Addition of alcohols to ketenes

Much rarer than the inclusion of phenols is complex formation between alcohols and pyridinomacrocycles. In some combinations (selected macro-cycles and alcohols) complexes could be isolated (Weber and Vogtle, 1980). TTie hydrogen bond formation between pyridines and alcohols is the basis for an application, the additions of alcohols to ketenes catalysed by concave pyridines [13] (Liining et al., 1991b Schyja, 1995). 

Hodous BL, Ruble JC, Fu GC (1999) Enantioselective addition of alcohols to ketenes catalyzed by a planar-chiral azaferrocene catalytic asymmetric synthesis of arylpropionic acids. J Am Chem Soc 121 2637-2638... 

The selectivity studies show that concave pyridines 3 (Table 1) not only catalyze the addition of alcohols to ketenes, but they may also differentiate between different OH groups in inter- and intramolecular competitions. They are not only reactive but also selective. First experiments with a chiral concave 1,10-phenanthroline show that enantioselectivity is also possible [20]. Structure 9 shows the concave 1,10-phenanthroline 21 g which catalyzes the addition of R-1-phenylethanol (R-68) to diphenylketene (59a) 20% faster than the addition of the S-enantiomer S-68. 

Alcoholysis of nitriles, of ortho and thio ortho esters (transesterification), and of halides is the most common method of preparing the ortho ester functional groups (see Eqs. 2-7). A less practical method is the addition of alcohols to ketene acetals. The latter method is used only when the other methods are not found applicable to the synthesis of specially substituted mixed ortho esters. 

The addition of alcohols to ketene acetals allows the synthesis of mixed ortho esters [96, 120a-c, 121a, b, 124, 125a, b]. a-Haloaldehydes may be converted to ortho esters by the following process (a) acetal formation, (b) de-hydrohalogenation, and (c) reaction with alcohols via addition reaction (33). In general, the method above, using ketene acetals, is not practical since ketene acetals are not readily available and are difficult to prepare. However, the method is useful because it allows the synthesis of mixed ortho esters and other ortho esters more difficult to synthesize [122-127]. Recently a simple one-step synthesis of ketene acetals and ortho esters has been reported (see p. 56). 

SCHEME 1. Asymmetric addition of alcohols to ketenes catalyzed by chiral amines. 

Mixed substituted orthoesters, e.g. (383 equation 180), can be obtained by addition of alcohols to ketene 0,0-acetals. With the aid of phosphoranes containing a ketene O,(7-acetal structure, various orthoesters, e.g. (384) and (385) (Scheme 70) were prepared. " Cyclic orthoesters (386)-(390) (Scheme 71) are formed in cycloaddition reactions of ketene 0,0-acetals with aldehydes, ketones, 7.848 gj.yj cyanides, oxiranes, a-keto esters, o-diketones or ketones (with irradiation), a,3-unsaturated aldehydes and ketones (under pressure or catalyzed by ZnCh), diazoaceto-phenone, 7 diazoacetone and azodicarboxylate. ... 

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]. 

S. Petersen, U. Liining, Concave reagents, 28 comparison of bimacrocyclic, monomacrocyclic and non-macrocychc bis(amidomethyl)pyridines as catalysts in the base catalysed addition of alcohols to ketenes, Em. J. Org. Chem., 1999, 847-854. 

Pyridine is well known as a catalyst in organic reactions. However, in a large number of reactions, only pyridine is reactive, a-substitution diminishes the reaction rates considerably, because it hinders the reaction of pyridine as a nucleophile. The formation of hydrogen bonds to the nitrogen atom of a pyridine is also hindered by a-substitution but only if these substituents are huge (for example tert-butyl). Therefore, concave pyridines 1 also form hydrogen bonds, and they thus can be used, for instance, to enhance the nucleophilicity of hydroxyl groups. This has been exploited for the addition of alcohols to ketenes. and rate enhancements with several concave pyridines have been measured " (see Fig. 5. ... 

Tertiary phosphines are known to behave as Lewis bases in acylation reactions that proceed through a nucleophilic activation mechanism (see Section 4.06.7 for possible mechanisms operating in organocatalyzed polymerization). Their use as nucleophilic catalysts in enantioselective processes, which include the addition of alcohols to ketenes, the rearrangement of O-acylated azlactones, and the kinetic resolution of alcohols, is also well documented. " ... 

Scheme 3.17 Proposed mechanism for the enantioselective addition of alcohols to ketene...

Following this work, Fu et al. [21] reconsidered the catalytic addition of alcohols to ketenes by using planar-chiral DMAP derivatives in a Br0nsted acid/base catalysis process. In order to favor the protonation of the catalyst, a prerequisite for a Brpnsted acid/base pathway, the more acidic phenols were anployed. After having checked that phenol protonates DMAP 45c, different other phenols were reacted with ethylphenylketene 35b in the presence of chiral DMAP 45c (3 mol%) at room temperature in toluene. The best level of stereoselection was obtained with the more sterically hindered 2-ferf-butylphenol affording ester 50b in 91% ee. 

Scheme 3.24 M-heterocyclic caibenes (NHC) catalyzed enantioselective addition of alcohols to ketenes...

---