Esters dehydroamino

A type Ilac synthesis of functionalized pyrroles was developed that adapted the Larock indole synthesis <06OL5837>. For example, treatment of iodoacrylate 19 and trimethylsilylphenylacetylene 20 with palladium acetate led to the formation of pyrrole-2-carboxylate 21 with excellent regioselectivity. 19 was prepared by iodinating (N-iodosuccinimide) the corresponding commercially available dehydroamino ester. 

Fig. 12.17 Agostic dihydride intermediate derived from a dehydroamino ester substrate.

A different variation on this theme has been developed by Ito, where the TRAP ligands (37) form a nine-membered metallocycle [157-162]. The ruthenium catalysts seem to function best at low pressures, but highly functionalized dehydroamino esters can be reduced with high degrees of asymmetric induction [157, 159-164], as well as indoles [165]. 

It transpires that most classes of monodentate ligands include members that are able to induce high enantioselectivity in the hydrogenation of the two benchmark substrates 52 a and 53 a. It is not clear whether their corresponding acids 52b and 53 b have been studied or, alternatively, if the authors decided not to include (disappointing) ee-values. For phosphoramidite MonoPhos (29 a), however, the ee-values are invariably excellent. Overall, the TOFs range from 50 to 170 IT1, but have not been optimized in most cases. Unfortunately, with one exception [87], the hydrogenation of dehydroamino esters in which R1 is a (functionalized) alkyl substituent has not been studied, probably because of their difficult accessibility. 

Fig. 31.10 Comparison of rate (schematic) and enantioselec-tivity for mono- and bidentate phosphorus ligands on 1 mM scale, (a) a-Dehydroamino ester, 2 bar H2 (b) jS-dehydroami-no ester, 10 bar H2.

Figure 1.3. Catalytic hydrogenation of A-acylated dehydroamino esters via an unsatu-rated/dihydride mechanism the p substituents in the substrates are omitted for clarity [P-P = (i ,R)-DIPAMP, (i ,i )-CHIRAPHOS, or (R)-BINAP S = solvent or a weak ligand].

A further step was taken when first Halpern [28] and then Brown [29] were able to identify a further intermediate, the rhodium alkyl hydride formed by addition of dihydrogen to the enamide complex with transfer of a single hydride to the benzylic carbon. For the simple dppe complex studied by Halpern, the interpretation of the experiment was straightforward, but the intermediate derived from DIPAMP by Brown and Chaloner provided a major surprise only the disfavored minor diastereomer of the enamide complex was reactive towards H2. The major/minor equilibrium is so strongly biased towards the former below -50 °C that reaction with H2 is undetected. Only when the solvate complex is allowed to react with the dehydroamino acid derivative under H2, well below -50 °C (under which conditions up to 35% of the minor diastereomer is initially observed) is the alkyl hydride observed, concomitant with disappearance of that minor diastereomer. This reactive intermediate was characterized by its H-NMR (hydride), the distinctive P-NMR and by both heteronuclear coupling and chemical shifts in the C-NMR spectra of alkyl hydrides derived from singly and doubly labeled dehydroamino esters. 

More Rh catalysts have been tested for the hydrogenation of dehydroamino ester derivatives. Two of them incorporate ligands 167 and 168. The latter seems to have a broader substrate scope, for example in reduction of acrylic esters. Also useful for the same purpose is an iridium(I) complex of 38B. Furthermore, 169 is active for hydrogenation of enol phosphinates. 

On the other hand, treatment of the dehydroamino ester 60 Z with Br2 in the presence of 2,6-lutidine afforded a mixture of the respective Z and E vinyl bromides 64 (1.5 1). Treatment of this mixture with TCA led to deprotection of the E -isomer more rapidly than the Z-isomer, followed by heating in NEts to afford a single azabicyclo[3.1.0] 65Z. The vinyl bromide 64E was deprotected by TCA in CD3CN and then cyclized with NEts to give [3.1.0] product 65E in 91% yield (Scheme... 

A reaction tube equipped with a stirring bar, in which 5 pmol of Rh(cod)2Bp4, 11 pmol of ligand 118, and 0.5 mmol of P-dehydroamino ester (155) were added under an inert atmosphere into an autoclave. After 5 mL of CH2CI2 were added, the inert atmosphere was replaced by 10 hydrogen/release cycles and the reaction mixture was allowed to stir under... 

In the same year, Glorius and coworkers successfully introduced dehydroamino ester 47 as the Michael acceptor for the Stetter reaction. Aromatic aldehydes 21 with an electron-withdrawing group worked well. However, electron-rich aromatic aldehydes did not (Scheme 20.23). 

Rh- and Ru-based systems are the catalysts of choice to hydrogenate dehydroamino acids. When those systems fail, switching to iridium can lead to improved results. An example is the hydrogenation of the sterically hindered dehydroamino ester 33 with a secondary phosphine oxide as ligand, depicted in Scheme 7.14. 

Genet, Darses, and coworkers reported an interesting enantioselective rhodium-catalyzed 1,4-addition of organotin reagents to electron-deficient a,a -disubstituted alkenes, to afford amino ester derivatives (Scheme 5.18). Indeed, it appeared that their optimized conditions, involving BINAP as the ligand for rhodium and guaiacol, as the proton source worked well for dehydroamino ester derivatives [61]. 

N-Protected a, 8-dehydroamino-acids and a,j8-dehydroamino-esters can be coupled simply by formation of the acid chloride of the former using PClg. " Dehydropeptides can also be prepared by reaction of a-amino-acid chlorides with adducts of a-azido-a,j8-unsaturated esters and triethyl phosphite. " Peptides can be cyclized using diphenylphosphoryl azide, on a large scale if necessary, in 40—50% yields in favourable cases. ... 

Rhodium complexes, formed in situ with [Rh(COD)2]BF4 and monodentate chiral spiro phosphite and phosphine ligands, catalyse the AH of both (Z)- and (E)-P-arylenamides with up to 97% ee. A library of 19 chiral binol-monophosphite ligands containing a phthalic acid secondary bis-amide group has been synthesized and screened for use in stereocontrol of rhodium-catalysed hydrogenation of several prochiral dehydroamino esters and enamides. Spectroscopic and computational studies... 

Secondly, it possible to use the reagent Selectfluor to electrophilically fluorinate silyl enol ethers under very mild conditions.( ) We have used this route to access p-fluoro-a-keto esters 8 as intermediates to fluorinated dehydroamino esters 9 (Scheme 4) (20)... 

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