Electron-withdrawing groups cycloaddition

For more reactive electrophilic alkenes possessing two or more electron-withdrawing groups, cycloadditions with enamines occur under mild conditions. The cycloadditions of A,A -dimethyl-2-methylprop-1-enamine (12) with a series of electrophilic alkenes 13 proceed at temperatures ranging from — 30 °C to room temperature in short reaction times to give good to very good yields of the aminocyclobutanes 14.30... 

The reactions of electrophilic alkenes (alkenes attached to electron-withdrawing groups) with enamines produce one or more of the following products simple alkylation (2), 1,2 cycloaddition (3), and 1,4 cycloaddition (4). Competition with C alkylation by N alkylation is inconsequential and therefore will be largely ignored (5,7). A stepwise ionic mechanism leading to these products necessarily involves the formation of a zwitterion intermediate (1) as the first step, which is then followed either by one of the... 

Olefins conjugated with electron-withdrawing groups other than a carbonyl group undergo reactions with enamines in a manner similar to the carbonyl-conjugated electrophilic alkenes described above. Namely, they condense with an enamine to form a zwitterion intermediate from which either 1,2 cycloaddition to form a cyclobutane ring or simple alkylation can take place. 

Terminal alkynes with no electron-withdrawing group next to the acetylenic linkage when treated with enamines merely add across the double bonds of the enamines (9i). But electrophilic alkynes (those with an electron-withdrawing group next to the acetylenic linkage) undergo cycloaddition reactions with enamines. 

A -Alkyl-l,2-dihydropyridines that are not stabilized by electron-withdrawing groups on the ring could behave as dienophiles towards alkynes. For example, N-methyl-l,2-dihydropyridine 41a reacts with dimethyl acetylenedicarboxylate (32) to give [2 + 2] cycloaddition product 42, which rearranges to give the azocine derivative 43 [74JCS(P1)2496],... 

Placing an electron-withdrawing group on the carbon atom of the imine also increases its reactivity toward TMM cycloaddition. Glyoxalate imine (90, R=H) and... 

Dienophile (Section 14.5) A compound containing a double bond that can take part in the Diels-Alder cycloaddition reaction. The most reactive dienophiles are those that have electron-withdrawing groups on the double bond. 

The reaction of several substituted imidazo[4,5-c/]-, pyrazolo[3,4-r/]- and triazolo[4,5-zf]pyrid-azines 3 with ynamines, in competition with [4 + 2] cycloaddition, leads to [2 + 2] derivatives 4, which rearrange to l,2-diazocines5.7 8 The reaction seems to be sensitive to the substituents, as replacement of the electron-withdrawing group R on the pyridazine ring of the pyrazolo compound (A = N, B = CH) by chlorine completely inhibits both the [4 + 2] and [2 + 2] cycloaddition reactions. The X-ray structure of the imidazo derivative 5 (R = Ms, A = CH, B = N) reveals a tub conformation of the eight-membered ring. 

The best known of metal carbene reactions, cydopropanation reactions, have been used since the earliest days of diazo chemistry for addition reactions to the carbon-carbon double bond. Electron-donating groups (EDG) on the carbon-carbon double bond facilitate this catalytic reaction [37], whereas electron-withdrawing groups (EWG) inhibit addition while facilitating noncatalytic dipolar cycloaddition of the diazo compound [39] (Scheme 5). There are several reviews that describe the earlier synthetic approaches [1, 2,4, 5,40-43], and these will not be duplicated here. Focus will be given in this review to control of stereoselectivity. 

Thioazadienes 90, formed in situ by the reaction of trimethylsilylimines and isothiocyanates, underwent cycloaddition reactions with nitriles bearing electron-withdrawing groups, to afford 1,3,5-thiadiazines [94] in excellent yield (Equation 2.26). 

When electron-withdrawing groups are introduced at the vinyl moiety, ary-lethenes may behave as dienophiles. Thus a-trifluoromethyl styrene (111) interacted with Danishefsky s diene (12b) under thermal or high pressure conditions [37] to regioselectively afford a 1 1 mixture of cycloadducts which were then converted to 4-phenyl-4-trifluoromethyl-2-cyclohexen-l-one (112) (Equation 5.12). A direct access to angularly trifluoromethyl-substituted tricyclic compounds may be achieved by cycloaddition of the l-trifluoromethyl-3,4-di-hydronaphthalene (113) with diene 12b (Equation 5.13). 

If an aliphatic amino group is next to an electron-withdrawing group such as CO2R, CN, CHO, COR and has a hydrogen, reaction with aqueous nitrous acid gives a diazo compound (Eq. 11.4). Such compounds are used widely in 1,3-dipolar cycloaddition reactions, which will be covered in Chapter 12. 

In the Diels-Alder reaction with inverse electron demand, the overlap of the LUMO of the 1-oxa-l,3-butadiene with the HOMO of the dienophile is dominant. Since the electron-withdrawing group at the oxabutadiene at the 3-position lowers its LUMO dramatically, the cycloaddition as well as the condensation usually take place at room or slightly elevated temperature. There is actually no restriction for the aldehydes. Thus, aromatic, heteroaromatic, saturated aliphatic and unsaturated aliphatic aldehydes may be used. For example, a-oxocarbocylic esters or 1,2-dike-tones for instance have been employed as ketones. Furthermore, 1,3-dicarbonyl compounds cyclic and acyclic substances such as Meldmm s acid, barbituric acid and derivates, coumarins, any type of cycloalkane-1,3-dione, (1-ketoesters, and 1,3-diones as well as their phosphorus, nitrogen and sulfur analogues, can also be ap-... 

A few examples of cycloadditions between nitroalkenes and vinyl ethers without the use of Lewis acids have been reported (Eq. 8.105), in which additional activating electron-withdrawing groups are generally required.161... 

Table 22. Regioselectivity of the cycloadditions of nitrone 256 to alkylidenecyclopropanes substituted with phenyl, electron-releasing and electron-withdrawing groups [67,68]...

The vinylcyclopropane 144, bearing two electron-withdrawing groups, undergoes the intermolecular palladium-catalyzed [3 + 2]cycloaddition reaction of the Jt-allylpalladium intermediate 145 with a,/ -unsaturated esters or ketones to provide a useful method for forming the cyclopentane ring of 146 [74], (Scheme 51)... 

Figure 17.1 A general Diels-Alder reaction consists of a 4 + 2 cycloaddition between a diene and an alkene, often called a dienophile. The reaction rate and yield increase if the diene contains an electron-donating group and the alkene contains an electron-withdrawing group.

As mentioned in chapter 4.2.3, aliphatic imines are photochemically rather unreactive. When the C—N double bond is conjugated to an electron withdrawing group (e.g. carbonyl group), as in O-alkyl derivatives of succinimide and phthalimide, the reactivity increases and azetidines are obtained in cycloadditions to olefins486). A somehow similar example is the photoaddition of a 6-azauracil derivative to 2,3-dimethyl-2-butene... 

An electron-withdrawing group on the alkenyl double bond has been shown to greatly facilitate the Diels-Alder cycloaddition with furan as depicted below < 00TL9387>. 

The cycloaddition-isomerization procedure can be accomplished in the presence of a catalytic amount of a transition metal salt. The reactions proceed at room temperature, neither air nor water needed to be excluded. The presence of an electron-withdrawing group is not necessary to activate the dienophile as the example below shows that gold coordination increases the electrophilicity of the triple bond. The presence of a terminal alkyne should also be important. In the case of a disubstituted alkyne no reaction can be observed <00JA11553>. 

A common method to synthesize pyridazines remains the inverse electron-demand Diels-Alder cycloaddition of 1,2,4,5-tetrazines with electron rich dienophiles. [4 + 2]-Cycloadditions of disubstituted 1,2,4,5-tetrazine 152 with butyl vinyl ether, acrylamide, phenylacetylene, and some enamines were performed to obtain fully substituted pyridazines 153 . This reaction was accelerated by electron withdrawing groups, and is slowed by electron donating groups, R1 and R2on the tetrazine. 

The asymmetric 1,3-dipolar cycloaddition of nitrones (515), possessing an electron-withdrawing group, to allylic alcohols was achieved by using diisopropyl (/ ,/ )-tartrate [(R,R-DIPT)] as a chiral auxiliary. The isoxazolidines (516) and... 

Using a stoichiometric amount of (i ,i )-DIPT as the chiral auxiliary, optically active 2-isoxazolines can be obtained via asymmetric 1,3-dipolar addition of achiral allylic alcohols with nitrile oxides or nitrones bearing an electron-withdrawing group (Scheme 5-53).86a Furthermore, the catalytic 1,3-dipolar cycloaddition of nitrile oxide has been achieved by adding a small amount of 1,4-dioxane (Scheme 5-53, Eq. 3).86b The presence of ethereal compounds such as 1,4-dioxane is crucial for the reproducibly higher stereoselectivity. 

Dipolar species have been observed in the cycloaddition of polar intermediates. Thus cyclobutanes can be formed by non concerted processes involving zwitter ionic intermediates. The combination of an electron rich alkene (enamimes, enol ethers) and an alkene having electron withdrawing groups (nitro a cyano substituted alkenes) first gives a zwitter ion which can rotate about the newly formed bond before cyclization and gives both a cis and a trans adduct. 

Niggli and Neuenschwander294 studied the reaction of fulvene (461) with cyclopen-tadiene. The main product fraction consisted of three 1 1 adducts, as illustrated in equation 138. Diels-Alder Adducts 462 and 463 resulted from attack of cyclopentadiene at the endocyclic and exocyclic double bonds of fulvene, respectively. The formation of 464 was rationalized by a [6 + 4] cycloaddition reaction followed by two [1,5] hydrogen shifts. It was stated that due to the absence of electron-donating and electron-withdrawing groups on both triene and diene, fulvene may have reacted via its HOMO as well as its LUMO. 

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