Electron-Deficient Ketones

Some electron deficient dienophiles are quinones, maleic ahydride, nitroalkenes, a,p-unsaturated ketones, esters and nitriles. 

Electron-deficient alkenes add stereospecifically to 4-hydroxy-THISs with formation of endo-cycloadducts. Only with methylvinyl-ketone considerable amounts of the exo isomer are produced (Scheme 8) (16). The adducts (6) may extrude hydrogen sulfide on heating with methoxide producing 2-pyridones. The base is unnecessary with fumaronitrile adducts. The alternative elimination of isocyanate Or sulfur may be controlled using 7 as the dipolarenOphile. The cycloaddition produces two products, 8a (R = H, R = COOMe) and 8b (R = COOMe, R =H) (Scheme 9) (17). Pyrolysis of 8b leads to extrusion of furan and isocyanate to give a thiophene. The alternative S-elimi-nation can be effected by oxidation of the adduct and subsequent pyrolysis. 

The exploration of the chemistry of azirines has led to the discovery of several pyrrole syntheses. From a mechanistic viewpoint the simplest is based upon their ability to behave as a-amino ketone equivalents in reactions analogous to the Knorr pyrrole synthesis cf. Section 3.03.3.2.2), as illustrated in Schemes 91a and 91b for reactions with carbanions. Parallel reactions with enamines or a-keto phosphorus ylides can be effected with electron-deficient 2//-azirines (Scheme 91c). Conversely, electron-rich azirines react with electron deficient alkynes (Scheme 91d). 

Homolytic cleavage of dlazonlum salts to produce aryl radicals is induced by titan1um(III) salt, which is also effective in reducing the a-carbonylalkyl radical adduct to olefins, telotnerization of methyl vinyl ketone, and dimerization of the adduct radicals. The reaction can be used with other electron-deficient olefins, but telomerization or dimerization are important side reactions. 

The major difference in reactivity between CF3OF and FCIO3 lies in the capacity of the former to react with olefins without the benefit of an electron releasing group and even with electron deficient olefins such as a,y5-un-saturated ketones. Reactions with nonactivated double bonds indicate the presence of an oc-fluoro cationic intermediate [e.g., (64)] as exemplified by the reaction with the -3-ketone (63), which yields the fluorophenol (65). 

Perfluorinated carbonyl compounds, especially hexafluoroacetone, are highly electron-deficient species and react vigorously with a wide variety of HX nucleophiles The reaction of these ketones and of most polyfluonnated imines toward nucleophiles can be generahzed by the scheme shown m equation 1... 

Four-membered heterocycles are easily formed via [2-I-2] cycloaddition reac tions [65] These cycloaddmon reactions normally represent multistep processes with dipolar or biradical intermediates The fact that heterocumulenes, like isocyanates, react with electron-deficient C=X systems is well-known [116] Via this route, (1 lactones are formed on addition of ketene derivatives to hexafluoroacetone [117, 118] The presence of a trifluoromethyl group adjacent to the C=N bond in quinoxalines, 1,4-benzoxazin-2-ones, l,2,4-triazm-5-ones, and l,2,4-tnazin-3,5-diones accelerates [2-I-2] photocycloaddition processes with ketenes and allenes [106] to yield the corresponding azetidine derivatives Starting from olefins, fluonnaied oxetanes are formed thermally and photochemically [119, 120] The reaction of 5//-l,2-azaphospholes with fluonnated ketones leads to [2-i-2j cycloadducts [121] (equation 27)... 

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. 

Alttmina-supported KF is an effecdve reagent for Michael addidon of nitroalkanes to electron-deficient olefins. Subsequent cycloalkyladons afford cyclopropanes.However, the reacdo n of a,fi-ttnsantrated ketones v/ithnitroalkanesin the presence of KF-A1,0 in acetonitrile gives 4,5-dihydrofliranes fEq. 7.39. ... 

Since equatorial attack is roughly antiperiplanar to two C-C bonds of the cyclic ketone, an extended hypothesis of antiperiplanar attack was proposed39. Since the incipient bond is intrinsically electron deficient, the attack of a nucleophile occurs anti to the best electron-donor bond, with the electron-donor order C—S > C —H > C —C > C—N > C—O. The transition state-stabilizing donor- acceptor interactions are assumed to be more important for the stereochemical outcome of nucleophilic addition reactions than the torsional and steric effects suggested by Felkin. 

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 Homer - Emmons reagent (52) is effective in the one carbon homologation of ketones possessing acidic a-hydrogen atoms <96SL875> and electron-deficient alkenes add to 2-phenylseleno-l,3-dithiane in a photo-initiated heteroatom stabilised radical atom transfer process, giving products of considerable synthetic potential <96TL2743>. 

The per acid first adds to the ketone to give adduct (30) which rearranges via a transition state (31) which is electron-deficient around the former carbonyl group. Consequently,the group which can best supply electrons to combat the deficiency migrates best. It does so with retention as it is a one step reaction in which the chiral centre ( in 30) never becomes detached. 

To explain the stereochemistry of the photoaddition, Buchi proposed that the reaction of electron-rich olefins and excited ketone involves an interaction of the electron-deficient carbonyl lone-pair orbital with the electron-rich 7r-olefin orbitals to form a diradical intermediate which could subsequently close to give the observed products. Indeed, reaction to yield the most stable diradical intermediate usually does nicely rationalize the observed product distribution. Examples of this are as follows11005 ... 

Catalytic enantioselective nucleophilic addition of nitroalkanes to electron-deficient alke-nes is a challenging area in organic synthesis. The use of cinchona alkaloids as chiral catalysts has been studied for many years. Asymmetric induction in the Michael addition of nitroalkanes to enones has been carried out with various chiral bases. Wynberg and coworkers have used various alkaloids and their derivatives, but the enantiomeric excess (ee) is generally low (up to 20%).199 The Michael addition of methyl vinyl ketone to 2-nitrocycloalkanes catalyzed by the cinchona alkaloid cinchonine affords adducts in high yields in up to 60% ee (Eq. 4.137).200... 

Alumina-supported KF is an effective reagent for Michael addition of nitroalkanes to electron-deficient olefins. Subsequent cycloalkylations afford cyclopropanes.37 However, the reaction of a, 3-unsaturated ketones with nitroalkanes in the presence of KF-A1203 in acetonitrile gives 4,5-dihydrofuranes (Eq. 7.39).40... 

Trapping experiments with electron deficient olefins such as acrylonitrile and 3-buten-2-one gave the expected 1,4-adducts from the proposed acylnickel intermediates. This provides strong support for the proposed mechanism. It was also demonstrated that allylic, vinylic and pentafluorophenyl halides could be cross-coupled with acid chlorides to give the corresponding ketones in good yields. 

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>... 

In the presence of Bu OK, (benzotriazole-l-yl)methyl isocyanide (BetMIC) 697 undergoes alkylation on the methylene group to give isocyanide 698. The anion derived from 698, upon its treatment with Bu OK, adds to the electron-deficient double bonds of ajl-unsaturated ketones, esters or nitriles to produce pyrroles 699. A similar reaction of isocyanide 698 with Schiff bases provides imidazoles 700. In both cases, use of unsubstituted isonitriles 697 in the reactions leads to heterocycles 699 and 700 with R1 = H (Scheme 108) <1997H(44)67>. 

Aldol-type reactions of nitrones (303) occur with electron-deficient ketones, such as a-keto esters, a, 3-diketones, and trifluoromethyl ketones. These reactions are catalyzed by secondary amines. The use of chiral cyclic amines A1-A7 leads to a-(2-hydroxyalkyl)nitrones (304) in moderate yields and rather high optical purity (Scheme 2.120) (381). The mechanism of the nitrone-aldol reaction of iV-methyl-C-ethyl nitrone with dimethyl ketomalonate in the absence and presence of L- proline has been studied by using density functional theory (DFT) (544). 

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