compoimd 51 was oxidized to the anhydride 52, which subsequently reacted with primary or secondary amines to form a-amino acids, a-amino amides and dipeptides 53 (Scheme 14) [48]. 3-Hydroxy j8-lactams obtained from imines derived from carbohydrates [49,50] or prepared via the Sharpless AD reaction [51-53] were directly oxidized to anhydrides by treatment with NaOCl and TEMPO. Anhydrides 54-56 were used for the synthesis of compounds related to the family of polyoxins represented by 57 (Scheme 15) [49-53]. 

The initially formed imine will tautomerize to a conjugated enamine and cyclization now occurs by electrophilic aromatic substitution. The enamine will normally prefer to adopt the first configuration shown in which cyclization is not possible, and (perhaps for this reason or perhaps because it is difficult to predict which quinoline will be formed from an unsymmetri-cal 1,3-dicarbonyl compound) this has not proved a very important quinoline synthesis. However, the synthetic plan is sound, and we shall describe two important variants on this theme, one for quinolines and one for quinolones. 

Vinyl ketene (392) is generated by the carbonylation of the allyl phosphate 390 in the presence of a base as shown by 391. A useful application of the ketene formation is the synthesis of -lactam skeleton by [2 -I- 2] cycloaddition of the ketene with imines. Thus, reaction of the imine 393, derived from vicinal dicarbonyl compounds, with the ketene 392 afforded cw-lactam 394 [152], On the other hand, the transAacism 397 was obtained by the carbonylation of the allyl phosphates 395 in the presence of the imine 396 derived from aldehyde [153]. 

Kobayashi et al. developed catalytic asymmetric 1,4-additions using chiral calcium species prepared from calcium isopropoxide and chiral bisoxazoline ligands 39, 166 and 168. They found that calcium pyBOX catalysts could effectively mediate catalytic asymmetric additions of 1,3-dicarbonyl compounds 4 to nitroalkenes 86, N-Boc-imines 138 or unsaturated amides 49 giving products 165,167 and 170, respectively. Neutral coordinative ligands worked well in these reactions, giving a noticeably faster rate of reaction... 

The reversibility problem in 1,2-additions is alleviated when imines bearing an electron-poor protecting group at nitrogen (sulfonyl, aeyl, ear-bamoyl) are employed as aeceptor partners, rendering possible even the use of 1,3-dicarbonyl compounds as donors. For example, Sehaus and eoworkers reported the highly enantioselective Mannich reaction of acetoacetates and cyclic 1,3-dicarbonyl compounds with N-carbamoyl imines derived from benzaldehydes and cinnamaldehydes catalysed by the natural Cinchona alkaloid cinchonine (CN) (Scheme 14.15). On the basis of the obtained results they developed a model that accounts for the observed diastereo- and enantioselectivity based on the bifunctional nature of the catalyst, which acts simultaneously as a hydrogen-bond donor and acceptor. 

A large number of papers have appeared concerned with the formation of /3-lactams from readily available open-chain precursors, using inexpensive reagents for the cyclization processes. Activation of phenoxyacetic acid (90) with cyanuric chloride to give (91) and protection of the N-terminal of amino-acids with /3-dicarbonyl compounds followed by reaction with imines i.e. (92) (93)] for example may be carried out on a large scale, cheaply and... 

Probably one of the commonest reactions encountered in the template synthesis of macrocycles is the formation of imine C=N bonds from amines and carbonyl compounds. We have seen in the preceding chapters that co-ordination to a metal ion may be used to control the reactivity of the amine, the carbonyl or the imine. If we now consider that the metal ion may also play a conformational role in arranging the reactants in the correct orientation for cyclisation, it is clear that a limitless range of ligands can be prepared by metal-directed reactions of dicarbonyls with diamines. The Tt-acceptor imine functionality is also attractive to the co-ordination chemist as it gives rise to strong-field ligands which may have novel properties. All of the above renders imine formation a particularly useful tool in the arsenal of preparative co-ordination chemists. Some typical examples of the templated formation of imine macrocycles are presented in Fig. 6-12. 

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