Cyclization tandem

Denmark et al. examined the tandem inter[4 + 2]/intra[3 + 2] cycloaddition of nitroalkenes to a functionalized propenyl ether using a variety of Lewis acids, such 

Kilburn et at. determined that various methylenecyclopropyl ketones [33], ketals and aldehydes function as new precursors of six- or seven-membered carbocycles by a transformation from the cyclopropyl systems using Lewis acid catalysts [34]. The ring expansion reaction using TiCU predominantly gave the dichlorinating compounds however, the SnCU promoted reaction alternatively gave the corresponding monochloro-methylenecyclohexane derivatives (S cheme 10.13). 

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A interesting and useful reaetion is the intramolecular polycyclization reaction of polyalkenes by tandem or domino insertions of alkenes to give polycyclic compounds[l 38]. In the tandem cyclization. an intermediate in many cases is a neopentylpalladium formed by the insertion of 1,1-disubstituted alkenes, which has no possibility of /3-elimination. The key step in the total synthesis of scopadulcic acid is the Pd-catalyzed construction of the tricyclic system 202 containing the bicyclo[3.2. Ijoctane substructure. The single tricyclic product 202 was obtained in 82% yield from 201 [20,164). The benzyl chloride 203 undergoes oxidative addition and alkene insertion. Formation of the spiro compound 204 by the intramolecular double insertion of alkenes is an exam-ple[165]. 

Tandem cyclization/3-substitution can be achieved starting with o-(trifluoro-acetamido)phenylacetylenes. Cyclization and coupling with cycloalkenyl trif-lates can be done with Pd(PPh3)4 as the catalyst[9]. The Pd presumably cycles between the (0) and (II) oxidation levels by oxidative addition with the triflate and the reductive elimination which completes the 3-alkenylation. The N-protecting group is removed by solvolysis under the reaction conditions, 3-Aryl groups can also be introduced using aryl iodides[9]. 

Tandem cyclization and 3-carboxylation has been done with o-(methanesulf-onamido)phenylacetylenes by conducting the reaction in methanol under a CO atmosphere[10]. 

Tandem cyclization-cycloaddition of diazoketones in the synthesis of some alkaloids 97F303. 

The field of alkaloid synthesis via tandem cyclizations favors the application of (TMSlsSiH over other radical-based reagents, due to its very low toxicity and high chemoselectivity. For example, cyclization of the iodoarylazide 102, mediated by (TMSlsSiH under standard experimental conditions, produced the N-Si(TMS)3 protected alkaloid 103 that after washing with dilute acid afforded the amine 104 in an overall 83% yield from 102 (Reaction 81). ° The formation of the labile N-Si(TMS)3 bond was thought to arise from the reaction of the product amine 104 with the by-product (TMSlsSil. The skeletons of ( )-horsfiline, ( )-aspidospermidine and (+ )-vindoline have been achieved by this route. - ... 

Alkenyl radicals generated by intramolecular addition to a triple bond can add to a nearby double bond, resulting in a tandem cyclization process. 

Entries 10 to 12 are examples of oxidative generation of radicals, followed by tandem cyclization. The reaction in Entry 10 includes a lanthanide catalyst. Entry 11... 

Barrero, Oltra and coworkers reported on the use of epoxygeranyl acetate in titanocene-mediated cyclizations and found that the termination of the reaction took place via a /i-hydride elimination after trapping of the radical by the second equivalent of Cp2TiCr [94,95]. This finding together with Takahashi s tandem cyclization [96] (see below) marks the first example of extremely interesting developments in epoxypolyene cyclizations via radicals that are discussed separately in the following section. 

Tandem cyclizations from [6+0] atom fragments, bond formations 7 to the bridgehead... 

The l,4-dihydropyrimido[l,2- ]pyridazine 101 was obtained by tandem cyclization from [4+2, 6+0] atom fragments by reacting [3-keto nitriles and the 2-cyanopropylhydrazine 100 (Equation 10) <2000MI639>. 

The quinazoline and the pyridazine rings of 110 are formed by tandem cyclizations from [5+1, 6+0] fragments when heating the benzoxazinones 109 with hydrazine or phenylhydrazine (Equation 11) <1996CHJ437, 1996CHJ532>. 

The saturated pyrazino[l,2- ]pyrimidin-9-one 129 was obtained by a tandem cyclization from the ct-keto carboxylic acid 128 and /V-(2-aminocthyl)-l,3-propancdiaminc (Equation 15) <1997ACS742>. 

Tripeptides with N-terminal anthranilic acid part were used as starting materials in the solid-phase synthesis carried out on TentaGel resin to prepare 1,4,11,1 l -tetrahydro-2//-pyrazino[2,l-3]quinazoline-3,6-diones with various N-l and N-3 substituents <2003EPP1471066>. Tandem cyclization from [6+0] atom fragments took place in the solid-phase synthesis of 143 from 142. Intermediate 141 was built on bromoacetal resin (Scheme 17) <1998JOC3162>. 

Tandem cyclization from [5+1,6+0] atom fragments took place when 3-isothiocyanatobutyraldehyde was reacted with 2-aminobenzylamine 228 (X = NH) to give 229. Based on literature analogies the first step involves the attack of the most nucleophilic aliphatic amino group onto the isothiocyanate and then onto the aldehyde carbon to form 1-(n-aminobenzyl)-6-hydroxytetrahydropyrimidine-2-thione, which undergoes intramolecular cyclocondensation to 229 (Scheme 38) <2005BMC3185>. 

In most cases, pyrazino[l,2- ]pyrazines have been synthesized as highly saturated derivatives with the aim of preparing conformationally restricted compounds which mimic the secondary structure of reverse-turn regions of peptides and proteins. The saturated pyrazino[l,2- ]pyrazine 241 was synthesized from readily available starting materials, the key steps being the preparation of the keto amide 239 and subsequent tandem cyclizations from [6+0] atom fragments (Scheme 42) <20000L301>. 

The disposition of the bridgehead proton with respect to the protons in position-3 and -6 was studied by ROESY 2-D NMR in four sets, 288-291 of 16 compounds bearing different substituents. The compounds were obtained via solid-phase syntheses by tandem cyclization <2004TL6333>. 

Intramolecular tandem cyclization of substituted piperidine-l-carboxamide 96 results in formation of cycloadduct 77 through the intermediary of A-sulfinylurea (Scheme 8) <2001JA8851, 2002JA3939>. 

The same pattern of reaction has been employed with symmetrical starting materials 124 and 126 to give tandem cyclizations yielding heptacyclic products 125 (Equation 29) and 127 (Equation 30), the latter being formed in near quantitative yields <1997KGS660>. 

Pattenden reported a tandem cyclization approach for the synthesis of estrone in 2004. Later, they further demonstrated that this strategy could be used to generate the veratramine skeleton [26]. 

The action of t-butyllithium on 5-methylene-8-nonenyl iodide (206) leads to the lithium compound 207, which undergoes a tandem cyclization to yield eventually 84% of 2-methylspiro[4.4]nonane (208) (equation 102). An analogous reaction of the iodide 209 (equation 103) results in the [4.3.3]propellane 210 (81%) as a mixture of endo- and excMSomers1. ... 

Tandem cyclization of l-cyclopropylidene-5-methylenecyclooctane (233) with palladium ) chloride/triphenylphosphine in the presence of diisobutylaluminium hydride leads to the [3.3.3]propellane 235 in 74% yield by way of the proposed intermediate 234 (L = ligand) (equation 119)120. 

An intramolecular palladium-catalyzed tandem cyclization of dienamides 67 in which the amide nucleophile adds twice has been developed (equation 29)60. This reaction constitutes a formal [4+1] cycloaddition and provides a new route to pyrrolizidine and indolizidine alkaloids. Reaction of dienamides 67 in the presence of catalytic amounts of Pd(OAc)2 and CUCI2/O2 as the oxidant afforded bicyclic compounds 68 in good yields. The pyrrolizidine derivative 68 (R = Me, n = 1) was transformed to the alkaloid ( )-heliotridane. 

Recently, a rhodium-catalyzed tandem cyclization has been reported with an arylboronic ester bearing a pendant Michael-type acceptor olefin and acetylenic65 or olefinic66 derivatives. This transformation proceeds in a water-containing medium as solvent and proton source. This catalyst system is optimized with electron-rich and bulky ligands to stabilize the rhodium intermediate and decrease the protonolysis of boron derivatives in a protic solvent. 

Grigg developed several palladium-catalyzed tandem cyclization-anion capture processes, and these include organoboron anion transfer agents [112, 164, 206]. Two examples of this methodology are shown. 

The research group of Cacchi made extensive use of these tandem cyclization-Heck reactions to prepare a wide variety of indoles [311-314], For example, vinyl triflates react with o-aminophenylacetylene to afford an array of 2-substituted indoles in excellent yield, e.g., 356 to 357 [312], and a similar reaction of 358 with aryl iodides leads to an excellent synthesis of 3-arylindoles 359 [313],... 

The same approach (Scheme 12) was used with the amide 35 involving a 5-endo 6-endo-trig-tandem cyclization, which afforded exclusively indolizidinone 36 <1998TL7197>. 

Scheme 26 Tandem cyclizations using atom transfer additions...

A radical tandem cyclization, consisting of two radical carbocyclizations and a heterocoupling reaction, has been achieved by electrolysis of unsaturated carboxylic acids with different coacids. This provides a short synthetic sequence to tricyclic products, for example, triquinanes, starting from carboxylic acids which are accessible in few steps (Scheme 6) [123]. The selectivity for the formation of the tricyclic, bi-cyclic, and monocyclic product depending on the current density could be predicted by applying a mathematical simulation based on the proposed mechanism. 

Scheme 6 Radical tandem cyclization to tricyclic compounds.

Scheme 32 Radical tandem cyclization initiated by Kolbe electrolysis.

Unsaturated carboxylic acids can be de-carboxylated to alkyl radicals that undergo an intramolecular addition. The S-exo-trig-cyclization of fi-allyloxy radicals, generated from an appropriate carboxylic acid, combined with a final heterocoupling has been applied to synthesize a precursor of prostaglandine PGF2q (Fig. 47) [246] and a branched carbohydrate (ratio of diastereo-mers 1.8 1) (Fig. 48) [247]. A radical tandem cyclization of a doubly unsaturated monocyclic carbocyclic acid provides a... 

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