Intermolecular Tandem Reactions

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. 

Extension of the linkage to hve atoms as in 285 provides routes to pyrazolines or pyrazoles 286, or 1,2,4-triazoles 287, fused to a seven-membered ring. The products are potentially biologically active and examples have been reported for X=N (177-181), X = 0 (181-185) and for a pyrazolo fused analogue (186) and X = S (187). In some cases, [e.g., (183)], these reactions are accompanied by tandem intramolecular-intermolecular reactions leading to the formation of macrocycles (see the section Tandem Intermolecular-Intramolecular Cycloaddition Reactions). 

Hashimoto has shown that the the valine-derived catalyst Rh2(S-BPTV)4 (5) is effective in intermolecular tandem cyclization/intermolecular cycloaddition resulting in the formation of 46 in 92% ee (Eq. (26) [10]. More recent studies have broadened the range of substrates that can be used in the reaction although the enantioselectivity is variable [38,39],... 

As a synthetic application to biologically active compounds, eq. 8.19a shows the preparation of nucleoside antibiotics (44a) and (44b). Tyromycin (45) inhibits the leucine and cysteine aminopeptidases, and it can be prepared in good yield from the photolytic treatment of the Af-acyloxy diester with citraconic anhydride, followed by silica gel treatment, as shown in eq. 8.19b [55-60]. Other synthetic applications using intra- and intermolecular tandem reactions were also studied [61, 62]. 

The great majority of radical cascades involve sequences of intramolecular steps where the overall propagation is a unimolecular process (with the exclusion of the initiation and termination steps), and recent overviews are given in Refs 1-5. However, meanwhile many tandem reactions involving both intra- and intermolecular steps, as well as multicomponent tandem reactions, have been reported in the literature, which are compiled in recent reviews. " ... 

Intermolecular additions of alcohols to alkynes can be coupled with other tandem reactions of the alkenyl-gold intermediate. Thus, reaction between salicylaldehyde and phenylacetylenes can give access to the isoflavanone skeleton (equation 7), whereas a three-component addition of methylenecylopropylcarbinols, arylalkynes, and alcohols leads to bicyclic compounds (equation 8). ... 

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. 

Tandem Reactions Involving Both Intra- and Intermolecular Steps... 

With Mn(OAc)3, generated by oxidation of Mn(OAc)2 as mediator, a tandem reaction consisting of an intermolecular radical addition followed by an intramolecular electrophilic aromatic substitution can be accomplished [Eq. (21b)] [225b]. Further Mn(III)-mediated additions of 1,3-dicarbonyl compound to olefins are shown in Table 11 (numbers 8b,c, and 9a). Mediated by in situ generated Mn(III), methyl dibromoacetate, trichloro-bromomethane, perfluoroctyl iodide, dimethyl bromomalonate, and active methylene compounds have been added via radicals to olefins [225d]. 

The Mannich reaction is a very common process that occurs in many tandem reaction sequences. For example, the Overman Aza-Cope cascade sequence is terminated by a Mannich reaction (cf. Scheme 35). Several groups have used variants of the Mannich reaction to initiate cascades that lead to the formation of heterocyclic molecules. For example, the Lewis acid-catalyzed intermolecular vinylogous Mannich reaction (01T3221) of silyloxy furan 281 with nitrone 282 produced a diastereomeric mixture (49 3 42 6) of azabicycles 284a-d in 97% combined yield (Scheme 52) (96TA1059). These products arose from an intramolecular Michael addition of the initially formed oxonium ion 283. 

During the following several years, many examples of organocatalytic tandem reactions such as the intramolecular a-alkylation step were developed, but they are not subjected in this chapter [113]. Unlike any yet published example of intermolecular a-alkylation of aldehydes and ketones via an Sat2 mechanism, several works via the SAr2 -type addition-elimination pathway were disclosed to date. 

In addition to the 1,3-dienes, in situ formed allenes were applied as substrates and cyclized with 2-iodophenols as well. In 2007, Liang and co-workers reported a novel palladium-catalyzed intermolecular tandem reaction for the synthesis of tetracyclic compounds from propargylic compounds and 2-iodophenols. The corresponding tetracyclic compounds were isolated in moderate to good yields (Scheme 2.47). In respect of the reaction pathway, the possible reaction intermediate was isolated and applied. In detail, this transformation consists of two catalytic cycles. The steps are (a) initial decarboxylation of propargylic compound by palladium(O) to... 

The ring closure product can also be obtained by intermolecular-intramoleeular tandem reactions. The first step is initiated by a bimoleetilar radical reaction, for example, the addition of radicals R onto unsaturated bonds (generally alkenes and alkynes [12]) to generate radieal 17, with the second step involving intramolecular HAS from 17 to yield the cyclohexadienyl radical 18, which finally affords 19 (Eq. 9.3). Another possibility is the addition of the radical R to a... 

Intermolecular and intramolecular HAMs are known. The transformation can be considered as a tandem reaction [2,3] consisting of three consecutive steps (i) hydroformylation, (ii) formation of an imine or an enamine, and (iii) reduction. Finally, the Af-alkylated amine is produced [4]. Clearly, these reactions can also be carried out in separate steps, but the application of uniform reaction conditions offers considerable advantages, such as the use of a single catalyst for the hydroformylation and the hydrogenation steps. Moreover, the equihbrium of the formation of the intermediate imine or enamine can be advantageously shifted by the irreversible hydrogenation in the last step [5]. 

Based on the concept of tandem reaction, a series of synthetic routes have been developed, including an intramolecular Aldol/Oxa-Michael/Aldol/Lactonization synthetic strategy (see Fig. 1.17). The retrosynthetic analysis indicated that the synthesis starts from compound 1.7.21, which first undergoes an intramolecular Aldol reaction then immediately intramolecular Oxa-Michael reaction to form the tricyclic system. Finally through the intermolecular Aldol reaction and intramolecular esterification reaction, the tetracyclic skeleton of Maoecrystal V can be constructed. And 1.7.21 can be provided by the relatively simple materials 1.7.22 and 1.7.23 through Suzuki cross-coupling reaction. 

As noted for polymerization reactions (Section 6.2.1.5), the first intermolecular coupling should be favored over the cydization. Thus, changing the propylene fragment to an ethylene or methylene group in the dicarbonyl precursor of compound 83 facilitated the tandem reaction [112]. The yields of such two-step pro-... 

Since its discovery just over thirty years ago, the Nicholas reaction has become a highly useful tool for the organic chemistry community. Applications of the Nicholas reaction fall into four categories intermolecular reactions, endocyclic intramolecular reactions, exocyclic intramolecular reactions, and tandem reactions. For this discussion, endocyclic means that the cobalt-complexed alkyne is in the ring formed during the Nicholas reaction, while exocyclic indicates that the cobalt-alkyne complex is outside the newly generated ring. 

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