Tandem process

The conjugate addition of a nucleophile to a, 3-unsaturated carbonyl compounds results in formation of the corresponding enolate subsequent to the initial addition step. This reactive intermediate can be trapped by a variety of electrophiles, and thus opens up opportunities for tandem reaction sequences [108]. 

In synthesis of complex molecules, well-designed synthetic strategies involving transition metal catalyzed intra- or intermolecular processes can lead to short cuts to target molecules by so-called tandem or domino reactions [148]. Further progress is expected in the field to accomplish efficient synthesis. 

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Metal carbenoid-mediated tandem processes in synthesis of azapolycycles 97MI36. 

Extension of this tandem process to create five conoguons stereogenic centers has been accomplishedbynsmgl-snbsdtutedvinylelhersfEq 8 114 Theresultsforlhecyclo idthdcii... 

RCM of a dienyne was also a key step in Mori s recent total synthesis of the alkaloid erythrocarine (447) [183]. The tetracyclic framework of447 was elaborated in the penultimate step, by exposing the hydrochloride of metathesis precursor 445 (1 1 diastereomeric mixture at the carbinol center) to first-generation catalyst A. The tandem process occurred smoothly within 18 h at room temperature leading to tetracycles 446 (1 1 mixture) in quantitative yield. Deprotection of the a-acetoxy isomer 446a led to 447 (Scheme 88). 

In the synthesis of a macrolide 17A, known as latrunculin A, the intermediate 17B was assembled from components 17C, 17D, and 17E in a one-pot tandem process. By a retrosynthetic analysis, show how the synthesis could occur and identify a sequence of reactions and corresponding reagents. 

The reduction can also be effected with diphenylsilane and the intermediate silyl enol ethers can be alkylated in a tandem process.159... 

An interesting one-pot hydroformylation/Fischer indole sequence can be achieved by running the hydroformylation in the presence of a phenylhy-drazine. This protocol gave access to the methyl ester of the plant growth regulator 3-indole butanoic acid (IBA) (Scheme 16) [61-63]. A review on related tandem processes involving the hydroformylation as a key step has appeared recently [9]. 

Selective transformations Selective styrene ring opening [103] One-pot domino process for regioselective synthesis of a-carbonyl furans [104] Tandem process for synthesis of quinoxalines [105] Atmospheric oxidation of toluene [106] Cyclohexane oxidation [107] Synthesis of imines from alcohols [108] Synthesis of 2-aminodiphenylamine [109] 9H-Fluorene oxidation [110] Dehydrogenation of ethane in the presence of C02 [111] Decomposition of methane [112] Carbon monoxide oxidation [113]... 

Sithambaram, S., Ding, Y., Li, W., Shen, X., Gaenzler, F. and Suib, S.L. (2008) Manganese octahedral molecular sieves catalyzed tandem process for synthesis of quinoxalines. Green Chemistry, 10, 1029-1032. 

Scheme 0.1. Synthesis of chlorothricolide (0-4) using a tandem process.

One-pot multi-bond-forming reactions are one of the ways to address the ever growing demand for efficiency in organic synthesis. Rosini and coworkers have developed (tandem) processes for the synthesis of a highly functionalized tricyclic system. The reaction is simply performed by bringing together, at room temperature, a-bromo aldehydes, ethyl nitroacetate, and chlorodimethylvinylsilane in the presence of imidazole as the base (Eq. 8.83).134... 

Recently, Denmark and coworkers have developed a new strategy for the construction of complex molecules using tandem [4+2]/[3+2]cycloaddition of nitroalkenes.149 In the review by Denmark, the definition of tandem reaction is described and tandem cascade cycloadditions, tandem consecutive cycloadditions, and tandem sequential cycloadditions are also defined. The use of nitroalkenes as heterodienes leads to the development of a general, high-yielding, and stereoselective method for the synthesis of cyclic nitronates (see Section 5.2). These dipoles undergo 1,3-dipolar cycloadditions. However, synthetic applications of this process are rare in contrast to the functionally equivalent cycloadditions of nitrile oxides. This is due to the lack of general methods for the preparation of nitronates and their instability. Thus, as illustrated in Scheme 8.29, the potential for a tandem process is formulated in the combination of [4+2] cycloaddition of a donor dienophile with [3+2]cycload-... 

Derivatives of the pyrrolo[2,l, 5-z/r quinolizinc system 88 were obtained from 2-benzoyl-iV-acetonylpyridinium bromide 86 in a single step through a tandem process of intramolecular aldol condensation and deprotonation, leading to intermediate 87, followed by 1,3-dipolar cycloaddition and oxidation (Scheme 6) <2001JPI1820>. 

Multiple mass analyzers exist that can perform tandem mass spectrometry. Some use a tandem-in-space configuration, such as the triple quadrupole mass analyzers illustrated (Fig.3.9). Others use a tandem-in-time configuration and include instruments such as ion-traps (ITMS) and Fourier transform ion cyclotron resonance mass spectrometry (FTICRMS or FTMS). A triple quadrupole mass spectrometer can only perform the tandem process once for an isolated precursor ion (e.g., MS/MS), but trapping or tandem-in-time instruments can perform repetitive tandem mass spectrometry (MS ), thus adding n 1 degrees of structural characterization and elucidation. When an ion-trap is combined with HPLC and photodiode array detection, the net result is a profiling tool that is a powerful tool for both metabolite profiling and metabolite identification. 

Scheme 43 In situ generation of allyl(hydrido)zirconocenes and their carbonyl reduction-allylation tandem processes.

This reaction is now well understood, including its stereochemical features.209 242 It should be noted that six-membered rings can be formed besides five-membered rings through this pathway, and their formation is facile with the catalytic system Pd(ll)-Pd(rv). All of these set the stage for numerous synthetic applications, such as cycloisomerization [4 + 2] tandem processes,243 and the enantioselective approach to the total synthesis of potent antiulcerogenic cassiol 247 (Scheme 62).244... 

Very recently, Wiedenhoefer272 has devised the first asymmetric 1,6-enyne hydrosilylation/cyclization tandem process using a rhodium(l) catalyst with (R)-276 as chiral ligand where rhodium-BINAP complexes were not effective (Scheme 70). More developments on this reaction are covered in Chapter 11.13. 

Negishi reported the zirconium-catalyzed enantioselective carboalumination of alkenes, which consisted of a hydroalumination/alkylalumination tandem process.133-135 This permits the asymmetric syntheses of methyl-substituted alkanols and other derivatives, typically with >90% ee, which represents an increase in ee value by 15% from the previously obtained 70-80%.136-138 The hydroalumination/zirconium-catalyzed enantioselective carboalumination of alkenes was carried out using (—)-bis(neomenthylindenyl)zirconium dichloride as the catalyst (Table 15).133... 

In the Zr-catalyzed cyclic carbometallation discussed above, a tandem process consisting of (i) transmetallation and (ii) P-H abstraction provides the missing link in the catalytic cycle. In a series of recent examples reported by Takahashi [206—208] and Hoveyda [209—214], the missing link has been provided by a process consisting of (i) [5-elimination or deheterometallation (Pattern 10), (ii) transmetallation, and (iii) P-H abstraction (Scheme 1.62). Some of these reactions have been developed into enantioselective C—C bond-forming processes, as discussed below. 

Scheme 42 Enantioselective cyclization in tandem processes leading to bicydic systems...

When the nucleophile bears an appropriately unsaturated chain, these enantioselective cyclizations can be used to advantage in tandem processes leading to bicyclic systems (Scheme 42) [131,141,142], The greater enantios-electivity observed with the mesylate group in this example may be due to the lower degree of stabilization of the alkene radical cation in the looser ion pair, which leads to more rapid cyclization. 

Tandem processes mediated by triethylborane involving conjugate addition to enones followed by aldol reaction are reported (Scheme 52, Eq. 52a). More recently, a tandem process involving addition of an isopropyl radical to an o ,/3-unsaturated oxime ether afforded an azaenolate intermediate that reacts with benzaldehyde in the presence of trimethylaluminum. The aldol product cyclizes to afford an isopropyl substituted y-bulyroloaclonc in 61% overall yield (Scheme 52) [116]. In these reactions, triethylborane is acting as a chain transfer reagent that delivers a boron enolate or azaenolate necessary for the aldolization process. 

Tandem pericyclic processes offer the opportunity to synthesize complex highly substituted cyclic molecules in a completely stereocontrolled fashion in a few consecutive steps. As a consequence, tandem processes have been studied extensively. Some tandem processes involving Diels-Alder reactions have recently been reviewed38,40,107. 

An irreversible consecutive reaction as a driving force to shift an unfavorable Cope rearrangement equilibria in the needed direction can be illustrated by the Cope-Claisen tandem process used for the synthesis of chiral natural compounds243. It was found that thermolysis of fraws-isomeric allyl ethers 484 or 485 at 255 °C leads to an equilibrium mixture of the two isomers in a 55 45 ratio without conversion into any other products (equation 184). Under the same conditions the isomer 487 rearranges to give the Cope-Claisen aldehyde 491 (equation 185). Presumably, the interconversion 484 485 proceeds via intermediate 486 whose structure is not favorable for Claisen rearrangement. In contrast, one of the two cyclodiene intermediates of process 487 488 (viz. 490 rather than 489) has a conformation appropriate for irreversible Claisen rearrangement243. 

Propargylamines could serve as a suitable allyl moiety in aza-Claisen rearrangements. The 3,3-sigmatropic bond reorganization led to allenes, which easily underwent consecutive processes like nucleophile addition and cycliza-tion in a tandem process. 

Hartwig and coworkers reported an approach to address this limitation involving tandem catalytic reactions. In this tandem process, sequential palladium-catalyzed isomerization of the branched isomer to the linear isomer, followed by iridium-catalyzed allylic substitution leads to the branched product with high enantiomeric excess [105]. More specifically, treatment of branched allylic esters with catalytic amounts of the combination of Pd(dba)2 and PPhs led to rapid isomerization of the branched allylic ester to the linear isomer, and the linear isomer underwent allylic substitution after addition of the iridium catalyst and nucleophile (Scheme 31). 

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