Acetylenic esters cycloadditions

Acyl-substituted quinolizinium ylide 63 was obtained by treatment of its 1,2-dihydro analogue with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ). Its 1,3-dipolar cycloaddition with an acetylenic ester in excess was regioselective and was accelerated in polar solvents yielding the intermediate adduct 64 and finally the corresponding cyclazine 65, as shown in Scheme 2 <2001JOC1638>. 

R2=MeC>2C, R3 = d-F CC F ), regioisomeric 4-trifluoromethyl-5-isoxazole-carboxylates, 213 (R1 =Me02C, R2 =CF3, R3 = 4-F3CC6H4) and unexpectedly oximinoyl chloride 214, resulted by 1,4-addition. Product distribution is rationalized in terms of two competing reactions, either 1,4-addition of the oximate anion to the acetylenic ester or formation of the nitrile oxide followed by 1,3-dipolar cycloaddition. Anionic 1,4-addition of the oximinoyl chloride to the acetylenic ester is favoured at low temperatures, while nitrile oxide formation, followed by cycloaddition, occur at temperatures above 0 ° (371). 

Also, tetrahydroquinolizinium ylides have found application in 1,3-dipolar cycloadditions with acetylenic esters <2001JOC1638>. 

Numerous reactions of acetylenic esters are reported in the literature, and many of these lead to heterocyclic compounds. Acetylenic esters undergo very facile addition reactions with several nucleophiles and also they participate as dipolarophiles in 1,3-dipolar cycloadditions, and as... 

Hashimoto and co-workers (206,207) recently published enantioselectivities of up to 92% ee in carbonyl ylide cycloadditions to acetylenic esters in the presence of a chiral rhodium catalyst (Scheme 11.58). 

Ene and 2 + 2 cycloaddition reactions of acetylenic esters (7, 7 8 8, 13). In the early studies on the reaction of acetylenic esters with alkenes, Snider used A1C1( as the Lewis acid catalyst. The presently preferred catalyst is C2H5A1C12, which is a Lewis acid and also serves as a proton scavenger by reaction with HC1 to give ethane and AIC13. It is generally used in amounts close to 1 equivalent for a neutral Hlkene. 

The catalyzed reaction of acetylenic esters and alkenes can lead to ene products and/or cis [2 + 2]cycloaddition. The relative reactivity of alkenes established by reactions with dienes is 1,1-disubstituted > trisubstituted > monosubstituted and 1,2-disubstituted. Ene reactions predominate with alkenes containing two substi tuents on one carbon.1... 

Developments in aziridine chemistry, including the synthetic applications of their cycloadditions, have recently been reviewed by Lown and Matsumoto.35-37 Many investigators have added aziridines to acetylenic esters. Russian workers38 treated aziridine in the cold with various esters and then heated the mixtures to 40°-60° for 3 hours. They obtained 59% of compound 16 with EP, and 71 % of 17 with EPP, no stereochemistry being defined. Diethyl acetylenedicarboxylate gave 24% of the maleate 18 (R = Et) and 16% of the fumarate 19 (R = Et). 

Anderson and co-workers86 used the cycloaddition of acetylenic esters to 19a and 19 (R = COPh) in the synthesis of the antimitotic agent Verrucarin E (28). The pyrrole 19a and DMAD gave 35% of 21a, whereas 19 (R = COPh) gave 67% of 21 (R = COPh) and 23% of recovered starting material 1-benzoylpyrrole gave 54% of 29 with DEAD. Further transformations produced the natural product. 

The cycloaddition of acetylenic esters (e.g., DMAD) to betaines (e.g., 58) derived from 3-hydroxypyridine gives 1 1-molar adducts (e.g., 59), and has been reviewed.266... 

Anomalous cycloaddition reactions from benzocinnoline A-alkyli-mides and acetylenic esters were also described, in 1974, by Rees et al. 59 Benzocinnoline Af-alkylimides (487 and 488) gave adducts 492 via the sequence shown in Scheme 10 with acid, they rearranged to the imidazoles 493 and 494. 

Vinylpyrroles 42 having electron-withdrawing substituents on the vinyl group are poor dienes for cycloaddition reactions with acetylenic esters. General reaction conditions such as heating at reflux in benzene or carbon... 

The cycloaddition reactions of 3-vinylindoles with acetylenic esters have been extensively studied. The reaction products generally obtained are [Z ]-annelated indoles, but Michael adducts can be isolated, depending on the substituents on the vinylindole (87HCA1419) (Scheme 1). 

The very reactive arynes have also been used as dienophiles in Diels-Alder cycloadditions with vinyl heterocycles and are included here, after the acetylenic esters, because of the similarity of their reactive functions. This reaction is of considerable importance because of its application in the synthesis of polycyclic compounds. 

Vinylpyrazoles react with NPMI to afford functionalized indazole derivatives through [4 + 2]-cycloaddition reactions in a way similar to that of other carbodienophiles such as acetylenic esters. So with 4-vinylpyrazole derivatives, mixtures of 1 1 and 1 2 cycloadducts (formed via an ene reaction) were obtained (86T6683 89MI113), whereas with the 5-isomer only the 1 1 cycloadduct was isolated (Scheme 7) [90JCS(P1 )2749]. 

Carboalkoxycyclopentenones.3 The zinc homoenolate 1, prepared as shown (13, 349-350), can undergo a formal [3 + 2]cycloaddition to acetylenic esters in the presence of CuBr-S(CH3)2, ClSi(CH3)3, and HMPA to give 2-carboalkoxycyclopen-tenones. The reaction probably involves conjugate addition to give an allenolate followed by intramolecular cyclization. 

The essential aspects of reaction (25) are depicted in Fig. 6. Huisgen et al. (1967) have provided a beautiful example of an odd electrocyclic change in (26). The aziridine opens up to a dipolar four-electron allylic species. Since the HOMO is b (Fig. 1), the thermal change is conrotatory and the excited state process is disrotatory. To avoid equilibration of the dipolar ions, these workers trap them with an acetylenic ester in a stereospecific cycloaddition, which we shall discuss presently. 

Methyl 4-hydroxy-2-butynoate has been used6 as a starting material for the preparation of an S-hydroxy-a, j8-acetylenic ester. It has also been employed8 as a dipolarophile in a 1,3-dipolar cycloaddition reaction that resulted in the first synthesis of 8-aza-3-deazaguanosine. 

This unique addition-transformation process has also been found in cycloaddition of acetylenic esters to dienes and azadienes containing the 5,6-double bond of uracil as part of the chromophore. Activated and polarized dienes of this type afford, with olefines, pyridol[2,3-Michael adducts, which are thermally converted into 8-(di-methylamino)theoph-ylline. 

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