Electron deficient alkenes

Crowe proposed that benzylidene 6 would be stabilised, relative to alkylidene 8, by conjugation of the a-aryl substituent with the electron-rich metal-carbon bond. Formation of metallacyclobutane 10, rather than 9, should then be favoured by the smaller size and greater nucleophilicity of an incoming alkyl-substituted alkene. Electron-deficient alkyl-substituents would stabilise the competing alkylidene 8, leading to increased production of the self-metathesis product. The high trans selectivity observed was attributed to the greater stability of a fra s- ,p-disubstituted metallacyclobutane intermediate. 

The range of alkenes that may be used as substrates in these reactions is vast Suitable catalysts may be chosen to permit use of ordinary alkenes, electron deficient alkenes such as a,(3-unsaturated carbonyl compounds, and very electron rich alkenes such as enol ethers. These reactions are generally stereospecific, and they often exhibit syn stereoselectivity, as was also mentioned for the photochemical reactions earlier. Several optically active catalysts and several types of chiral auxiliaries contained in either the al-kene substrates or the diazo compounds have been studied in asymmetric cyclopropanation reactions, but diazocarbonyl compounds, rather than simple diazoalkanes, have been used in most of these studies. When more than one possible site of cyclopropanation exists, reactions of less highly substituted alkenes are often seen, whereas the photochemical reactions often occur predominantly at more highly substituted double bonds. However, the regioselectivity of the metal-catalyzed reactions can be very dependent upon the particular catalyst chosen for the reaction. 

The photoaddition of simple aldehydes and ketones to alkenes, electron-deficient alkenes, electron-rich alkenes, and carbohydrate-... 

Although simple isocyanates are not electrophilic enough to add to alkenes, electron-deficient isocyanates will add to alkenes. Chlorosulfonyl isocyanate is the most reactive and most commonly used isocyanate105-107. It undergoes stereospecific syn addition to alkenes. The carbonyl group adds to the most nucleophilic end of the double bond. The chlorosulfonyl group can be reductively hydrolyzed with sodium sulfite. Asymmetric induction will result from addition to... 

Toward this end, Caryn Kenny set out to investigate the scope and limitations of the process. Indeed, the reaction turned out to be quite versatile (Eqs. 4 and 5). Both p-keto esters and p-keto amides could be used as substrates. Unactivated alkenes, electron deficient alkenes, and alkynes all served as suitable ketyl acceptors under Sm(II)-promoted conditions. As anticipated, high diastereoselectivity over three stereocenters could be achieved. However, although five-membered rings could be formed with exceptional ease, in these systems virtually all attempts at forming six-membered rings met with disappointment. 

A major difficulty with the Diels-Alder reaction is its sensitivity to sterical hindrance. Tri- and tetrasubstituted olefins or dienes with bulky substituents at the terminal carbons react only very slowly. Therefore bicyclic compounds with polar reactions are more suitable for such target molecules, e.g. steroids. There exist, however, several exceptions, e. g. a reaction of a tetrasubstituted alkene with a 1,1-disubstituted diene to produce a cyclohexene intermediate containing three contiguous quaternary carbon atoms (S. Danishefsky, 1979). This reaction was assisted by large polarity differences between the electron rich diene and the electron deficient ene component. 

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. 

Hydroxy-THISs react with electron-deficient alkynes to give nonisol-able adducts that extrude carbonyl sulfide, affording pyrroles (23). Compound 16 (X = 0) seems particularly reactive (Scheme 16) (25). The cycloaddition to benzyne yields isoindoles in low- yield. Further cyclo-addition between isoindole and benzyne leads to an iminoanthracene as the main product (Scheme 17). The cycloadducts derived from electron-deficient alkenes are stable (23, 25) unless highly strained. Thus the two adducts, 18a (R = H, R = COOMe) and 18b (R = COOMe, R = H), formed from 7, both extrude furan and COS under the reaction conditions producing the pyrroles (19. R = H or COOMe) (Scheme 18). Similarly, the cycloadduct formed between 16 (X = 0) and dimethylfumarate... 

In the case of vinylfurans and vinylpyrroles there is the possibility of cycloaddition involving either the cyclic diene system or the diene system including the double bond. 2-Vinylfuran reacts in high yield with maleic anhydride in ether at room temperature to form the adduct involving the exocyclic double bond. Similarly, 2- and 3-vinylpyrroles react with 7T-electron-deficient alkenes and alkynes under relatively mild conditions to give the corresponding tetrahydro- and dihydro-indoles (Scheme 51) (80JOC4515). 

Intramolecular alkylnitrene addition to an alkenic moiety situated S,e to the electron deficient center has been utilized for the preparation of bi- and tri-cyclic aziridines (Scheme 11) (68JA1650). Oxidation of the primary alkylamine can be effected cleanly with NCS, LTA or mercury(II) oxide. 

Electron deficient carbon-carbon double bonds are resistant to attack by the electrophilic reagents of Section 5.05.4.2.2(t), and are usually converted to oxiranes by nucleophilic oxidants. The most widely used of these is the hydroperoxide ion (Scheme 79). Since epoxidation by hydroperoxide ion proceeds through an intermediate ct-carbonyl anion, the reaction of acyclic alkenes is not necessarily stereospecific (Scheme 80) (unlike the case of epoxidation with electrophilic agents (Section 5.05.4.2.2(f)) the stereochemical aspects of this and other epoxidations are reviewed at length in (B-73MI50500)). 

Seven procedures descnbe preparation of important synthesis intermediates A two-step procedure gives 2-(HYDROXYMETHYL)ALLYLTRIMETH-YLSILANE, a versatile bifunctional reagent As the acetate, it can be converted to a tnmethylenemethane-palladium complex (in situ) which undergoes [3 -(- 2] annulation reactions with electron-deficient alkenes A preparation of halide-free METHYLLITHIUM is included because the presence of lithium halide in the reagent sometimes complicates the analysis and use of methyllithium Commercial samples invariably contain a full molar equivalent of bromide or iodide AZLLENE IS a fundamental compound in organic chemistry, the preparation... 

Small shift values for CH or CHr protons may indicate cyclopropane units. Proton shifts distinguish between alkyne CH (generally Sh = 2.5 - 3.2), alkene CH (generally 4, = 4.5-6) and aro-matic/heteroaromatic CH (Sh = 6 - 9.5), and also between rr-electron-rich (pyrrole, fiiran, thiophene, 4/ = d - 7) and Tt-electron-deficient heteroaromatic compounds (pyridine, Sh= 7.5 - 9.5). 

In contrast to H shifts, C shifts cannot in general be used to distinguish between aromatic and heteroaromatic compounds on the one hand and alkenes on the other (Table 2.2). Cyclopropane carbon atoms stand out, however, by showing particularly small shifts in both the C and the H NMR spectra. By analogy with their proton resonances, the C chemical shifts of k electron-deficient heteroaromatics (pyridine type) are larger than those of k electron-rieh heteroaromatic rings (pyrrole type). 

As will be indicated when the mechanism is discussed in more detail, discrete carbocations may not be formed in all cases. An unsymmetrical alkene will nevertheless follow Markownikoff s rule, because the partial positive charge that develops will be located preferentially at the carbon that is better able to accommodate the electron deficiency, that is, the more substituted one. 

Reactions of fluorinated dipolarophiles. Electron-deficient unsaturated species generally make better dipolarophiles, therefore, fluonnated alkenes become better dipolarophiles when vinylic fluonnes are replaced by perfluoroalkyl groups For example, perfluoro-2-butene is unreactive with diazomethane, but more highly substituted perfluoroalkenes, such as perfluoro-2-methyl-2-pentene, undergo cycloadditions in high yields [5] (equation 2) Note the regiospecificity that IS observed in this reaction... 

The first example of a cyclization of fluorine-containing 5-hexenyl radicals was the study of the radical-iniOated cyclodimenzation reaction of 3,3,4,4-tetra-fluoro-4-iodo-1-butene. In this reaction, the intermediate free radical adds either to more of the butene or to an added unsaturated species [54, 55] (equation 56). Electron-deficient alkenes are not as effective trapping agents as electron-nch alkenes and alkynes [55]. 

Although hexafluoro-l,3-butadiene is better known for its [2+2] reactions, its Diels-Alder reactions, particularly with electron-deficient alkenes such as acrylonitrile and perfluoropropene, are not unknown [9] The first report of a Diels-Alder reaction is with an acetylenic dienophile Although the major product of Us reaction with phenylacetylene is its [2+2] adduct, a 3 5% yield of products of a Diels-Alder reaction is also observed [123] (equation 103)... 

Dipolar cydoadditions are one of the most useful synthetic methods to make stereochemically defined five-membered heterocydes. Although a variety of dia-stereoselective 1,3-dipolar cydoadditions have been well developed, enantioselec-tive versions are still limited [29]. Nitrones are important 1,3-dipoles that have been the target of catalyzed enantioselective reactions [66]. Three different approaches to catalyzed enantioselective reactions have been taken (1) activation of electron-defident alkenes by a chiral Lewis acid [23-26, 32-34, 67], (2) activation of nitrones in the reaction with ketene acetals [30, 31], and (3) coordination of both nitrones and allylic alcohols on a chiral catalyst [20]. Among these approaches, the dipole/HOMO-controlled reactions of electron-deficient alkenes are especially promising because a variety of combinations between chiral Lewis acids and electron-deficient alkenes have been well investigated in the study of catalyzed enantioselective Diels-Alder reactions. Enantioselectivities in catalyzed nitrone cydoadditions sometimes exceed 90% ee, but the efficiency of catalytic loading remains insufficient. 

The parent five-membered nitronate having no substituent at the 3-position was too unstable to be isolated. However, 3-substituted derivatives were highly stabilized. Especially, the 3-ethyl derivatives having a terminal electron-withdrawing substituent are readily available by the dehydrochlorination of 3-chloro-l-nitropropane in the presence of electron-deficient alkenes. It was our delight that the reaction of 3-al-kyl-substituted five-membered nitronates was also successfully catalyzed by R,R-DBFOX/Ph-Ni(SbFg)2 complex to at room temperature. This reaction was highly endo-selective (cisjtrans= 91 9) and enantioselective for the endo cycloadduct (92% ee). 

When electron-deficient alkenes are very rf triphenylphosphinerEq 4 105/ dre... 

In Table 4 1, the Michael addidon of nitto compounds to various electron deficient alkenes is shovm... 

AlkenyldQon using nitroalkanes foUowedby theselecQve reducQonof the double bends with NiCl and NdBbb, can be regarded as the addition of alkyl aruons to electron-deficient alkenes... 

Nitro compounds have been converted into various cyclic compounds via cycloaddidon reactions. In particular, nitroalkenes have proved to be nsefid in Diels-Alder reactions. Under thermal conditions, they behave as electron-deficient alkenes ind react v/ith dienes to yield 3-nitrocy-clohexenes. Nitroalkenes c in also act as heterodienes ind react v/ith olefins in the presence of Lewis acids to yield cyclic alkyl nkronates, which undergo [3- 2 cycloaddidon. Nitro compounds are precursors for nitnie oxides, alkyl nitronates, and trialkylsilyl nitronates, which undergo [3- 2 cycloaddldon reacdons. Thus, nitro compounds play important roles in the chemistry of cycloaddidon reacdons. In this chapter, recent developments of cycloaddinon chemistry of nitro compotmds and their derivadves are summarized. 

Nitroedianeundergoes base-catrilyzed addidon to to give3-hydroxy-l,3-dihydrofu]leryl ketoxime by way of a unique intramolecidar redox process, which is not observed in normal electron deficient alkenes fEq. S.77. " FSee Secdon 4.3 Michael addidon of nitroalkanes. ... 

Hetero Diels-Alder reacdons using nitroalkenes followed by 1,3-dipolar cycloaddidons provide a nsefid strategy for the constnicdon of polycychc heterocycles, which are found in naturM products. Denmark has coined the term tandem [4t-2 /[3t-2 cycloaddidon of nitroalkenes for this type of reacdon. The tandem [4-i-2 /[3-i-2 cycloaddidon can be classified into font famihes as shown in Scheme 8.31, where A and D mean an electron acceptor and electron donor, respecdvely. " In generril, electron-rich alkenes are favored as dienophdes in [4-i-2 cycloaddidons, whereas electron-deficient alkenes are preferred as dipolarophdes in [3-i-2 cycloaddidons. 

Isonitnle cyclizadon provides a useful altemadve method of the Knorr type cyclizadon for pyrrole synthesis. In 1972, Lensen and coworkers reported pyrrole synthesis based on the reacdon of tosylmeJhyl isocyanide (TosMICi with electron-deficient alkenes FEq. 10.12. ... 

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