Aldehydes intermolecular additions

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). 

All the examples presented under Sect. 4.1 used an iodine atom transfer to generate the desired radicals. Another approach involving abstraction of hydrogen atom is also reported. For instance, ethers and acetals undergo direct intermolecular addition to aldehydes under treatment with Et3B/air... 

In a related paper, Scheldt and co-workers described a stereoselective formal [3 + 3] cycloaddition catalyzed by imidazolinylidine catalyst 256 Eq. 25 [130]. Ultimately this is an intermolecular addition of the homoenolate intermediate to an azomethine ylide followed by intramolecular acylation and presumably follows the same mechanistic path as described previously. Pyridazinones are obtained as single diastereomers in good to high yield from a number of aldehydes. Unfortunately no reaction occurs with the presence of electron-withdrawing groups on the aryl ring of the enal. 

Padwa and Dehm62 have prepared furanones (36) by reaction of carbox-ylates with bromo aldehydes, catalyzed by 18-crown-6. The first step of the reaction is also an esterification of the potassium phenylacetate the next step is equivalent to an intermolecular addition of a carbanion to an aldehyde, followed by elimination. 

Intermolecular addition and addition-cyclization reactions of aminium cation radicals with electron-rich alkenes such as ethyl vinyl ether (EVE) allow an entry into products containing the N—C—C—O moiety of 13-amino ethers 70 or the equivalent of /3-amino aldehydes 71. The mild conditions under which aminium cation radicals are generated from PTOC carbamates makes the reactions described in Scheme 22 possible. In the absence of hydrogen atom donors, the /3-amino ethoxy(2-pyridylthio) acetal 71 was the major product. The mixed acetal can easily be converted... 

A more recent study reached a similar conclusion [78]. It was found that cycliza-tions of (Z)- and ( )-3-phenyl-8-tributylstannyl-6-octenal were highly diastereoselec-tive (Fig. 17). The (Z) isomer yielded cis, fra/js-3-phenyl-2-vinylcyclohexanol as the major product (96 4) whereas the (E) isomer afforded the trans, trans isomer (95 5). A favorable HOMO-LUMO interaction was proposed as a decisive factor in stabilizing the favored synclinal transition states. This stabilization is lacking in the alternative synclinal and antiperiplanar transition states, neither of which has the correct geometry for orbital overlap. As in the previous study, the aldehyde and double bond substituents (asterisked carbons in Fig. 17) are unable to attain an anti orientation in the antiperiplanar transition states, as has been proposed for the intermolecular additions. 

Stereochemistry of addition reactions involving allylsilanes 23.4.12 Intermolecular additions to aldehydes, ketones and acetals... 

Usefiil levels of stereoselectivity were obtained in intermolecular addition reactions of C(3)-sub-stituted allylsilanes to chiral aldehydes. Lewis acids that are citable of chelating to heteroatoms have been used to direct the stereochemical course of allylsilane additions to a-alkoxy and a,p-dialkoxy carbonyl compounds. The allylation of a-benzyloxy iddehyde (94) in the presence of TiG4 and SnOt furnished products with high levels of syn stereoselection (syn-9. In contrast, under nonchelation-controlled reaction conditions (BF3-OEt2) allyltrimethylsilane reacted to form predonunantly the anti-1,2-diol product (anti-95), as shown in Scheme 45. 

These results do not provide suitable models or predictions for the intermolecular addition of 2-butenylstannanes to aldehydes. The -2-butenylstannanes generally provide higher levels of stereoselectivity than the corresponding Z-2-butenylstan-nanes in intermolecular reactions. However, the hypothesis of secondary orbital overlap influencing stereoselectivity could also be applied to the intermolecular reactions. 

Intramolecular transition metal-catalyzed hydro acylation reactions have opened up a new area of synthesizing cyclic ketones. This reaction can also be extended to intermolecular addition reactions. Miller et al. found the first example of an intermolecular hydroacylation of an aldehyde with an olefin giving ketones, when they were studying the mechanism of the rhodium-catalyzed intramolecular cyclization of 4-pentenal using ethylene-saturated chloroform as the solvent (Eqs.46,50) [112]. 

Few examples of what might be described as an intermolecular coupling reaction on inactivated alkenes has appeared [62], Thus ketyl radicals generated from aromatic aldehydes and ketones underwent intermolecular addition to the para position of another aldehyde. Cross-coupling reactions are not feasible in these systems and typically yields are quite low. 

Alkylation of the enolate of (138) with methallyliodide gave the product (149) whose stereochemistry was assigned on the basis of equilibration experiment. It was converted to the dione (150) by oxidation with osmium tetrooxide and sodiumperiodate. The aldol cyclization of (150) effected with sodium hydride and trace of t-amyl alcohol in refluxing benzene afforded the enone (151) in 88% yield. Normal protic conditions (sodium hydroxide, ethanol) were not effective in this transformation. All attempts for its conversion to aphidicolin (148) by intermolecular additions proved fruitless and therefore were turned to intramolecular methods. Molecular models show clearly that the top face of the carbonyl group is less hindered to nucleophilic attack than is the bottom face. Thus the reduction of (151) with lithium aluminium hydride afforded the alcohol (152) whose vinyl ether (153) was subjected to pyrolysis for 2 hr at 360 C in toluene solution containing a small amount of sodium t-pentoxide to obtain the aldehyde (154) in 69% yield. Reduction and then tosylation afforded the alcohol (155) and tosylate (156) respectively. Treatment of this tosylate with Collman s reagent [67] (a reaction that failed in the model system) afforded the already reported ketoacetonide (145) whose conversion to aphidicolin (148) has been described in "Fig (12)". 

Lewis acid complexes of p-substituted a,p-unsaturated ketones and aldehydes are unreactive toward alkenes. Crotonaldehyde and 3-penten-2-one can not be induced to undergo ene reactions as acrolein and MVK do. 34 The presence of a substituent on the p-carbon stabilizes the enal- or enone-Lewis acid complex and sterically retards the approach of an alkene to the p-carbon. However, we have found that a complex of these ketones and aldehydes with 2 equivalents of EtAlQ2 reacts reversibly with alkenes to give a zwitterion. 34 This zwitterion, which is formed in the absence of a nucleophile, reacts reversibly to give a cyclobutane or undergoes two 1,2-hydride or alkyl shifts to irreversibly generate a p,p-disubstituted-o,p-unsaturated carbonyl compound (see Figure 19). The intermolecular addition of an enone, as an electrophile, to an alkene has been observed only rarely. The specific termination of the reaction by a series of alkyl and hydride shifts is also very unusual. 35 The absence of polymer is remarkable. 

The annual industrial production volume of aldehydes and their downstream products (alcohols, carboxylic acids, esters, plasticizers, detergents, surfactants, lubricants, fuel additives, solvents, fine chemical intermediates, etc.) is rather impressive. Between 9 and 10 million tons of aldehydes are produced worldwide. Over 5 million tons just of C oxo products per year come from chemical industry s hydroformylation plants. In the light of today s discussion about sustainability issues of chemical synthesis, the atom economy of the oxo process as a (formally) waste-free intermolecular addition reaction of three molecular components is well worth mentioning. 

Intermolecular addition of aldehydes and ketones to 1,6-enynes is also feasible. 1,6-Enynes with a tenninaUy monosubstituted alkene 1-9 react with carbonyl compounds to give tricychc derivatives of type I-IO with a highly diastereose-lective control (Scheme 2.3) [Ref. 229 in Chap. 1]. The reaction proceeds with complete diastereoselectivity with respect to the stereogenic centers Cla, C3, C3a, and C6a. 

Fig. 2.2 Products of the intermolecular addition of different aldehydes and ketones to 1,6-enynes 1-9...

Despite significant research into new chiral carbene catalysts, few improvements in the direct asymmetric intermolecular addition of aldehydes to activated olefins have been possible. An innovative alternative was reported by Johnson and co-workers, who showed that chiral metallophosphite 31 could catalyze an asymmetric sila-Stetter reaction with high enantioselectivity. Due to the absence of a silyl scavenger, catalyst turnover occurs by a [l,4]-retro-Brook reaction, and the initially isolated a-silylamide product is recrystallized to improve the enantiomeric purity from 90 to 99% ee. Desilylation completes the three-step procedure to give y-ketoamide 32 in good yield and excellent enantiomeric purity. The reaction... 

Enamine-intermolecular Addition Cascades It was suggested that the intermediate y-nitroaldehyde 91 in Scheme 1.31 might react with an aldehyde via an oxo-Henry sequence, and subsequent hemiacetalization would provide tetrahydropy-ran derivatives. Uehara et al. [50] and Iskikawa et al. [51] realized this hypothesis independently through a four-component reaction in one pot to furnish highly substituted tetrahydropyran derivatives 102 with excellent diastereo- and enantioselec-tivity (up to 98 2 dr and 99% ee) (Scheme 1.35). These two methods are complementary because anti-Michael products were synthesized using catalyst 101 [50], while syn-Michael products were obtained with diphenylprolinol silyl ether catalyst 34 [51]. 

Stereoselectivity can also be imposed on intermolecular additions of lithium acetylides onto aldehydes (Scheme 1-155). Thus, (/ )- -(trimethylsilyl)undec-l-yn-3-ol is formed in 83% yield and with 80% ee when the reaction is carried out in the presence of the proline-derived (25, 2 5)-2-hydroxymethyl-1 -[(1 -methylpyrrolidin-2-yl)methyl-pyrrolidine (212). ... 

The elaboration of the polyunsaturated side chain of asteltoxin requires a stereoselective coupling of aldehyde 2 with a suitable synthetic equivalent for the anion of 4-formyl-1,3-butadiene (see intermediate 3 in Scheme 4). Acid-induced skeletal reorganization of the aldehyde addition product, followed by an intermolecular... 

The values of x = 0.5 and = 1 for the kinetic orders in acetone [1] and aldehyde [2] are not trae kinetic orders for this reaction. Rather, these values represent the power-law compromise for a catalytic reaction with a more complex catalytic rate law that corresponds to the proposed steady-state catalytic cycle shown in Scheme 50.3. In the generally accepted mechanism for the intermolecular direct aldol reaction, proline reacts with the ketone substrate to form an enamine, which then attacks the aldehyde substrate." A reaction exhibiting saturation kinetics in [1] and rate-limiting addition of [2] can show apparent power law kinetics with both x and y exhibiting orders between zero and one. 

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