Dipolarophiles acrylonitrile

Dipolarophiles D4. 1,3-Dipolar cycloaddition between acrylonitrile (D4) and chiral nonracemic nitrones is a key step in an efficient synthetic route to isoxa-zolidinyl analogs of thiazofurin (540) (Scheme 2.253). Opposite diastereofacial induction was observed when the chiral group was placed at either the carbon or the nitrogen atom of the nitrone function (753). 

Quaternarization of 43 with phenacyl bromide produced the corresponding salt 51 that was reacted with several triple-bond-containing dipolarophiles (Scheme 4), such as dimethyl acetylenedicarboxylate (DMAD) or alkyl propiolates to give tricyclic compounds 52, 53 and 54, 55. Compound 51 reacted also with acrylonitrile as dipolaro-phile in MeCN/K2C03 to give the cycloadduct 56 as a mixture of diasteroisomers. 

The reactions of 1,2,3-triazolium 1-imide (277) with a range of alkene and alkyne dipolarophiles give rise to a variety of new ring systems (Scheme 54). Compounds (276) and (278) are obtained from (277) by reaction with acrylonitrile and DMAD, respectively. These reactions are tandem 1,3-dipolar (endo) cycloadditions and sigmatropic rearrangements which are regio- and stereospecific <90JCS(Pl)2537>. Kinetic and mechanistic studies show that these reactions are dipole-HOMO controlled. The second-order rate constants are insensitive to solvent polarity, the reaction indicates... 

Mangalagiu studied the regioselectivity of the 1,3-dipolar cycloaddition of several pyridazinium methylides 105 to ethyl acrylate, ethyl propiolate, and acrylonitrile. The reaction is HOMO controlled from ylides and only one regioisomer 106 (major isomer as and minor isomer trans) or 107 is formed, namely the one in which the ylide carbanion makes a new bond with the most electrophilic carbon of the 1,3-dipolarophile. In some cases oxidation of 106 to 107 is observed in the reaction mixture in contact with the air (Scheme 23), which can be avoided by working in N2 atmosphere <1996T8853, 1997ACS927, 1999EJO3501>. 

Unsymmetrical dipolarophiles led to the formation a single regioisomeric product acrylonitrile delivered adduct 19 exclusively while maleic anhydride... 

Due to the increased reactivity of the reaction in the presence of a Lewis acid, the reaction scope was extended to singly activated alkenes. Previous results had shown either no reaction or extremely poor yields. However, under the Lewis acid catalyzed conditions, acrylonitrile furnished a 1 1, endo/exo mixture of products. The addition of the catalyst gave unexpected regiochemistry in the reaction, which is analogous with results described in Grigg s metal catalyzed reactions. These observations in the reversal of regio- and stereocontrol of the reactions were rationalized by a reversal of the dominant, interacting frontier orbitals to a LUMO dipole-HOMO dipolarophile combination due to the ylide-catalyst complex. This complex resulted in a further withdrawal of electrons from the azomethine ylide. 

Trapping of the analogous ylide (18) by dipolarophiles has also been observed (Scheme 4.14). Oxadiazolidine (66) generated ylide 67 upon heating, followed by cycloaddition with electron-poor alkenes such as methacrylate and acrylonitrile to generate cyclic acetals such as 68 as a 1 1 mixture of stereoisomers in 25% yield. 

Confirmation was provided by the observation that the species produced by the photolysis of two different carbene sources (88 and 89) in acetonitrile and by photolysis of the azirine 92 all had the same strong absorption band at 390 nm and all reacted with acrylonitrile at the same rate (fc=4.6 x 10 Af s" ). Rate constants were also measured for its reaction with a range of substituted alkenes, methanol and ferf-butanol. Laser flash photolysis work on the photolysis of 9-diazothioxan-threne in acetonitrile also produced a new band attributed the nitrile ylide 87 (47). The first alkyl-substituted example, acetonitrilio methylide (95), was produced in a similar way by the photolysis of diazomethane or diazirine in acetonitrile (20,21). This species showed a strong absorption at 280 nm and was trapped with a variety of electron-deficient olefinic and acetylenic dipolarophiles to give the expected cycloadducts (e.g., 96 and 97) in high yields. When diazomethane was used as the precursor, the reaction was carried out at —40 °C to minimize the rate of its cycloaddition to the dipolarophile. In the reactions with unsymmetrical dipolarophiles such as acrylonitrile, methyl acrylate, or methyl propiolate, the ratio of regioisomers was found to be 1 1. 

In general, LiBr and NEt3 are employed in 1.5 and 1.2 equiv, respectively. Although the reaction becomes rather slower, catalytic amounts of LiBr/NEt3 (0.1 equiv each) are also sufficient. In reactions with the highly reactive dipolarophile N-methylmaleimide, the catalytic reaction results in a better yield. A similar lithiation is possible with a-substituted (alkylideneamino)acetates and (alkylideneamino)-acetamides to generate lithium enolates (86). Cycloadditions with a variety of a,(3-unsaturated carbonyl compounds leads to endo cycloadducts. However, the reaction with acrylonitrile is again nonstereoselective. 

The 4-phospha-1,3-butadiene 77/80 serves as an effective synthon for the unknown H-substituted nitrile ylide 79 in [3 + 2]-cycloaddition reactions with a range of electron-poor dipolarophiles (e.g., reaction with DMAD gave 78 in 80% yield). Similar yields were also obtained using methyl propiolate, azodicaboxylic esters, ethyl acrylate, and acrylonitrile (39). The reactant was generated under very mild conditions from 75 as shown below. 

When acrylonitrile or ethyl acrylate was used as the dipolarophile, the azomethine adducts (134) and (135) were formed no thiocarbonyl ylide addition products were isolable in refluxing toluene or xylene, although the isoindoles (136a) and (136b) derived from them were isolated. In contrast to the reactions with fumaronitrile or AT-phenylmaleimide, the azomethine adducts (134) and (135) were still present at higher reaction temperatures — almost 50% in toluene and 4-5% in xylene. Under the same reaction conditions other electron-deficient dipolarophiles like dimethyl fumarate, norbornene, dimethyl maleate, phenyl isocyanate, phenyl isothiocyanate, benzoyl isothiocyanate, p-tosyl isocyanate and diphenylcyclopropenone failed to undergo cycloaddition to thienopyrrole (13), presumably due to steric interactions (77HC(30)317). 

Azine approach. Heteroaromatic TV-oxides will undergo 1,3-dipolar cycloaddition as a nitrone. Thus quinoxaline 1-oxide reacts with a variety of dipolarophiles, e.g. in the formation of the adduct (85). The 1,4-dioxide can form cycloadducts at both N-oxide functions. The adduct from 2H-1,4-benzoxazine 4-oxide and acrylonitrile is the isoxazolo[3,2-c][l,4]benzoxazine (86) (79T1771). 

Azine approach. 4,5-Dihydro-6//- 1,2-oxazine 2-oxides undergo 1,3-dipolar cyclo-addition reacting with appropriately substituted alkenes and alkynes to form isoxazolo-[2,3-Z>][l,2]oxazines. With styrene as the dipolarophile in the reaction with the oxazine (87), the product (88) with cis methyl and phenyl groups is formed. With acrylonitrile and methyl acrylate, some trans isomer is formed, but the cis isomer is predominant. The rings are always c/s-fused (77IZV211). 

Although the reaction mechanism depends upon the nature of the reacting anionic species (as illustrated in the scheme), a chelation between the lithium and the carbonyl oxygen of the dipolarophiles may be responsible for the exclusive regio- and endo selectivity. This chelation is so rigid that the high endo selectivity as well as the enhanced reactivity remains even when the a substituent of the ylide is a sterically bulky isopropyl group and the p substituent an olefinic methyl. On the other hand, the selectivity of cycloadditions of ylides 141 is very poor when the olefin dipolarophiles bear a noncarbonyl substituent (e.g., acrylonitrile) or when s-(rans-enones (e.g., 2-cyclopentenone) are used as dipolarophiles. 

Both with olefinic dipolarophiles such as A-arylmaleimide, acrylonitrile, or ethyl acrylate and with azirines, stable 1 1 adducts are formed. 

---