Proline derivatives, decarboxylative

This route relies on 1,3-dipolar cycloaddition reactions a series of dihydropyrrolizines 213 were synthesized by heating the proline derivatives 211 with dimethyl acetylenedicarboxylate (DMAD) at 130-140 °C in the presence of acetic anhydride. Reaction between 211 and AczO provides the mesoionic oxazalone intermediate 212 which adds to dimethyl acetylenedicarboxylate, giving a cycloadduct, which undergoes spontaneous decarboxylation leading to 213 (Scheme 50) <1998JME4744, 1977JME812>. 

Murahashi and co-workers (49) extensively studied the synthesis of nitrones such as 29 by a decarboxylative oxidation of proline derivatives (Scheme 12.12). However, these nitrones were primarily used in nucleophilic addition reactions rather than 1,3-dipolar cycloadditions. Others have synthesized cyclic nitrones 30 and 31 having a chiral center adjacent to the nitrogen atom (50,51). Saito and co-workers (51) applied nitrone 31 in reactions with fumaric and maleic acid... 

Although the mechanism of the transformation of single into double bonds has not been investigated in detail, a heteroatom attached to the single bond is necessary for an efficient introduction of the double bond. Trisubstituted pyrazo-lines 46 can be oxidized with (diacetoxyiodo)benzene 3 to the corresponding pyrazoles 47 in good yields [98]. Two double bonds can be introduced in easy accessible proline derivatives 48 [99] by an oxidative decarboxylation with [bis(trifluoroacetoxy)iodo]benzene 4 yielding tetrasubstituted pyrroles of type 49, Scheme 22 [100]. 

Hexenyl radicals cyclize to cyclopentylmethyl radicals (see Volume 4, Chapter 4.2). Thus radical decarboxylation of 6-heptenoic acids, by whatever means, usually results in die formation of five-mem-v beied rings. Although this fact had been appreciated previously it is only recendy, widi the advent of the 0-acyl thiohydroxamates, that it has been exploited from a syndietic point of view. An example is provided by the synthesis of bicyclo[4.3.0]proline derivatives from aspartic acid carried out by the Barton group (equation 51). It will be noted that activation of die C—C double bond acting as a radical trap is not necessary in these intramolecular reactions. 

Decarboxylation of a-heteroatom-functionalized carboxylic acids occurs smoothly using PhI(OAc)2 and I2 without the requirement for photolysis. When proline derivatives are employed for this reaction, the intermediate A,0-acetal may be treated with nucleophilic agents to give 2-substituted pyrrolidine products (eq 55). 

Another compound obtained from 3-deoxyosone via a relatively complex reaction is maltoxazine (VII in Formula 4.59), which has been identified in malt and beer. This compound could be formed from 3,4-dideoxyosone, which first undergoes a Streaker reaction with the secondary amino acid proline with decarboxylation to give the 1-pyrroline derivative (Formula 4.65). Enolization, formation of a five-membered carbocyclic compound and nucleophilic addition of the hydroxymethyl group to the pyrroline cation yields the tricyclic maltoxazine. In general, the formation of such carbocyclic compounds is favored in the presence of secondary amino acids like proline. 

It must be noted that when the saturated cyclic amine was protected in 2-position by an ester group (proline derivative), sp C-H bond activation did not operate at C5 but a decarboxylative arylation took place in the absence of pinacolone leading to monoarylated pyrroline products (Scheme 19) [13]. 

An iron-catalyzed decarboxylative Csp3-Cjp2 coupling of proline derivatives and naphthols has been described. Iron(II) sulfate is used as catalyst and di-/er/-butyl peroxide functions as oxidant (Scheme 4-261). ... 

Scheme 4-261. Decarboxylative coupling of proline derivatives with...

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

Isatin derivatives and proline react to give stereospecific formation of an azo-methine ylide intermediate via the decarboxylation route. The resulting 1,3-dipole undergoes a cycloaddition reaction with N-substituted maleimide (6), as a dipolaro-... 

The effectiveness of various precursors of these compounds was investigated quantitatively by Ottinger and Hofmann.283 Hexose-derived cyclotene was the common precursor for both 33 and 35, as well as 34 and 36. The formation of each compound is very much determined by the nature of the N-containing precursor. Thus, for example, pyrrolidine (e.g., formed by thermal decarboxylation of proline) plus cyclotene produced 33 and 35 only, whereas 1-pyrroline (derived from proline... 

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