Multicomponent coupling-cycloaddition

Multicomponent Coupling-Cycloaddition Sequences via Alkynone Intermediates 72... 

MULTICOMPONENT COUPLING-CYCLOADDITION SEQUENCES VIA ALKYNONE INTERMEDIATES... 

This new multicomponent cascade reaction can also be performed with a large variety of aryl halides, most favorably iodides (Scheme 7). The yields in this coupling-cycloaddition sequence are particularly high with the parent... 

Multicomponent Synthesis of Heterocycles by Coupling-Cycloaddition Sequences... 

Annulated pyridines have also been synthesized via a (4+2) cycloaddition strategy involving oxazole 6, which is made via a multicomponent coupling reaction in a single step <01OL877>. Acylation of 6 with a a,P-unsaturated acyl chloride is the first step in a domino reaction where an intramolecular Diels-Alder reaction is followed by a retro-Michael reaction (7-+8). 

Another recent development in the field of palladium-catalyzed reactions with alkynes is a novel multicomponent approach devised by the Lee group. Starting from a-bromovinyl arenes and propargyl bromides, the assembly ofeight-membered car-bocycles can be realized via a cross-coupling/[4+4] cycloaddition reaction. The authors also presented the combination of a cross-coupling and homo [4+2], hetero [4+2], hetero [4+4] or [4+4+1] annulation leading to various cyclic products [147]. 

Likewise, an efficient one-pot multicomponent synthesis of annelated 2-amino pyridines (e.g., 17) utilizing [4+2] cycloadditions has been described <06JOC3494>. The process involves the in situ generation of 1-aza-1,3-butadiene from a palladium-catalyzed coupling-isomerization reaction of aryl halides (e.g., 18) with propargyl V-tosylamines (e.g., 19). The resulting butadiene then undergoes cycloadditions with V.S -ketene acetals (e.g., 20) to form annelated pyridines (e.g., 17). 

The same group reported on a library synthesis of 3-aminoimidazo[l,2-a]-pyridines/pyrazines by fluorous multicomponent reactions. Here the overall yields, as well as the yields for the separate Suzuki-Miyaura reactions that were a part of the synthesis, were relatively low due to competing reactions and the poor reactivities of the substrates, but the speed of the microwave-mediated syntheses and ease of separation underlined the usefulness of fluorous reagents [140]. A recent paper further illustrated the use of Suzuki-Miyaura couplings of aryl perfluorooctylsulfonates in the decoration of products derived from 1,3-dipolar cycloadditions [141]. 

Pyranoisoxazoles 425 have been prepared by intramolecular 1,3-dipolar cycloaddition of nitrile oxides obtained by treatment of nitrooxaheptynes with -BuLi and AC2O (Scheme 102) <2003H(59)685>. The coupling of the Ugi multicomponent reaction with the intramolecular T-oxide cyclization (Ugi/INOC) provided access to novel fused isoxazoles 426 in two steps from easily available starting materials in moderate to good overall yields... 

An alternative approach to multicomponent heterocycle synthesis involves the use of palladium catalysis to construct keto-alkynes for cycloaddition reactions. Muller has demonstrated the power of this approach in the construction of a range of aromatic heterocycles. For example, the palladium-catalyzed coupling of acid chlorides with terminal alkynes provides a method to assemble 36. The trapping of this substrate can provide routes to aromatic heterocycles. As an example, the addition of amidines provides a multicomponent synthesis of pyrimidines (Scheme 6.69) [97]. This same substrate 36 is available via the carhonylative coupling of aryl halides with terminal alkynes, providing a four-component synthesis of pyrimidines (98j. 36 can also be employed in 1,3-dipolar cydoaddition reactions. For example, cydoaddition... 

As the intermolecular multicomponent reactions, three-component cycloaddition reactions (21.2 [2+2-1-2] cycloaddition and 21.3 [3+2+1] cycloaddition) and two-component cycloaddition reactions (21.4 [4+2] cycloaddition) are described. As the intramolecnlar single-component reactions, cycloaromatization reactions (21.5 intramolecular hydroarylation of alkynes and cychzation via transition metal vinybdenes) are described. Aromatic ring constrnction reactions involving aryne reactions (Chapter 12), rearrangement reactions (Chapters 16 and 18), metathesis reactions (Chapter 17), and coupling reactions (Chapters 19 and 20) are described in these different chapters. 

Some interesting multicomponent syntheses of simple furan derivatives in water have been disclosed. For instance, Yadav reported the preparation of highly functionalized 2-aminofuran derivatives 26 in water via the coupling of aldehydes with dimethyl acetylenedicaiboxylate and cyclohexyl isocyanide [20]. This transformation presumably starts by the initial Michael addition of the isocyanide onto the acetylenedicaiboxylate diester, generating the 1,3-dipole 27, whose subsequent [3+2] cycloaddition to the aldehyde carbonyl followed by tautomerization leads to the observed product (Scheme 1.14). 

Additionally, Pd-catalyzed cross-coupling reactions were explored in pyridines synthesis also. In 2007, a multicomponent sequential process for the synthesis of trisubstituted pyridines was reported [59]. The reaction involves the formation of an enamine by Pd-catalyzed amination of an alkenyl bromide, formation of a 2-aza-1,3-butadiene by Pd-catalyzed cross-coupling of a trimethylsilylimine with an alkenyl bromide, and Lewis acid (Yb(OTf)3 (20mol%)) catalyzed cycloaddition between the enamine and the azadiene. Moderate yields can be achieved (Scheme 3.26). A zinc-mediated tandem reaction of nitriles... 

One of the most appealing aspects of these multicomponent syntheses is the reactivity of the components. Often, the reaction sequence commences without the aid of external catalysts and still preserves selectivity. However, sometimes the reactive center is created in situ, which does require the assistance of an external catalyst. Transition metals, for instance, can be effectively used to induce reactivity, like in the synthesis of another viral protein inhibitor. The work of Garner and coworkers provided a new route to the core of a novel influenza neuramidase inhibitor in one pot [38]. The [C -I- NC -I- CC] coupling reaction proceeds via a metalated azomethine ylide by condensation of the amine 134 and aldehyde 132, which undergoes a [3 -l- 2] cycloaddition with activated dipolarophile 133 (Scheme 14.17). 

IL-supported one-pot multicomponent reaction for the construction of bi-heterocyclic-fused pyrrolo[l,2-a]benz-imidazoles 114 under microwave irradiation were reported by Sxm and coworkers (Scheme 12) [47]. The IL-anchored diamines 97 were coupled with cyanoacetic acid followed by cyclodehydration to generate key intermediate 2-sub-stituted benzimidazoles 113. IL-supported 113 reacted with aldehyde and isocyanide through Knoevenagel condensation followed by [4 +1] cycloaddition in one-pot affording pyrrolo[l,2-fl]benzimidazole 114. Remarkably, this is the first time applied IL support and isocyanide-based multicomponent react for the synthesis of fused tricyclic heterocycles under microwave irradiation. 

Several multicomponent cascade reactions involving a critical Diels-Alder cycloaddition have been recently described by Huang and Xu. Thus, a one-pot preparation of isoindoles such as 172 involves an Ugi four-component coupling of furfural (167a) with benzyl amine (168a), 2-(phenylselanyl)acrylic acid (169a), and benzylisonitrile... 

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