Electrophilic Additions of Aldehydes

Electrophilic addition of aldehydes to [CpMo(CO)2(Tl -6-R-cyclohexadien-l-yl)] (R = H, Me, Ph) catalysed by boron trifluoride was reported to afford isolable (Tj -diene) cationic salts of molybdenum. Demetallation by trimethylamine-N-oxide afforded functionalised cyclohexadiene compounds in good yields. The stereochemistry of the carbon-carbon bond forming reaction was clarified. 

The condensation of 2,5-diunsubstituted pyrroles with formic acid20 is a viable method to produce porphyrins. However, the most common procedure21 22 involves the heating of the corresponding pyrroles 1 with aldehydes and aldehyde derivatives like imines or a Mannich reagent in the presence of acid. The reaction is initiated by electrophilic attack of the aldehyde (or aldehyde derivative) to the pyrrole 1. The formed (hydroxyalkyl)pyrrole 3 then undergoes electrophilic substitution with another pyrrole to form a dipyrrylmethane 4. Repeated addition of aldehyde and pyrrole finally forms a tetrameric (hydroxyalkyl)bilane 5. 

In addition to the results described, enantioselective access to 2-phosphino alcohols could be accomplished, too [71]. Starting from a borane-protected a-phosphino aldehyde hydrazone 91 as the key intermediate and available by two different approaches, the enantioselective synthesis of the desired 2-phosphino alcohols 93 could be accomplished. Thus, the electrophilic phosphinylation of aldehyde hydrazones 90 (via route I with the chlorodiphenylphosphine-borane adduct or via route II with chlorophosphines and subsequent phosphorus-boron bond formation) and the alkylation of phosphino acetaldehyde-SAMP hydrazones 92 (route III) was carried out (Scheme 1.1.26). 

Electrophilic addition of hydrogen halides to a,/f-unsaturated aldehydes and ketones places the halogen on the /3 carbon. This orientation is opposite to that observed for related additions to conjugated dienes ... 

Ar- 7/-Butoxycarbonyl-2-cyanopiperidines such as 277 undergo reductive decyanation-lithiation with lithium di- v/-butylbiphenylidc (LiDBB) to give a-lithiopiperidines which can then undergo addition of numerous electrophiles, to give 2-substituted piperidines. The addition of aldehydes and ketones results in formation of bicyclic carbamates such as 278. Transmetalation of the initial lithiate, with hexynylcopper, forms the cuprate which results in the formation of the 1,4-addition product 279 upon addition of enones, such as cyclohexenone, while the lithiate gives only 1,2-addition product 280 (Scheme 66) <2004OL2745>. 

Reactions of Enamines with Other Electrophilic Reagents Addition of aldehydes to enamines, followed by hydrolysis, leads to monoalkylidene and monoarylidene ketones (81).272 An example in which this reaction occurs intramolecularly is provided by the alkaloid ajmaline.273... 

Functional Group Transformation Alcohols can be prepared by nucleophilic substitution of alkyl halides, hydrolysis of esters, reduction of carboxylic acids or esters, reduction of aldehydes or ketones, electrophilic addition of alkenes, hydroboration of alkenes, or substitution of ethers. 

The Catalyzed Nucleophilic Addition of Aldehydes to Electrophilic Double Bonds... 

Stetter H, Kuhhnann H, Haese W (1987) The Stetter reaction 3-methyl-2-pentyl-2-cyclo-penten-l-one (dihydrojasmone) (2-cyclopenten-l-one, 3-methyl-2-pentyl-). Org Synth 65 26-31 Stetter H, Kuhhnann H (1991) The catalyzed nucleophilic addition of aldehydes to electrophilic double bonds. Org React 40 407 96... 

Stetter, H., Kuhimann, H. The catalyzed nucleophilic addition of aldehydes to electrophilic double bonds. Org. React. 1991,40, 407-496. 

It has long been known that unsymmetrical ketones can be prepared by the reaction of aldehydes with alkenes under free-radical reaction conditions. Recently the revision of this chemistry has been reported by the Roberts group [42], They introduced thiols as a polarity reversal catalyst for the addition of aldehydes to alkenes. Thiyl radicals are electrophilic, and therefore a polar Sh2 type transition state for the hydrogen transfer step from an aldehyde would be ideal in this situation. Indeed, the addition of aldehydes to a variety of alkenes can be effected by... 

Taillefer et al. have reported a one-pot method for the preparation of a, 3-unsaturated organophosphorus compounds through the reaction of lithium diphenylphosphonium diylides with phosphorus electrophiles and aldehydes. In the first step, treatment of diylides (91) with chlorodiphenylphosphine results in the formation of mono-ylide intermediates (92) and (93). Subsequent addition of aldehyde (94) produces either alkenes (95) or phosphines (96) (Scheme 22). The product obtained is critically dependent upon the nature of the ylide substituents and the aldehyde employed. For example, non-stabilised ylide (91a) reacts with chlorodiphenylphosphine and aromatic, heteroaromatic or enolisable aldehydes (94a-f) producing the corresponding phosphines (96), predominantly as the Z isomer. However, with 4-phenylcyclohexanone the only product obtained from (91a) is the alkene, (4-methylenecyclohex-l-yl)benzene. Non-stabilised ylide (91b) reacts with chlorodiphenylphosphine and benzaldehyde (94a) to give primarily alkene product whereas para-nitrobenzaldehyde (94c) yields only the phosphine product. Semi-stabilised ylide (91c), and stabilised ylide (91d), react... 

The above-mentioned effects of slow addition of the aldehydes on the enanti-oselection can be best explained as follows. Heterobimetallic catalysts such as LLB are believed to activate both nucleophiles and electrophiles. For the hydrophosphonylation of comparatively unreactive aldehydes the activated phosphite can react only with aldehydes which are pre-coordinated to lanthanum. However, in the case of reactive aldehydes such as benzaldehyde and cinnamaldehyde, the Li-activated phosphite may be able to undergo a competing reaction with the unactivated aldehyde. If such aldehydes are added in one portion, the ee of the product will be reduced. Slow addition of aldehyde,in contrast, has the effect of maximizing the ratio of activated to unactivated aldehyde present in solution, by allowing time for the catalytic cycle to complete and regenerate the catalyst, thereby facilitating aldehyde activation. Reactive aldehydes should, therefore, be added slowly in order to avoid the side reaction which proceeds without activation of the aldehyde by LLB (Scheme 19). 

Manganese(III) can oxidize carbonyl compounds and nitroalkanes to carboxy-methyl and nitromethyl radicals [186]. With Mn(III) as mediator, a tandem reaction consisting of an intermolecular radical addition followed by an intramolecular electrophilic aromatic substitution can be accomplished [186, 187). Further Mn(III)-mediated anodic additions of 1,3-dicarbonyl and l-keto-3-nitroalkyl compounds to alkenes and alkynes are reported in [110, 111, 188). Sorbic acid precursors have been obtained in larger scale and high current efficiency by a Mn(III)-mediated oxidation of acetic acid acetic anhydride in the presence of butadiene [189]. Also the nitromethylation of benzene can be performed in 78% yield with Mn(III) as electrocatalyst [190]. A N03 radical, generated by oxidation of a nitrate anion, can induce the 1,4-addition of aldehydes to activated olefins. NOj abstracts a hydrogen from the aldehyde to form an acyl radical, which undergoes addition to the olefin to afford a 1,4-diketone in 34-58% yield [191]. 

Electrophilic addition of the protonated aldehyde to the alkene yields a carbenium ion which reacts with water yielding a 1,3-diol 17. Acetal formation with another molecule of aldehyde affords the 1,3-dioxane 16. 

Electrophilic quench of aryllithium species with carbonyl electrophiles is particularly efficient. However, alkyl halides (other than iodomethane) are poor electrophiles, probably owing to competing elimination reactions (see Section 2.1). The formation of alkyl-substituted aromatic compounds can be achieved, however, by using epoxide electrophiles or by lithiation and reaction of 2-methylbenzamides, themselves generated by orr/ o-lithiation. For example, the benzamide 128 can be deprotonated at the benzylic position and treated with a variety of electrophiles. Addition of aromatic aldehydes gives, after lactonization, 3-aryl-3,4-dihydroisocoumarins (1.119). 

Actually the reaction formulated in equation (I) involves formation of lithium N,N-dimethylamide, which is a very strong base in HMPT. Electrophiles other than H can be used. Alkylating reagents can be used to form substituted nitriles (equation IV). 3-Hydroxy nitriles are obtained by addition of aldehydes... 

Alkylidenemalonates and malononitriles constitute another class of doubly activated olefins that can be used as highly electrophilic Michael acceptors in this reaction. For example, the Michael addition of aldehydes with these compounds has been reported to proceed with very good yields and enantioselectivities using 0-TMS diphenylprolinol 31a as catalyst (Scheme 2.29). On the other hand, the Michael addition of ketones to alkylidenemalonates has... 

---