Alkynals intramolecular cyclization

Particularly interesting are the results obtained with the phosphonium ylides including an acyl rest derived from aminoacid if the N-H bond reactivity is blocked by an amide protection, the alkyne formation takes place [25,27], but if the N-H bond is not deactivated, an intramolecular cyclization occurs to give a new stabilized ylide [27,28]. 

Other intramolecular cyclizations can follow generation and fragmentation of cyclo-propylcarbinyl radicals. In the example below, the fragmented radical adds to the alkyne. 

Diterpenoids related to lambertianic acid were prepared by intramolecular cyclization of either an alkene or an alkyne with a furan ring <2005RJ01145>. On heating amine 101 with allyl bromide, the intermediate ammonium ion 102 was formed which then underwent [4+2] cycloadditions in situ to give the spiroazonium bromides 103 and 104 (Scheme 13). These isomers arose from either endo- or co-transition states. The analogous reaction was also carried out with the same amine 101 and propargyl bromide. The products 105 and 106 contain an additional double bond and were isolated in 58% yield. The product ratios of 103 104 and 105 106 were not presented. 

Intramolecular cyclizations of species containing two alkynes and an alkene group have been reported these take place in an aqueous basic medium and evolve heat as they progress to give isoindolium salts. In the example of 112 cyclizing to give 113, the products were not isolated but were used in subsequent intramolecular cyclizations (Equation 23 and Table 6) <2004KGS177>. 

The base-catalyzed intramolecular cyclization of appropriately substituted 4-alkyn-1-ols, followed by in situ Claisen rearrangement, has been investigated by Ovaska and coworkers (Scheme 6.85) [179]. The tandem cydization-Claisen rearrangements were best carried out in N,N-dimethylformamide or phenetole as solvent in the pres-... 

Although terminal acetylenes themselves do not form stable titanium—acetylene complexes upon reaction with 1, the reaction with terminal alkynes having a keto group at the 5- or y-position induces an intramolecular cyclization, apparently via the above titanium-acetylene complex to afford the four- and five-membered cycloalkanols, as shown in Eq. 9.6 [28]. 

Several routes to the pyrrolo[l,2-f][l,2,3]triazole skeleton have been described. Intramolecular dipolar cycloaddition of azido-alkenes or alkynes seems to be the most convenient process, although the cyclization efficiency seems to be highly substrate dependent (Scheme 16) <2002JA2134, 2003T1477, 2005SL2187, 2005TL8639>. The formation of this bicyclic system by an intramolecular Heck reaction is an attractive alternative. The recent syntheses of sulfamides by intramolecular cyclization of alkenes or allenes offer a complementary route to the classical... 

The Pd-catalyzed electro-cleavage of the C—O bond of allyl aryl ether proceeds smoothly in a DMF-Bu4NBp4-(Mg)-(Stainless Steel) system, giving depro-tected products in 73 99% yield [437]. The sp-sp intermolecular coupling reaction with the Pd water-soluble catalyst prepared in situ from Pd(II) acetate and sul-fonated triphenylphosphine in an MeCN-H2O system yields diynes in 45 65% yields [438]. Similarly, the sp -sp coupling of 2-iodophenols or 2-iodoanilines and terminal alkynes followed by intramolecular cyclization gives indol and furan... 

Radical intermediates are also trapped by intramolecular reaction with an alkene or alkyne bond. At a mercury cathode this process competes with formation of the dialkylmercury [51], At a reticulated vitreous carbon cathode, this intramolecular cyclization of radicals generated by reduction of iodo compounds is an important process. Reduction of l-iododec-5-yne 5 at vitreous carbon gives the cyclopentane... 

Intramolecular cyclization is particularly effective to terminal alkynes containing three or four methylene units between acetylenic and silyl moieties such as 158, 160, and 162. But-3-ynylmethylphenylsilane does not give any positive result for CO incorporation. Regioselectivity for the silylformylation is completely reversed from the one in the standard silylformylation discussed in Section 11.14.2.2. A bulky /ft7-butyl group in 162 (R = Bu ) plays an... 

Pd/tppts-catalysed intermolecular sp-sp couplings to afford diynes and sp2-sp coupling of 2-iodophenols or iodoanilines with alkynes followed by intramolecular cyclization to benzofurans and indoles, respectively, with moderate to good yields in H20/CH3CN solvent mixtures have also been described.517 8... 

Nitrile imine cycloadditions provide access to pyrazolines and pyrazoles. Intramolecular cyclizations to alkynes were first reported in 1974.88 Perhaps the most useful method for generation of nitrile imines involves 1,3-elimination of hydrogen chloride from an a-chlorohydrazone. Tetrazoles and sydnones are also precursors to nitrile imines. 

Acylation of alkynes, cyclopentenones. Acylation of alkynes with a,a-disubsti-llllotE/f, y-unsaturated acid chlorides, catalyzed with A1C13> results in 5,5-disubstituted-2-cyclopentenones by an unexpected intramolecular cyclization-rearrangement.2 Example ... 

The treatment of 1,2,3-selenadiazoles (79) with a catalytic amount of tributyltin hydride and AIBN in the presence of an excess of olefin, gives 2,3-dihydroselen-ophenes (80) in good yield (Scheme 20). The reaction proceeds via tributyltin radical-promoted denitrogenation to give a vinyl radical, which then adds to the olefin followed by intramolecular cyclization. Under similar conditions 1,2,3-selenadiazoles and aliphatic or aromatic ketones afford alkynes as the sole products [114, 115]... 

Alkynes continue to be used as a reactive functionality in quinoline synthesis. The readily available thiocarba-mates, thioamides, and thioureas allow intramolecular cyclization of pendant alkynes to give modest to good yields of the quinolines (Equation 118) <20030L1765>. An intermolecular reaction involving a zinc-mediated alkynylation-cyclization provides an efficient route to 4-trifluoromethyl-substituted quinolines (Equation 119) <2002JOC9449>. 

All the examples described above involved the reaction of diazoacetate derivatives with silver salts to initiate the formation of a putative silver carbene however, other pathways exist. For example, Porcel and Echavarren have reported an intramolecular cyclization of an allylstannane to a pendent alkyne (Scheme 8.22) that involves the intermediacy of a silver carbene.52 As can be seen in Table 8.12, the reactions proceeded in moderate to excellent yield, providing the dienylstannane, while in some cases, reductive destannylation occurred. Several asymmetric reactions were reported with substrate ( )-145d, leading to the formation of the expected adduct in reasonable enantioselectivities (ee = 73-78%) in a preliminary screen with a number of different ligands. 

The exploitation of intramolecular Diels-Alder reactions has included synthetic applications in the thienopyrimidine series as well. Thus, the 1,2,4-triazine with a tethered alkyne (276) participates in an intramolecular cyclization, with concomitant loss of RCN, to produce the thienopyrimidine (277) (Equation (97)) <87JOC4287>. A similar reaction occurs with oxygen analogues. 

Highly enantioselective Rh-catalyzed intramolecular Alder-ene reactions for the synthesis of chiral 3-alkylidene-4-vinyltetrahydrofurans were reported by Zhang, as illustrated below <02AG(E)3457>. Metallic indium was also shown to mediate the intramolecular cyclization of tethered allyl bromides onto terminal alkynes to afford 3-methylene-4-vinyltetrahydrofurans in 50-62% yield <02SL2068>. 

The intramolecular cyclization of tethered allyl bromides onto terminal alkynes mediated by metallic indium proceeds smoothly and cleanly in a mixture of THF and water to give unsaturated carbocycles and heterocycles in good yields. The reaction does not proceed efficiently under rigorously anhydrous conditions (Scheme 72). 

Additionally, Arcadi and co-workers developed an electrochemical approach for the synthesis of 3,4-disubstituted-2(l//)-quinolones in moderate yields through an intramolecular cyclization of alkynes and malonyl moieties <07EJ02430>. 

Pd-catalyzed cycloisomerization of (Z)-2-en-4-yne-l-thiols 111 gives substituted thiophenes 112. The mechanism involves electrophilic activation of the alkyne moiety by Pd(ll) followed by intramolecular cyclization, protonolysis, and aromatization (Scheme 25) <20000L351>. S-Endo cyclization of alkynyl thiols 113 using a Mo, W, or Cr catalyst affords dihydrothiophene 114 <2000S970>. 

In contrast to intramolecular cyclizations, the intermolecular addition of O-centered radicals to ti systems as initiating step in complex radical cyclization cascades has only recently attracted considerable attention. The reason for the low number of papers published on O radical addition to alkenes and alkynes could originate from the perception that O-centered radicals, such as alkoxyl radicals, RO, or acyloxyl radicals, RC(0)0", may not react with 7t systems through addition at rates that are competitive to other pathways, for example, allylic hydrogen abstraction and p-fragmentation in the case of RO" or decarboxylation in the case of RC(0)0" (Scheme 2.9). 

Later, Arcadi showed that /J-keto-imines react with alkynes intramolecularly to give pyrroles. The intermolecular animation with aniliaes was later developed by Hayashi and Tanaka using a cationic Au(I) catalyst to form imines (equation 27). More recently, Arcadi etal. developed an intramolecular version for the cyclization of o-alkynylanilines to form indoles (equation 28) and Li reported a double intra- and intermolecular hydroamination to obtain A-vinylindoles. " O-Substituted hydroxylamines can also undergo this type of transformation to dihydroisoxazole derivatives. " " Tandem sequences that involve a first alkyne-hydroamination step with anilines have been recently developed " " and are similar to the previonsly discnssed additions with phenols that access isoflavone skeletons. 

Endo-skeletal rearrangements also take place with 1,6-enynes, bnt the proposed mechanism is just a variation of the exo-single-cleavage rearrangement. Formed by endo cyclization, bicyclo[4.1.0]hept-4-ene derivatives arise in some cyclizations of 1,6-enynes by proton loss and protodemetalation ofthe endo cyclopropylcarbene. " That is the case from 1,6-enynes tethered as sulfonamides and in the intramolecular cyclization of 1,6-enol ethers with alkynes (equation 40). ... 

In addition to cationic cyclizations, other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol. For example, treatment of (259) and (260) with Mn(III) and Cu(II) afford the D-homo-5a-androstane-3-ones (261) and (262), respectively, in approximately 30% yield. In this cyclization, seven asymmetric centers are established in one chemical step (226,227). Another intramolecular cyclization reaction of iodo-ene poly-ynes was reported using a carbopaUadation cascade terminated by carbonylation. This carbometalation—carbonylation cascade using CO at 111 kPa (1.1 atm) at 70°C converted an acycHc iodo—tetra-yne (263) to a D-homo-steroid nucleus (264) [162878-44-6] in approximately 80% yield in one chemical step (228). Intramolecular aimulations between two alkynes and a chromium or tungsten carbene complex have been examined for the formation of a variety of different fiised-ring systems. A tandem Diels-Alder—two-alkyne annulation of a triynylcarbene complex demonstrated the feasibiHty of this strategy for the synthesis of steroid nuclei. Complex (265) was prepared in two steps from commercially available materials. Treatment of (265) with Danishefsky s diene in CH CN at room temperature under an atmosphere of carbon monoxide (101.3 kPa = 1 atm), followed by heating the reaction mixture to 110°C, provided (266) in 62% yield (TBS = tert — butyldimethylsilyl). In a second experiment, a sequential Diels-Alder—two-alkyne annulation of triynylcarbene complex (267) afforded a nonaromatic steroid nucleus (269) in approximately 50% overall yield from the acycHc precursors (229). 

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