Electron-Deficient Aldehydes

The observations that heteroaromatic amino compounds are not easily diazotized, are quite readily hydrolyzed,and often do not form Schiff bases with aldehydes have all been incorrectly interpreted as indications that these compounds exist principally in the imino form, whereas these observations can reasonably be attributed to the fact that the amino groups in compounds of the type of 4-aminopyridine are electron deficient as a result of the contribution of structures of type 36. ... 

The [ 2 + 4]-cycloaddition reaction of aldehydes and ketones with 1,3-dienes is a well-established synthetic procedure for the preparation of dihydropyrans which are attractive substrates for the synthesis of carbohydrates and other natural products [2]. Carbonyl compounds are usually of limited reactivity in cycloaddition reactions with dienes, because only electron-deficient carbonyl groups, as in glyoxy-lates, chloral, ketomalonate, 1,2,3-triketones, and related compounds, react with dienes which have electron-donating groups. The use of Lewis acids as catalysts for cycloaddition reactions of carbonyl compounds has, however, led to a new era for this class of reactions in synthetic organic chemistry. In particular, the application of chiral Lewis acid catalysts has provided new opportunities for enantioselec-tive cycloadditions of carbonyl compounds. 

This method is particnlarly useful for electron-deficient aromadc aldehydes, but it is not efficient v/ith aliphadc aldehydes, probably a consequence of compeddve aldol reacdon. 

Ally 1(trialky 1)- and allyl(triaryl)stannanes react with aldehydes and electron-deficient ketones on heating to give homoallylic alcohols48, although rather high temperatures are required. 2-Methylene-l,3-bis(tributylstannyl)propane is somewhat more reactive49-50, as are allyltin halides, which can be used in the presence of water51. 

The cyclization involves a nucleophilic attack of the malonic ester car-banion on the carbonyl carbon atom of the aldehyde, and the substituted malonic ester carbanion attacks the electron-deficient carbon atom bearing the iodine atom, or in the reverse order, to give 119. The hydroxyl group generated in the first step of the reaction attacks the carbon atom, giving the pyranose product. 

The intramolecular asymmetric Stetter reaction of aliphatic aldehydes is generally more difficult to achieve due to the presence of acidic a-protons. Rovis and co-workers have demonstrated that the NHC derived from pre-catalyst 130 promotes the intramolecular Stetter cyclisation with enoate and alkyhdene malonate Michael acceptors 133. Cyclopentanones are generally accessed in excellent yields and enantioselectivities, however cyclohexanones are obtained in significantly lower yields unless very electron-deficient Michael acceptors are employed... 

Cyclopentadienylindium(I) has been shown to be effective in the reaction with aldehydes or electron-deficient alkenes to form highly functionalized cyclopentadienes in aqueous media (See Section 8.4.3).101 This reaction with the appropriate substrates can be followed by an intramolecular Diels-Alder reaction in the same pot to provide complex tricyclic structures in a synthetically efficient manner (Scheme 12.4). 

The criss-cross addition of azines of aromatic aldehydes with various electron-deficient olefins in which the double bond is terminal, for example, methyl acrylate, acrylonitrile, or in which allylic substituents do not sterically hinder the reaction, for example, maleic anhydride, is well known and was duly covered in CHEC-II(1996)<1996CHEC-II(8)747>, as well as in a review <1997ALD97>. Recently, the reaction has been used for the preparation of hyperbranched polymers <1998MI2655, 2002MAC712>. 

Tandem reaction of aromatic aldehydes with electron-deficient acetylenes and dialkyl acetylenedicarboxylates in the presence of I it iN led to the formation of fully substituted furans in moderate yields. One appropriate example is shown below <06EJOC5174>. 

The quantum yields for oxetane formation have not been determined in every case, and only a few relative rate constants are known. The reactivities of singlet and triplet states of alkyl ketones are very nearly equal in attack on electron rich olefins. 72> However, acetone singlets are about an order of magnitude more reactive in nucleophilic attack on electron-deficient olefins. 61 > Oxetane formation is competitive with a-cleavage, hydrogen abstraction and energy-transfer reactions 60 64> so the absolute rates must be reasonably high. Aryl aldehydes and ketones add to olefins with lower quantum yields, 66> and 3n-n states are particularly unreactive. 76>... 

The Bulfington group [17] at Johnson and Johnson Pharmaceutical have also developed a very efficient and concise synthesis (Scheme 5) of the Furst-ner intermediate (6) to lukianol A. The synthesis relies on the condensation of benzyl nitriles with aromatic aldehydes under basic conditions to give the corresponding electron deficient alkenes (23). 

Azomethine ylides. The reaction of 1 with the oxime of an aldehyde results in an iminium salt 2. Desilylation of 2 (CsF) gives rise to an azomethine ylide (a) that undergoes 1,3-dipolar cycloaddition with electron-deficient alkenes (equation I). 

In addition to electron-deficient alkenes, under the catalysis of TiCLt, 1,2-allenylsi-lanes can react with aldehydes or N-acyliminium ion to afford five-membered vinylic silanes 71 and 72. Here the carbocations generated by a Lewis acid regiospecifically attack the C3 of the 1,2-allenylsilanes to produce a vinyl cation stabilized by hyper-... 

The base-catalysed Michael addition of a,/J-unsaturated nitro compounds 363 to electron-deficient olefins 364 (R4 = Ac, CC>2Me or CN) results in the formation of ally lie nitro compounds 365 aldehydes give alcohols 366 in this reaction409. 

Many reductive cyclizations, including many of those that are not initiated electrochemically, correspond to variations on the electrohydrocyclization theme. The so-called electroreductive-cyclization reaction, for example, involves cyclization between the /I-carbon of an electron-deficient alkene and an aldehyde or ketone tethered to it, to form a new a-bond between these formally electron deficient centers (Scheme 2). 

As noted previously, many of the cathodic cyclizations discussed in this article are variations on the electrohydrocyclization theme developed by Baizer and coworkers [8-14,16,17,21], The next section of this article, for example, deals with what has been referred to as the electroreductive cyclization (ERC) reaction, a process that leads to cycUzation between an electron-deficient alkene and an aldehyde or ketone. With this thought in mind, several of the section titles are formulated to highlight the functional groups to be joined the following is representative. 

The conjugate addition of organometallic reagents R M to an electron-deficient alkene under, for instance, copper catalysis conditions results in a stabilized car-banion that, upon protonation, affords the chiral yS-substituted product (Scheme 7.1, path a). Quenching of the anionic intermediate with an electrophile creates a disubstituted product with two new stereocenters (Scheme 1, path b). With a pro-chiral electrophile, such as an aldehyde, three new stereocenters can be formed in a tandem 1,4-addition-aldol process (Scheme 1, path c). 

S.3 Cytochrome P450 Model Compounds Functional. Ferric-peroxo species are part of the cytochrome P450 catalytic cycle as discussed previously in Section 7.4.4. For instance, these ferric-peroxo moieties are known to act as nucleophiles attacking aldehydic carbon atoms in oxidative deformylations to produce aromatic species.An example of this work, establishing the nucleophilic nature of [(porphyrin)Fe (02)] complexes, was achieved for alkene epoxidation reactions by J. S. Valentine and co-workers. The electron-deficient compound menadione (see Figure 7.18) yielded menadione epoxide when reacted with a [(porphyrin)Fe X02)] complex. 

The Baylis-Hillman reaction (Scheme 3) of ethyl vinyl ketone with electron-deficient aromatic aldehydes (e.g. where R = 0-NO2C6H4), in MeCN or EtCN solution, has been found to proceed enantioselectively in presence of catalytic base (32) derived from proline. The Michael adduct formed between the catalyst and the vinyl... 

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