Intermolecular domino reactions

A domino reaction,in this case consisting of an inter- and an intramolecular Diels-Alder reaction, is a key step in the synthesis of the hydrocarbon pago-dane 30, reported by Prinzbach et al When the bis-diQnQ 27 is treated with maleic anhydride 4, an initial intermolecular reaction leads to the intermediate product 28, which cannot be isolated, but rather reacts intramolecularly to give the pagodane precursor 29 ... 

For clarification, individual transformations of independent functionalities in one molecule - also forming several bonds under the same reaction conditions -are not classified as domino reactions. The enantioselective total synthesis of (-)-chlorothricolide 0-4, as performed by Roush and coworkers [8], is a good example of tandem and domino processes (Scheme 0.1). I n the reaction of the acyclic substrate 0-1 in the presence of the chiral dienophile 0-2, intra- and intermolecular Diels-Alder reactions take place to give 0-3 as the main product. Unfortunately, the two reaction sites are independent from each other and the transformation cannot therefore be classified as a domino process. Nonetheless, it is a beautiful tandem reaction that allows the establishment of seven asymmetric centers in a single operation. 

One of the first enantioselective transition metal-catalyzed domino reactions in natural product synthesis leading to vitamin E (0-23) was developed by Tietze and coworkers (Scheme 0.7) [18]. This transformation is based on a Pdn-catalyzed addition of a phenolic hydroxyl group to a C-C-double bond in 0-20 in the presence of the chiral ligand 0-24, followed by an intermolecular addition of the formed Pd-spe-cies to another double bond. 

Alkenones were used by Rao and coworkers [40] to prepare cyclohexane derivatives which, for example, can be transformed into substituted arenes in a single step. Another interesting intermolecular Michael/intramolecular aldol reaction sequence for the construction of the highly substituted 2-hydroxybicy-clo[3.2.1]octan-8-one framework has been described by Rodriguez group [41]. This process can be extended to a three- and even a fourfold domino reaction [41a, 42, 43],... 

Scheme 3.2. General scheme for an intermolecular domino radical reaction.

The occurrence of the indole subunit is well established within the class of natural products and pharmaceutically active compounds. Recently, the Reissig group developed an impressive procedure for the assembly of highly functionalized in-dolizidine derivatives, highlighting again the versatility of domino reactions [8]. The approach is based on a samarium(II) iodide-mediated radical cydization terminated by a subsequent alkylation which can be carried out in an intermolecular - as well as in an intramolecular - fashion. Reaction of ketone 3-11 with samarium(ll) iodide induced a 6-exo-trig cydization, furnishing a samarium enolate intermediate... 

The first example of an intermolecular radical addihon/intermolecular trapping domino reactions of an acyclic system in a stereocontrolled fashion to build stereo-genic centers at the a- and 3-carbons was described by Sibi and coworkers [59]. Enantioselective addition of in-sitw-prepared alkyl radical to crotonate or cinnamate,... 

As shown in the preceding examples, although intramolecular Pd-catalyzed poly-cyclization is a well-established procedure, some few examples exist of polycycliza-tions where the first step is an intermolecular process. In this respect, the Pd°-cata-lyzed domino reaction of allenes in the presences of iodobenzene reported by Tanaka and coworkers [40] is an intriguing transformation. As an example the Pd-catalyzed reaction of 6/1-60 in the presence of iodobenzene led to 6/1-61 in 49% yield, allowing the formation of three rings in one sequence (Scheme 6/1.14). 

Today, multi-parallel synthesis lies at the forefront of organic and medicinal chemistry, and plays a major role in lead discovery and lead optimization programs in the pharmaceutical industry. The first solid-phase domino reactions were developed by Tietze and coworkers [6] using a domino Knoevenagel/hetero-Diels-Alder and a domino Knoevenagel/ene protocol. Reaction of solid-phase bound 1,3-dicarbonyl compounds such as 10-22 with aldehydes and enol ethers in the presence of piperidinium acetate led to the 1-oxa-1,3-butadiene 10-23, which underwent an intermolecular hetero-Diels-Alder reaction with the enol ethers to give the resin-bound products 10-24. Solvolysis with NaOMe afforded the desired dihydro-pyranes, 10-25 with over 90 % purity. Ene reactions have also been performed in a similar manner [7]. 

An efficient and also elegant synthesis of the active anti-influenza A virus indole alkaloid hirsu-tine 67 is performed by an inter-intermolecular anionic-pericyclic three- component domino reaction followed by solvolysis and hydrogenation (scheme 13).[261 The synthetic sequence developed by us contains first a Knoevenagel condensation of enantiopure 61 and 62 with the formation of the... 

A combination of an intramolecular [5+21-cycloaddition of the pyrone 110 followed by an intermolecular [4 + 2]-cycloaddition with dimethyl-butadiene leads to the fused 6,7,5-tricyclocarboxylic system 112 via 111 as described by Rodriguez et al (scheme 22).1621 The prepared skeleton is found in nature in several terpenes. The starting material for this domino reaction is obtained from maltol 109... 

Scheme 13 Intra-intermolecular domino Heck-Diels-Alder reactions [57-60]...

Abstract Radical tandem reactions—and in a wider context radical dominos or cascades—have attracted a lot of attention because of their intrinsic elegance and the construction of a hroad and sometimes unique array of molecular architectiu es they allow in a single step. This review focuses on the latest progress in the design and development of new tandem reactions. The first part is devoted to intramolecular processes the second part covers tandem and domino processes involving both intra- and intermolecular steps. The third part introduces intermolecular-only reactions. Finally, the last part focuses on tandem reactions involving both radical and non-radical elementary steps. 

Four subtypes of this domino reaction are possible, in which each cycloaddition step can be intra- or intermolecular [12-14]. The domino intermolecular [4 -F 2]/ intramolecular [3 + 2] cycloaddition has been studied extensively, mainly by Denmark and coworkers [12]. The domino intermolecular [4 + 2]/intermolecular [3 + 2] cycloaddition, which has been studied less extensively [13], mostly leads to a lower degree of stereoselectivity than the domino inter/intra cycloadditions. From a combinational point of view however, domino inter [4 + 2 /inter [3 + 2] cycloadditions are more attractive as a high degree of structural diversity can be obtained from simple building blocks. 

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. 

The remainder of this section will focus on the different ways carbopalladation has been used to consuuct natural products. First, Sect. B will consider intermolecular cases. Then, Sect. C will discuss innamolecular carbopalladation showing the potential of the reaction to create small, medium, or large rings. Finally, domino reactions, cycloiso-merizations of enynes, and asymmetric reactions will be highlighted. 

Zhu and coworkers [12] reported the synthesis of unsymmetrically substituted 3-(diarylmethylenyljindolinones via a palladium-catalyzed domino reaction involving intermolecular carbopalladation and C-H activation. For example, the reaction between propiolamide 31 and aryl iodide 32 afforded the oxindole product 33 in 82% yield as a single stereoisomer (Scheme 3.8). The h-configuration of the tetrasubstituted double bond was confirmed by X-ray analysis. 

Subsequent C-H activation generates the five-membered paUadacycle 65, which undergoes intermolecular carbopalladation with aryne 66 to give seven-membered paUadacycle 67. FinaUy, reductive ehmination furnishes the product 62 and regenerates the palladium catalyst. Overall, three C-C bonds are constructed in this reaction sequence. In an earher report, Tanaka and coworkers [23] had observed similar domino reactions with bromoenynes to synthesize benzoisoindoles in the absence of external benzyne acceptors. 

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