Aldehydes, single-step condensation

Arylidene-33-diethyl-3,4,6,7-tetrahydro-2//-thiazolo[3,2-/j][l, 4 ]-tetrazin-6-ones 53 have been synthesized in a single step by the condensation of tetrahydro-l, 4 -tetrazin-3-thione 52 with ethyl chloioacetate and aldehydes in the presence of pyridine and piperidine. Condensation of 53 with hydrazine afforded fused derivatives 54 <98IJC(B)819>. 

Fig. 11.23. Julia-Kocienski olefination to obtain tmns-alkenes from aldehydes in a single step their condensation reaction with the sulfonyl anion B, followed by an Ar-SN reaction (- E) and a fragmentation.

The structures of the vast majority of PD-5 inhibitor compounds aimed at erectile dysfunction consist of modified purines. The structure of the recently approved drug for this indication tadalafll (113) differs markedly from the prototypes. Tryptophan methyl ester (108) provides the starting material for large scale enantioselective synthesis. Condensation of that compound with piperonal (109) in the presence of acid leads to formation of the tricyclic intermediate (110). This transform involves initial addition of the amine to the aldehyde. The carhocation from the newly formed carhinolamine then attacks the indole 2-position to form the the fused piperidine. The stereochemistry of the new chiral center is guided by that from the tryptophan carhon across the ring. The secondary amine is next acylated with chloroacetyl chloride in the presence of triethylamine to afford 111. Reaction of this intermediate with methylamine goes on to form the desired product in a single step. This reaction can he rationalized... 

The condensation equilibrium is displaced to the right by removing the unsaturated cyano ester as it is formed by the addition of hydrogen cyanide The effect is analogous to the single-step formation and hydrogenation of a,/S-unsaturated cyanoacetic esters (method 394). The yields are good with most aliphatic ketones and aldehydes (49 75%), but poor results are obtained with aromatic carbonyl compounds and diisopropyl ketone. 

Trimethyl-l,6-dihydropyrimidine-2-thione (113), on condensation with aromatic aldehydes in ethanolic KOH, gives arylidene derivatives 114 which react with chloroacetic acid in the presence of anhydrous sodium acetate in acetic anhydride to afford a cyclized product formulated as 115 (81 Mil) that can also be represented by the alternate structure 116 (Scheme 25). Similarly, the thione 113 reacts with chloroacetic acid and aromatic aldehydes in the presence of anhydrous sodium acetate in acetic acid and acetic anhydride to furnish a cyclized product for which structure 117 has been assigned without any evidence (81 Mil). The cyclized product can also be represented by the other isomeric structure 118. The bicyclic compound (115 or 116) condenses with aromatic aldehydes to give arylidene derivatives that are also obtained in a single-step synthesis involving the reaction of 114 with chloroacetic acid and aromatic aldehydes in the presence of anhydrous sodium acetate in acetic acid and acetic anhydride. 

More impressive and more important is the performance of these lithium enolates in aldol reactions. Ester enolates are awkward things to use in reactions with enolisable aldehydes and ketones because of the very efficient self-condensation of the aldehydes and ketones. The traditional solutions involve such devices as Knoevenagel-style reactions with malonates.11 Lithium enolates of esters, e.g. 76, react cleanly with enolisable aldehydes and ketones to give high yields of aldols,12 e.g. 79 in a single step also involving a six-membered cyclic transition state 77. 

Aldol condensations occur, particularly under basic conditions. This property has been used to form higher aldehydes and alcohols directly in a single step under hydroformyiation conditions , the so-called Aldox process. 

The synthesis of phosphinic peptides by a reverse sequence of P-C bond formation events (N+PC approach) is a less frequently applied strategy which may offer important diversification possibilities. In particular, an amidoalkylation condensation reaction between amides, aldehydes, and alkylphosphinic acids (the three-component Kabachnik-Fields reaction) affords in a single step the main pseudopeptidic backbone, thus facilitating fast screening of the nature of Pi position. In 1996, Chen and Coward observed that a mixture of benzyl carbamates, aldehydes, and alkylphosphinic acid 23 in AcCl can lead to Cbz-protected phosphinic pseudodipeptides 24 (Scheme 10a) [53]. This method was adjusted by Matziari et al. to the synthesis of Fmoc-protected phosphinic building blocks 25 and peptides thereof (Scheme 10b) [54]. 

Further exploitation of this synthetic methodology was able to take advantage of not only ester formation and B-N interactions but also the condensation of aldehydes with primary amines. The flexibility of this methodology was demonstrated in the construction of dendritic nanostructures, in a single step. 

---