Three-component coupling approach

For three-component coupling approach in natural product syntheses, see ... 

Promothiocin A was initially synthesised by a three-component coupling approach <1998CC2049>. A Bohlmann-Rahtz pyridine synthesis established the oxazoyl-thiazole-pyridine heterocyclic centerpiece. The thiazole building blocks were obtained by the Hantzsch reaction. Two different strategies for macrocylization were successfully employed, with the dedroalanine side-chain being introduced in the last steps of the synthesis <2000JA3301>. 

The ultimate in the three-component coupling approach to prostaglandins has now been achieved by Noyori (48). As illustrated in Fig. 15, the cuprate derived from iodide [82] was added to enone [80] in the usual fashion. Then, after addition of hexamethylphosphoramide, triphenyltin chloride was used to effect enolate interchange. As opposed to lithium (or copper) enolates, the tin enolate is cleanly alkylated with allylic iodide [81]. The protected PGE2 [83] was obtained in 78% yield. Two-step deprotection to PGEj was straightforward. 

Scheme 8.82. Three-component coupling approach to quinoxaline derivatives on clay.

An inherent advantage of the Petasis borono-Mannich reaction is the ability to conduct reactions in a three-component fashion, since the imine or iminium ion intermediates can be formed in situ from the condensation of either primary or secondary amines with the corresponding aldehydes or ketones. The operational advantages of such a three-component coupling approach, combined with the practical benefits outlined above, render the Petasis borono-Mannich reaction particularly desirable for parallel synthesis applications and in the generation of combinatorial libraries. In-... 

Takahashi and collaborators [92] have recently reported a three-component coupling approach to RAL framework involving alkylation of a protected cyanohydrin... 

Scheme 7.30 Three-component coupling approach to RAL framework [92].

The third strategy mentioned on Prostaglandins-13 was the a-methylenecyclopentane strategy. This route was introduced by the Stork group and followed the reaction sequence outlined at the bottom of this page. This is clearly a variation of the three-component coupling approach, but it is less efficient because two carbon-carbon bond-forming reactions are used to transform 139 to the PCs. 

Describe the relevance of this observation to the choice of electrophile for introducing the Cg sidechain in the three-component coupling approach to the prostaglandins. (Prostaglandins-17)... 

Scheme 12.52 Three-component coupling approach to 3-substituted JV-aryl piperidines.

Recently, Larock and coworkers used a domino Heck/Suzuki process for the synthesis of a multitude of tamoxifen analogues [48] (Scheme 6/1.20). In their approach, these authors used a three-component coupling reaction of readily available aryl iodides, internal alkynes and aryl boronic acids to give the expected tetrasubsti-tuted olefins in good yields. As an example, treatment of a mixture of phenyliodide, the alkyne 6/1-78 and phenylboronic acid with catalytic amounts of PdCl2(PhCN)2 gave 6/1-79 in 90% yield. In this process, substituted aryl iodides and heteroaromatic boronic acids may also be employed. It can be assumed that, after Pd°-cata-lyzed oxidative addition of the aryl iodide, a ds-carbopalladation of the internal alkyne takes place to form a vinylic palladium intermediate. This then reacts with the ate complex of the aryl boronic acid in a transmetalation, followed by a reductive elimination. 

During the last decade, a substantial number of novel (sometimes even stereoselective) strategies for the preparation of allenic prostaglandins have been devised. The approach used by Patterson involves a three-component coupling via a 1,4-addi-tion of the organocopper compound 121 to the enone 120, followed by alkylation of the enolate formed with the bromide 122 (Scheme 18.40) [121]. However, due to the notoriously low reactivity in the alkylation of the mixed copper-lithium enolate formed during the Michael addition [122], the desired product 123 was obtained with only 28% chemical yield (the alkylation was not even stereoselective, giving 123 as a 1 1 mixture of diastereomers). 

Cycloisomerization represents another approach for the construction of cyclic compounds from acyclic substrates, with iridium complexes functioning as efficient catalysts. The reaction of enynes has been widely studied for example, Chatani et al. reported the transformation of 1,6-enynes into 1-vinylcyclopentenes using [lrCl(CO)3]n (Scheme 11.26) [39]. In contrast, when 1,6-enynes were submitted in the presence of [lrCl(cod)]2 and AcOH, cyclopentanes with two exo-olefin moieties were obtained (Scheme 11.27) [39]. Interestingly, however, when the Ir-DPPF complex was used, the geometry of olefinic moiety in the product was opposite (Scheme 11.28) [17]. The Ir-catalyzed cycloisomerization was efficiently utilized in a tandem reaction along with a Cu(l)-catalyzed three-component coupling, Diels-Alder reaction, and dehydrogenation for the synthesis of polycyclic pyrroles [40]. 

Scheme 3 illustrates retrosynthetic analysis of the E and F series of PGs. The widely used Corey synthesis (2) takes notice of the presence of the two olefinic bonds in the side chains of PGF2a. The actual synthesis consists of a two-fold Wittig-type chain extension of a chiral dialdehyde equivalent with four defined stereogenic centers derived from cyclopentadiene via a series of bicyclic intermediates. A similar sequential synthesis has been developed at Upjohn Co. (la). These chemical syntheses are much more economical than enzymatic methods and are used for commercial synthesis of certain PGs. An alternative pathway pioneered by Sih is the conjugate addition approach (3). Nucleophilic addition of an E-olefinic co side-chain unit to a cyclopentenone in which the a side chain is already installed leads directly to PGE-type compounds. Untch and Stork used an co chain unit with a Z-olefinic bond (4). The most direct and flexible synthesis is the convergent three-component coupling synthesis via consecutive linking of the two side chains to unsubstituted 4-hydroxy-2-cyclopentenone derivatives (5, 6). 

Microwave irradiation has been proven useful in accelerating chemical reactions. A unique approach to multicomponent reactions - the combination of microwave irradiation and microreactors - was developed by Organ and Bremner [25]. The three-component coupling reaction of amino pyrazole with an aldehyde and diketone in a glass capillary tube microflow system (1180 pm i.d.) under microwave irradiation (170 W) proceeded smoothly to give the desired quinolinone in high yield (Scheme 4.16). Without microwave irradiation, the reaction efficiency was very low. 

Tetrahydroisoquinolonic acids are formed in good yields and enhanced rates from three-component coupling reactions of benzaldehydes, amines, and homophthalic anhydride. The key feature of this approach is the use of ionic liquids <03T1805>. 

Bose, D. S., Fatima, L., Mereyala, H. B. Green Chemistry Approaches to the Synthesis of 5-Alkoxycarbonyl-4-aryl-3,4- dihydropyrimidin-2(1 H)-ones by a Three-Component Coupling of One-Pot Condensation Reaction Comparison of Ethanol, Water, and Solvent-free Conditions. J. Org. Chem. 2003, 68, 587-590. 

An impressive alternate approach to the synthesis of furans beginning with alkynols was developed by Balme [160, 161] and subsequently applied in a total synthesis by Morimoto [162]. Balme discovered that a three-component coupling reaction between a propargylic alkoxide, a conjugate addition acceptor, and an unsaturated halide yields a variety of di- and trisubstituted furans. In one example, propargyl alcohol, diethyl ethoxymethylene malonate (193), and iodobenzene combine to furnish disubstituted furan 194 in... 

Several examples have appeared in the literature in which this linker has been employed in combinatorial chemistry strategies. Thus, it has been used in a Pd-mediated three-component coupling strategy for the solid-phase synthesis of tropane derivatives [46], in the solid-phase synthesis of aspartic acid protease inhibitors [47], in the attachment of cholic acid as a template for a combinatorial approach [48] and, more recently, in the solid-phase synthesis of pyrrolidines via 2-aza allyl anion cycloadditions with alkenes [49]. 

Some catalytic pathways have been exploited to assist the cyclization step or even the initial O-acylation of the amidoxime. In this context, Zn(II) catalysts have been explored and efficiendy used for 1,2,4-oxadiazole production, although the proposed catalytic role still remains to be supported by further mechanistic studies (2014IC10312). An interesting approach to 5-aryl derivatives 14, still involving an O-acylamidoxime intermediate (13), produces such an intermediate by a three-component coupling using a haloarene 12, the amidoxime 5, and carbon monoxide in the presence of a Pd(0) catalyst (Scheme 4 2014ASC3074). 

Mi, Chen, and Xu described their synthetic approach to SFs-substituted quinohnes via the FeCls-catalyzed three-component coupling reaction of... 

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