Domino cyclization reaction mechanisms

Scheme 5.2. Proposed mechanism of the domino cyclization of photochemically induced reaction of 5-4.

The formation of spirolactams 47-49 could be rationalized in terms of a sequence domino cyclization of a-allenols-cross coupling reactions. A palladium (Il)-catalyzed mechanism for the domino sequence leading to spiranic adducts 47-49 is proposed in Scheme 17. It could be presumed that the initially formed allenepalladium complex 50 undergoes an intramolecular attack by the hydroxyl group (oxypalladation), giving rise to the spirocyclic vinylic palladium species 51. 

A three-component domino reaction catalyzed by palladium that produces 4,5-disubstituted dihydrobenzo[ ]furans from readily available starting materials has been developed by Pache and Lautens. The reactions of iodobenzenes of type 61 with Bui and tert- mx acrylate, as shown, give good yields of cyclization products (Scheme 96) <2003OL4827>. A reaction mechanism which involves sequential alkylation-alkenylation has been proposed. 

The cycloisomerization of 1,6-enynes proceeds smoothly in the presence of AcOH or HCO2H and the reaction is explained by the following mechanism (hydridopalladium acetate mechanism) [45]. Most importantly, oxidative addition of AcOH to Pd(0) generates H-Pd-OAc 143, and the cyclization of 1,6-enynes starts by insertion of the triple bond to 143 to afford the alkenylpalladium 144. Subsequent intramolecular insertion of the double bond gives the alkylpalladium 145. The termination step is (i-R elimination and either the diene 136 or 138 is formed with regeneration of H-Pd-OAc. It should be noted that the alkenylpalladium 144 is a similar species formed in a Heck reaction by oxidative addition of alkenyl halide to Pd(0). Based on this reaction, alkyne is a useful starter in domino cyclization of polyenynes. 

A domino reaction of 1,1-diphenyl-3,3-dilithioallene (157) with benzonitrile yields both a yellow imidazole (158 R = Ph X = NH) (12%) and a colourless 5-imidazol-5-yl-l,4-dihydropyrimidine (159 R = Ph) (51%), the products, respectively, of the incorporation of three and four nitrile molecules. The proposed mechanism (Scheme 13) involves initial formation of an intermediate (160) that is the product of the interaction of three molecules of benzonitrile with l,l-diphenyl-3,3-dilithioallene (157), which cyclizes to (162 R = Ph) and then eliminates a molecule of benzonitrile to produce (161 R = Ph). Re-addition of benzonitrile at a different locus produces... 

The domino cycloaddition-iV-acyliminium ion cyclization cascade has been extensively reviewed. Tandem reactions combining Diels-Alder reactions and sigma-tropic rearrangement reactions in organic synthesis have been extensively reviewed. The tandem Diels-Alder reaction between acetylenedicarboxaldehyde and N,N -dipyrrolylmethane has been extensively studied at the RHT/3-21G and RHF/6-31G levels.The molecular mechanism of the domino Diels-Alder reaction between hexafluorobut-2-yne and A,A -dipyrrolylmethane has been studied using density functional theory. 

The formation of compound 175 could be rationalized in terms of an unprecedented domino allene amidation/intramolecular Heck-type reaction. Compound 176 must be the nonisolable intermediate. A likely mechanism for 176 should involve a (ji-allyl)palladium intermediate. The allene-palladium complex 177 is formed initially and suffers a nucleophilic attack by the bromide to produce a cr-allylpalladium intermediate, which rapidly equilibrates to the corresponding (ji-allyl)palladium intermediate 178. Then, an intramolecular amidation reaction on the (ji-allyl)palladium complex must account for intermediate 176 formation. Compound 176 evolves to tricycle 175 via a Heck-type-coupling reaction. The alkenylpalladium intermediate 179, generated in the 7-exo-dig cyclization of bro-moenyne 176, was trapped by the bromide anion to yield the fused tricycle 175 (Scheme 62). Thus, the same catalytic system is able to promote two different, but sequential catalytic cycles. 

The domino carbonylation and Diels-Alder reaction proceed only as an intramolecular version. Attempted carbonylation and intermolecular Diels-Alder reaction of conjugated 2-yne-4-enyl carbonates 101 in the presence of various alkenes as dienophiles give entirely different carbocyclization products without undergoing the intermolecular Diels-Alder reaction. The 5-alkylidene-2-cyclopenten-4-onecarboxy-lates 102 were obtained unexpectedly by the incorporation of two molecules of CO in 82% yield from 101 at 50 °C under 1 atm [25], The use of bidentate ligands such as DPPP or DPPE is important. The following mechanism of the carbocyclization of 103 has been proposed. The formation of palladacyclopentene 105 from 104 (oxidative cyclization) is proposed as an intermediate of 108. Then CO insertion to the palladacycle 105 generates acylpalladium 106. Subsequent reductive elimination affords the cyclopentenone 107, which isomerizes to the cyclopentenone 108 as the final product. 

A gold(I)-catalyzed domino reaction sequence involving pentenynyl tosylamides led to the formation of 2,3-disubstituted pyrroles containing a quaternary center in the 2-substituent <07OL3181>. The mechanism of the reaction involved a 5-endo-dig cyclization followed by an aza-Claisen rearrangement. 

Based upon the studies on the mechanism of the Cl sequence we rationalized that the elusive allenol intermediate 19 (Chap. 2.2) could participate in intramolecular trapping reactions as an allenyl ether. Furthermore, vinyl allenes are perfectly suited as dienes in Diels-Alder reactions. Considering both reactive functionalities, allenyl ethers and vinyl allenes, which are perfectly suited for domino processes, we designed an insertion sequence based upon cyclizing carbopalladation [76], where the vinyl aUene results from an isomerization of an alkynylation of a vinyl... 

In this protocol the pyridine- and the pyrrolidine-ring of 1 are built up in a one-pot radical domino reaction." Photolysis of iodopyridone 11 in the presence of hexamethylditin provides radical 56, which attacks the reactive isonitrile 15. The resulting radical 57 reacts with the alkyne group in a 5-exo-dig cyclization (see Chapter 11). Next, the newly formed vinyl radical 58 cyclizes onto the aryl ring generating speeies 59. Final oxidation via a so far unknown mechanism yields 1 with 31 % yield. For the generation of radical 56 by photolysis two ways (A and B) are possible. 

Treatment of the l-isopropenyl-2-(3-butenyl)cyclobutanol 508 with Pd(II) afforded the bicyclo[4.3.0]nonane 512. The reaction can be understood by domino -carbon elimination as shown by 509, followed by 5-exo and 6-exo cyclizations of 510 to give 511, and f-H elimination and isomerization afforded 512 [208], A different mechanism based on ring expansion was given before. 

The first total synthesis of this natural product was achieved by Chiu and Lam [139]. Key step of the synthesis is a rhodium-catalyzed domino cychza-tion/cycloaddition reaction to form the tricyclic core of the diterpenoid from hnear a-diazoketone 337. Concerning the mechanism of the reaction, it is hkely that the rhodium catalyst, when reacted with 337 at 0 °C, formed a carbenoid species which immediately cyclized to 341 (Scheme 14.53). This 1,3-dipole then underwent an intramolecular cycloaddition with the aUcene to give a mixture of two cycloadducts in 81% yield with 339 as the major product (dr= 1 3.1 338 339). The minor diastereomer 338 was probably formed via a less stable boat conformation of the tether in contrast to the chair conformation shown in 341, leading to the desired product Decreasing the temperature from 0 to —15 °C did not increase the dr but lowered the yield. It is also remarkable that the reaction afforded no more than 0.5 mol% of the rhodium(II)octanoate dimer ([Rh2(Oct)4]). Further transformation of 339 finally furnished (—)-indicol (340) in an overall yield of 10% over 21 steps. 

Starting from tetrahydrocyclopenta[f)]furan-2-one 342, enyne 343, the substrate for the domino reaction, was prepared in 12 steps and with an overall yield of 45%. Exposure of 343 to the electron-rich gold(I) complex (t-Bu)2P(o-biphenyl)AuCl at room temperature afforded cis-hydrindanone 344 in 78% yield as a single stereoisomer (Scheme 14.54). The postulated mechanism involved Au(I) activation of the alkyne to initiate the cationic olefin cyclization of 346 to give carbocation 347, which then underwent a pinacol rearrangement to the final product 344. An originally attempted Lewis acid-catalyzed domino Prins/pinacol rearrangement of... 

A library of novel 5-amino-2,7-diaryl-2,3-dihydrobenzo[l)]thiophene-4,6-dicarbonitriles was synthesized by a one-pot domino reaction of 5-aryldihydro-3(2H)-thiophenes, malonitrile, and aromatic aldehydes in the presence of morpholine (13BMCL2101). A mechanism was proposed that involves a sequence of Knovenagel condensation, Michael addition, intramolecular Thorpe-Ziegler cyclization, tautomerization, and elimination. The compounds were evaluated for their AChE (acetylcholinase) activity. The 5-amino-2,7-bis(4-methoxyphenyl)-2,3-dihydrobenzo[l)] thiophene-4,6-dicarbonitrile was found to be the most potent with IC50 4.16 xmol/L. 

---