Three-component Rout

A short three-component route to prostaglandins was developed involving a number of novel steps, several of which were based on special properties of the (9-methyloxime function. 

LTA4 was also synthesized by a three-component route to the oxiranyl carbinol intermediate (Ref. 7). 

Scheme 32 TMSCl-catalyzed three-component route to indazolophthalazide-trione derivatives...

Dey S, Pal C, Nandi D, Giri VS, Zaidlewicz M, Krzeminski M, Smentek L, Hess BA, Gawronski J, Kwit M, Babu NJ, Nangia A, Jaisankar P (2008) Lewis acid-catalyzed one-pot, three-component route to chiral 3,3 -bipyrroles. Org Lett 10 1373-1376... 

Zhu et al. described two independent one-pot three-component routes to Ceo pyrrolidines 174 and 175 involving microwave activation (Scheme 11.42) [104]. In the first approach, a solution of Ceo, 171, amino acid 172 and fluorinated benzaldehyde 173 was heated at reflux in o-dichlorobenzene under the action of microwave irradiation. The in sitw-generated fluorinated azomethine ylides undergo cydoaddition... 

Sayyafi, M., Seyyedhamzeh, M., Khavasi, H.R., Bazgir, A. 2008. One-pot, three-component route to 2H-indazolo[2,l-fc]phthalazine-triones. Tetrahedron 64(10) 2375-2378. 

Two-component methods represent the most widely applied principles in sulfone syntheses, including C—S bond formation between carbon and RSOz species of nucleophilic, radical or electrophilic character as well as oxidations of thioethers or sulfoxides, and cheletropic reactions of sulfur dioxide. Three-component methods use sulfur dioxide as a binding link in order to connect two carbons by a radical or polar route, or use sulfur trioxide as an electrophilic condensation agent to combine two hydrocarbon moieties by a sulfonyl bridge with elimination of water. 

The coupling reactions of alkynes and aldehydes catalyzed by iron(III) salts have been discussed above (Scheme 10, routes B and C). The three-component coupling of aldehydes, alkynes, and amines is equivalent to the coupling reaction between alkynes and imines. Wang et al. reported such a three-component coupling catalyzed by FeCls in the absence of any ligand (Scheme 17) [33]. 

AGE3808, 2004T6197>, and the alkaloid itself has subsequently been obtained in 5.6% overall yield by an alternative route from the three components shown in the retrosynthetic equation , Equation (238), the longest linear sequence consisting of 19 steps <2005OL3247>. 

A different multicomponent route to imidazoles has been described by the group of O Shea, involving the diversity-tolerant three-component condensation of an aldehyde, a 2-oxo-thioacetamide, and an alkyl bromide (5 equivalents) in the presence of ammonium acetate (Scheme 6.201) [364]. This allowed the preparation of a 24-membered 4(5)-alkylthio-lH-imidazole demonstration library from 21 different aldehydes, 12 alkyl bromides, and two 2-oxo-thioacetamides. The library was synthesized in a parallel format using a custom-built reaction vessel. Alkylthioimidazoles... 

Elegant contributions to this fidd have also been made by Grigg et al espedally interesting are his palladium-anion capture domino processes. By this way a direct route to protected pseudoargiopinine III 127, a toxine from Argiope bbata, has been developed using a three-component process of allene 125... 

Betaines 375 and 376 could be isolated in the three-component reaction of carboxyclic iminophosphoranes (374) with aryl isocyanates and pyridines or quinolines as heteroarene components (93UP1). This route (Scheme 135) opens another broad range of novel heterocyclic systems. 

The imidazole ring is often found in biologically active molecules and is as such important in medicinal chemistry [16]. An interesting route for the production of substituted imidazoles is the Debus-Radziszewski reaction. This is a three-component reaction of a diketone, an amine and an aldehyde to form trisubstituted imidazoles (Scheme 3). 

Scheme 40 Formation of a-aminophosphonates by a three-component (a) or a two-component (b) route [97]...

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

An alternative route for installing a methyl ketone is the three component carbonylative-Stille coupling with tetramethyltin. An indolopyridine alkaloid, naucletine (58), was prepared using such a sequence from pyridyl bromide 57 <95CC1675>. 

Dialkylzinc derivatives are inert towards conjugated enones (e.g. 181) in hydrocarbon or ethereal solvents. The discovery that a conjugate addition can be promoted by Cu(I) salts in the presence of suitable ligands L (e.g. sulphonamide 182) opened a new route to zinc enolates (e.g. 183), and hence to the development of three-component protocols, such as the tandem 1,4-addition/aldol addition process outlined in equation 92186. If the addition of the aldehyde is carried out at —78 °C, the single adduct 184 is formed, among four possible diastereomeric products. The presence of sulphonamide is fundamental in terms of reaction kinetics its role is supposed to be in binding both Cu(I) and Zn(II) and forming a mixed metal cluster compound which acts as the true 1,4-addition catalyst. 

The 1,2,4-thiadiazole ring (2) may obviously be built up from simpler fragments in many ways, but of these only three general routes are important these approaches, classified according to the nature of the components which join to form the ring, are illustrated by A-C. A... 

Tanaka and co-workers have reported two routes for the catalytic synthesis of cyclic silyl enol ethers from silacylobutanes. The strained silacarbo-cycle174 can react directly with an acid chloride175,176 or in a three-component reaction with an organic halide and carbon monoxide177 to yield cyclic products that contain an Si-O bond [Eqs. (68) and (69)]. 

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