Pyridines ketene acetal addition

A nucleophilic addition of bis(TMS) ketene acetals to pyridines (223), aided by acylation of the pyridine nitrogen with methyl chloroformate, has been reported to produce the 1,4-adduct (224).264... 

The use of substituted pyridines in organic synthesis has broad application. The activation of the pyridine ring toward nucleophilic attack is well known in the literature. The products of such reactions are often dihydropyridines which can serve as intermediates in more complex synthetic strategies. Rudler and co-workers have reported on the nucleophilic addition of bis(trimethylsilyl)ketene acetals to pyridine (26). The 1,4-addition product 27 was then cyclized with iodine to afford bicycle 28 in 90% overall yield <02CC940>. Yamada has elegantly shown that facial selectivity can be achieved and chiral 1,4-dihydropyridines accessed in high yield and de (29—>30) <02JA8184>. 

Schramm nee Dediu OG, Oeser T, Muller TJJ (2006) Coupling-isomerization-iV,5-ketene acetal-addition sequences - a three-component approach to highly fluorescent pyrrolo[2,3-h] pyridines, [l,8]naphthyridines, and pyrido[2,3-b]azepines. J Org Chem 71 3494—3500 Wiesner J, Ortmann R, Jomaa H, Schlitzer M (2003) New Antimalarial Drags. Angew Chem... 

Extension of this work by reacting 5-nitropyrimidine with 0,0-ketene acetals and with other cyclic and non-cyclic enamines showed that also with these electron-rich dienophiles the addition is regioselective and gives rise to the formation of 2-mono- or 2,3-disubstituted 5-nitropyridines (Scheme 30). Thus, reaction of 5-nitropyrimidine with the cyclic N,S-ketene acetals 4,5-dihydro-1 -methyl-2-methylthiopyrrole and 4,5,6,7-tetrahydro-1 -methyl-2-methylthioazepine gives in low yields 2,3-dihydro-1-methyl-5-nitropyr-olo[2,3-h]pyridine and the 5,6,7,8-tetrahydro-9-methyl-3-nitropyrido [2,3-Z)]azepine, respectively (89T2693) (Scheme 30). 

Roush WR, Hall SE (1981) Studies on the total synthesis of chlorothricol-ide stereochemical aspects of the intramolecular Diels-Alder reactions of methyl undeca-2,8,10-trienoates. J Am Chem Soc 103 5200-5211 Rudler H, Denise B, Xu Y, Parlier A, Vaissermann J (2005) Bis(trimethylsilyl)-ketene acetals as C,0-dinucleophiles one-pot formation of polycyclic y-and 8-lactones from pyridines and pyrazines. Eur J Org Chem 3724-2744 Sekino E, Kumamoto T, Tanaka T, Ikeda T, Ishikawa T (2004) Concise synthesis of anti-HIV-1 Active (+)-inophyllum B and (+)-calanolide A by application of (-)-quinine-catalyzed intramolecular oxo-michael addition. J Org Chem 69 2760-2767... 

Olefinic pyrazines like 108 were shown to react with QH in the superacid TfOH to give anti-Markovnikov addition products like 109 <050L2505>. The orientation observed is presumed to be due to the multiply charged heterocycle adjacent to the olefin. Pyrazine o-quinodimethanes underwent Diels-Alder condensation with meso-tetraarylporphyrins to give new jt-extended porphyrins <05TL2189>. A one-pot formation of polycyclic - and -lactones like 111 was developed using the reaction of pyridine and pyrazine (110) with bis(trimethylsilyl)ketene acetals. Many of them were characterized by X-ray <05EJO3724>. 

C2-symmetric bis(oxazolinyl)pyridine (pybox)-Cu (II) complex 27 has been shown to catalyze highly enantioselective Mukaiyaraa aldol reactions between (benzyloxy)acetaldehyde and silyl ketene acetals by Evans and co-workers as exemplified in Scheme 1-9 [38]. Here, the requirement for a chelating substituent on the aldehyde partner is critical to catalyst selectivity, as a-(terl-butyldimethylsil-oxy)acetaldehyde gave lower enantioselectivity (56% ee). In addition, P-(benzyl-oxy)propionaldehyde provided the racemic product, indicating a strict requirement for a five-membered catalyst-substrate chelate. 

However, because the addition of an alcohol to a ketene acetal is an acid-catalyzed reaction, formation of polymers by the addition of diols to this diketene acetal is greatly complicated by the extreme susceptibility of this monomer towards a competing cationic polymerization. Nevertheless, linear polymers could be prepared by using iodine in pyridine catalysis [24], This polymerization, illustrated for 1,6-hexanediol, is shown in Scheme 9. The polymer was characterized by 13C-NMR spectroscopy shown in Fig. 5 [24], The band assignments are shown in the figure. 

The addition of silyl ketene acetals to chiral aldonitrones requires the use of Lewis acids as activating reagents. Whereas activation with TMSOTf followed by a treatment with hydrofluoric acid-pyridine leads to the syw-adducts of isoxazolidin-5-ones (eq 91), the use of diethylaluminium chloride or boron trifluoride etherate leads to awft -compounds. ... 

A pyridine derivative bearing an electron withdrawing group in the position p to the nitrogen can undergo addition with silyl ketene acetals in the presence of some ion-exchanged montmorillonite clays (e.g. equation 4.36) [148]. The nature of the cation present is vital to the activity of the catalyst. 

Aldol Additions to Ketones. Traditionally, cerium enolates or the Reformatsky-type reaction have been employed to achieve high-yielding aldol additions to enolizable ketones. In this regard, methyl trichlorosilyl ketene acetal provides a reliable alternative for the synthesis of tertiary -hydroxy esters. In the absence of a Lewis base promoter, the aldol additions of 1 to ketones are too slow to be synthetically useful. On the contrary, with pyridine A-oxide as catalyst, methyl trichlorosilyl ketene acetal reacts smoothly with nearly all classes of ketones (7) (Scheme 1). Good yields of the tertiary alcohol products (8) are obtained (eq 4), table 2 from aromatic (entries 1-2 and 4—6), hetereoaromatic (entry 3), olefinic (entries 7-8), acetylenic (entries 9-10), and aliphatic (entries 11-14) ketones. The only poorly performing substrate is 2-tetralone (7o), which affords a 45% yield of the addition product and returns 45% of unreacted starting material, most likely from competitive enolization. 

In 1993, Vedejs et al. [5,6] showed that tributylphosphine is a potent catalyst for the acylation of alcohols by acetic and benzoic anhydrides as efficient as 4-(di-methylamino)pyridine DMAP [7,8]. However, the DMAP catalyst is more versatile since it presents catalytic activity in the reaction of alcohols with a larger variety of electrophiles. Due to these properties, Fu [9] realized the design and synthesis of a new family of chiral nucleophilic catalysts illustrated by the planar-chiral DMAP derivative I which is a very efficient catalyst in different enantioselective reactions such as addition of alcohols to ketenes [10], rearrangement of O-acylated azalactones [11], and kinetic resolution of secondary alcohols [12-14]. 

The acid-catalyzed reaction of methanimines with jS-substituted enamines, utilized for the preparation of symmetrical 3,5-disubstituted pyridines [Eq. (10)], has been carefully investigated and shown to proceed by in situ generation and subsequent [4 + 2] cycloaddition of electrophilic 1-aza-1,3-butadienes with the electron-rich enamine. Additional studies have reduced this process to a controlled [4 + 2] reaction of the isolated A -tert-butyl-l-aza-1,3-butadienes with enamines or related electron-rich olefins including ketene 0,A -acetals [Eq. (11)]. 

Formaldehyde is a strong electrophile, allowing acetal to polymerize by nucleophilic, anionic, or cationic addition of an alcohol to ketene carbonyl groups. Relatively weak bases such as pyridine initiate anionic addition polymerization cationic addition polymerization is catalyzed by strong acids. When the cyclic trimer trioxane is used as a copolymer to polymerize acetal copolymers, Lewis acids such as boron tiifluoride promote copolymerization. A more fundamental description is polymerization of an aldehyde or ketone -l- alcohol -i- an acid or base catalyst to form hemiac-etal, which further converts to acetal. The hemiacetal reaction is reversible to aldehyde and alcohol. 

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