Carbonyl compounds intermolecular

The selective intermolecular addition of two different ketones or aldehydes can sometimes be achieved without protection of the enol, because different carbonyl compounds behave differently. For example, attempts to condense acetaldehyde with benzophenone fail. Only self-condensation of acetaldehyde is observed, because the carbonyl group of benzophenone is not sufficiently electrophilic. With acetone instead of benzophenone only fi-hydroxyketones are formed in good yield, if the aldehyde is slowly added to the basic ketone solution. Aldols are not produced. This result can be generalized in the following way aldehydes have more reactive carbonyl groups than ketones, but enolates from ketones have a more nucleophilic carbon atom than enolates from aldehydes (G. Wittig, 1968). 

As was mentioned in Section 13.2, the [27t + 27i] photocycloaddition of alkenes is an allowed reaction according to orbital symmetry considerations. Among the most useful reactions in this categoty, from a synthetic point of view, are intramolecular [27t + 2ti] cycloadditions of dienes and intermolecular [2ti + 2ti] cycloadditions of alkenes with cyclic a, -unsaturated carbonyl compounds. These reactions will be discussed in more detail in Section 6.4 of Part B. 

Discovered more than a century ago, the Knorr and Paal-Knorr (PK) pyrrole syntheses are similar intermolecular condensations of amines with carbonyl compounds to give pyrroles. 

The intermolecular McMurry reaction is first of all a suitable method for the synthesis of symmetrical alkenes. With a mixture of carbonyl compounds as starting material, the yield is often poor. An exception to this being the coupling of diaryl ketones with other carbonyl compounds, where the mixed coupling product can be obtained in good yield. For example benzophenone and acetone (stoichiometric ratio 1 4) are coupled in 94% yield. ... 

A rather new concept in the context of domino radical cydizations has been developed by Gansauer and coworkers utilizing titanocene-complexes for the radical opening of unsaturated epoxides. The titanocene-catalyzed reactions [61] of 3-145 primarily led to radical 3-146, which underwent a subsequent intermolecular addition to a present a,(3-unsaturated carbonyl compound to form bicyclic carbocy-cles of type 3-148 via the intermediate 3-147 after aqueous work-up (Scheme 3.38) [62]. From a kinetic point of view, the reaction is remarkable since the intermolecular addition of simple radicals to a,(3-unsaturated carbonyl compounds is not an easy task, as highlighted above. 

Although a cobalt-catalyzed intermolecular reductive aldol reaction (generation of cobalt enolates by hydrometal-lation of acrylic acid derivatives and subsequent reactions with carbonyl compounds) was first described in 1989, low diastereoselectivity has been problematic.3 6 However, the intramolecular version of this process was found to show high diastereoselectivity (Equation (37)).377,377a 378 A Co(i)-Co(m) catalytic cycle is suggested on the basis of deuterium-labeling studies and the chemistry of Co(ll) complexes (Scheme 81). Cobalt(m) hydride 182, which is... 

For a review encompassing the intermolecular nickel-catalyzed reductive coupling of dienes to carbonyl compounds, see Tamaru, Y. /. Organomet. Chem. 1999, 576, 215-231. 

Although intermolecular additions to a,f5-unsaturated carbonyl compounds have not been used as often, these transformations are also attractive from a synthetic point of view for the synthesis of 5-lactones or 5-hydroxy esters. An example is shown in Scheme 12.11 [5d]. 

Scheme 12.11. Intermolecular addition to a,p-unsaturated carbonyl compounds.

Intermolecular coupling Many papers on hydrodimerization of aromatic carbonyl compounds have appeared indicating the importance of this reaction. The rac/meso ratio for the pinacolization of acetophenone in aqueous ethanol ranges between 0.9 and 1.4 in acidic medium and between 2.5 and 3.2 in basic medium. The diastereoselectivity is independent of the cathode material mercury, tin, or copper. Electrolysis conditions such as current density, potential, or current-controlled electrolysis also do not influence the diastereoselectivity. The same holds for propiophenone. For benzaldehyde, the rac/meso ratio is 1.1 to 1.2 in acidic as well as in basic media [283]. In the presence... 

Aldol reactions have also been used as a means of macrocychzation in total synthesis and were quite successful in some cases. However, over a broader spectrum of substrates, the results are unpredictable at best and yields and stereochemical outcome vary greatly. The predominant reasons are difficulties in selective enolate formation in multi-carbonyl compounds, competing and equilibrating retro-aldolizations—especially with polyketides, which often possess several aldol moieties—and intermolecular instead of intramolecular reaction preference. Whereas most of these drawbacks may be overcome, substrate-independent stereocontrol plays a crucial role. At least one new stereocenter is formed during a macroaldolization, and because of the folding constraints involved, its configuration cannot be adequately predicted. Therefore, this can be useful in special cases but with the current possibilities is not the method of choice for a general diversity-oriented synthesis. 

The ability to produce 1,3-dipoles, through the rhodium-catalyzed decomposition of diazo carbonyl compounds, provides unique opportunities for the accomplishment of a variety of cycloaddition reactions, in both an intra- and intermolecular sense. These transformations are often highly regio- and diastereoselective, making them extremely powerful tools for synthetic chemistry. This is exemplified in the number of applications of this chemistry to the construction of heterocyclic and natural-product ring systems. Future developments are likely to focus on the enantioselective and combinatorial variants of these reactions. 

It is difficult to obtain cross-coupling products of two different carbonyl compounds by an intermolecular version of the McMurry reaction. Examples that use excess amounts of one carbonyl component are few. "" When one carbonyl component is replaced by a 1,1-dihalo compound or dithioacetal and the alternative is reduced with a low-valent metal such as low-valent titanium or chromium(ii), cross-coupling products, that is, Wittig-type olefins, are produced in high yields. Because the alternative approach is described elsewhere, we concentrate on only its important features here. 

Cyclopropane formation occurs from reactions between diazo compounds and alkenes, catalyzed by a wide variety of transition-metal compounds [7-9], that involve the addition of a carbene entity to a C-C double bond. This transformation is stereospecific and generally occurs with electron-rich alkenes, including substituted olefins, dienes, and vinyl ethers, but not a,(J-unsaturated carbonyl compounds or nitriles [23,24], Relative reactivities portray a highly electrophilic intermediate and an early transition state for cyclopropanation reactions [15,25], accounting in part for the relative difficulty in controlling selectivity. For intermolecular reactions, the formation of geometrical isomers, regioisomers from reactions with dienes, and enantiomers must all be taken into account. 

Due to a partial 77-character, aromatic carbonyl compounds have an activation energy barrier for rotation around the phenyl-carbonyl bond, the value of which is substantially increased upon protonation.44 In para-anisaldehyde a second protonation of the methoxy group will drastically decrease their barrier. The temperature-dependent NMR spectrum will reflect both exchange processes, intra- and intermolecular, as shown in Scheme 1.1. 

Electrophilic ring closure of aryl-substituted compounds such as alkenes, halides, alcohols, and carbonyl compounds called cyclialkylation can be induced by conventional Friedel-Crafts catalysts309 and by superacids. Examples are also known in which an intermolecular alkylation step is followed by intramolecular alkylation of the intermediate to furnish a cyclic product. 

The intermolecular Mannich reaction combines an aldehyde, an amine and an enolizable carbonyl compound for the one-pot synthesis of yfi-amino ketones or... 

---