Aldol trimerization

Lawrence T. Scott, from Boston College, Chestnut Hill, Massachusetts, has been possibly the most successful chemist on the trail of the construction of C60 fragments, as illustrated in particular by his recent success in the synthesis of C60 [91]. His chapter (No. 1), prepared together with his co-author M. M. Boorum, deals with the synthesis of C60 fragments, namely tris-annulated benzenes by aldol trimerization of cyclic ketones. 

The Synthesis of Tris-Annulated Benzenes by Aldol Trimerization of Cyclic Ketones... 

For the synthesis of tris-annulated benzene rings, the aldol trimerization of cyclic ketones has been known as a powerful tool since the 19 century. Why the reaction works so well with some ketones (e.g., indanone) but fails so miserably with others (e.g., tetralone), however, has never been adequately explained. This chapter outlines the development and scrutiny of a hypothesis that says formation of an a,/ -unsaturated (conjugated) dimer from a cyclic ketone is vital to the success of an aldol trimerization reaction for the synthesis of a tris-annulated benzene the reaction will fail with ketones that form only / ,y-unsaturated (unconjugated) dimers. This hypothesis unifies much experimental chemistry and is supported by theoretical calculations. 

Fig. 1. Generalized synthesis of a tris-annulated benzene by aldol trimerization of a cyclic ketone.

The first thorough investigation of an aldol trimerization to produce a tris-annulated benzene ring from three cyclic ketone monomer units was performed over 100 years ago. It focused on the conversion of hydrindone (1, a compound known today as 1-indanone) to truxene (2) (Figure 2). 

Fig. 6. Mechanism for the acid-catalyzed aldol trimerization ofl-indanone (1) to truxene (2).

Truxene and truxone were the first members of what is now a large family of tris-annulated benzenes that have been synthesized by aldol trimerizations of cyclic ketones during the past 125 years. Table 1 provides some additional representative examples [6, 10, 21-29]. 

It is equally noteworthy that both aliphatic and aromatic ketones undergo the aldol trimerization reaction. 

Finally, as one might expect, aldol trimerizations that lead to sterically crowded products generally fail or give the trimer only in modest yield (e.g., 21 and 27, the quoted yields for which represent optimized values). The high degree of regioselectivity seen in the trimeri-... 

We have performed single-point energy calculations, using density functional theory with AMI optimized geometries (pBP/DN //AMl) [31], on many of the ketones discussed above that are known to give tris-annulated benzenes by the aldol trimerization reaction (1, 5, 8,10, 22, 24, 26, and 28). In agreement with our hypothesis, the a,y -unsaturated aldol dimer is calculated to be more stable than the //,y-unsa turated isomer in every case, sometimes by as much as 10 kcal mol-1 or more. In those cases in which the a,y -unsaturated aldol dimer can adopt either an E- or a Z-configuration, the more stable of the two was used for the comparison. 

Fig. 9. Aldol trimerization of 6-chloro-5-acephenanthrenone (39) to form a tris-annulated benzene. This behavior contrasts sharply with that of the closely related 6-chloro-4-acephenanthrenone (36) in Figure 7.

Side reactions of the product aldehydes to form heavier products generally occur, particularly at higher-reaction temperatures, and usually account for s 9% of the product distribution. Aldol condensations, aldols, trimerizations, and Guerbet dimerizations of product alcohols are some of the more common ways to form heavy by-products. These side reactions are common to varying extents for all long-term... 

In addition to ketones, aldehydes can also be used as aldol donors in pro-line-catalyzed reactions [144]. Barbas et al. found that treating acetaldehyde solutions tvith proline provided aldehyde 185, an aldol trimer of acetaldehyde, in 84% ee and 4% yield (Scheme 4.42, Eq. (1)) [145, 146]. As shotvn by Jorgensen et al., other simple a-unbranched aldehydes can also be used as donors in proline-catalyzed cross aldolization tvith activated non-enolizable ketone acceptors to give aldols 188 in high enantioselectivity and yield (Scheme 4.42, Eq. (2)) [147]. 

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