Coupling three component

To a solution of methyl 3-oxobutanoate 127 (580 mg, 5 mmol) and l-methyl-2-methylthio-l//-imidazole-5-carboxaldehye 128 (390 mg, 2.5 mmol) in 5 mL of absolute methanol was added a solution of ammonium hydroxide (25%, 0.4 mL). The reaction was heated at reflux overnight before cooling to room temperature and removing the solvent. The crude product was purified by preparative TLC to afford 526 mg of dimethyl l,4-dihydro-2,6-dimethyl-4-(l-methyl-2-methylthio-5-imidazolyl)-3,5-pyridine-dicarboxylate 129 (60%) as a solid, mp = 200-201 °C (MeOH). 

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Three-component coupling with vinylstannane. norbornene (80). and bro-mobenzene affords the product 91 via oxidative addition, insertion, transme-tallation, and reductive elimination[85]. Asymmetric multipoint control in the formation of 94 and 95 in a ratio of 10 1 was achieved by diastereo-differ-entiative assembly of norbornene (80), the (5 )-(Z)-3-siloxyvinyl iodide 92 and the alkyne 93, showing that the control of four chiralities in 94 is possible by use of the single chirality of the iodide 92. The double bond in 92 should be Z no selectivity was observed with E form[86]. 

The Hantzsch pyridine synthesis involves the condensation of two equivalents of a 3-dicarbonyl compound, one equivalent of an aldehyde and one equivalent of ammonia. The immediate result from this three-component coupling, 1,4-dihydropyridine 1, is easily oxidized to fully substituted pyridine 2. Saponification and decarboxylation of the 3,5-ester substituents leads to 2,4,6-trisubstituted pyridine 3. 

It has been shown that TMSI is capable of mediating the reaction at room temperature. The classical three component coupling was carried out using aldehyde 82 and ketoester 83 with ammonium acetate in acetonitrile at room temperature with in situ generated TMSI. This gave a 73-80% yield of 1,4-dihydropyridines 84 in 6-8 h. The best results were obtained with 1 equivalent of TMSCl and 1 equivalent of Nal. 

The Doebner reaction is a three component coupling of an aniline (1), pyruvic acid (2), and an aldehyde (3) to provide a 4-carboxyl quinoline (4). That product can be decarboxylated to furnish quinoline 5. 

Doebner also found that under certain conditions (specifically cold ether), the result of the three-component coupling was not the quinoline but diketopyrrolidine 10." ... 

The preparation and use of derivatized Meldrum s acid has led to an alternative preparation of 2-substituted quinolines (49 and 50) and the preparation of pyridopyrimidines (52). When Meldrum s acid derivatives are used (as shown in this example) decarboxylation occurred under the cyclization conditions. Three component coupling has been used to readily assemble the desired 3-anilino-acrylate from reaction of Meldrum s acid, (EtO)3CH and an aniline (e.g. 54 or 55).< ... 

A short synthesis of ptostaglandm derivatives via a three component coupling reaction reported, in which the enolates are trapped v/ith nitroalkenes. The nitro group is removed v... 

Scheme 5. Larock s palladium-promoted, three-component coupling strategy for prostaglandin synthesis.

Iwasawa et al. also developed a new reaction involving a three-component coupling process which affords five-membered heterocycles. This [2s+2sh-1c] cycloaddition reaction supposes the consecutive addition of an alkynyllithium derivative to a Fischer carbene complex followed by the addition of a third component which can be an aldehyde, an imine, an isocyanate, or C02 [119] (Scheme 74). 

Radical-based carbonylation procedures can be advantageously mediated by (TMSlsSiH. Examples of three-component coupling reactions are given in Reactions (74) and (75). The cascade proceeds by the addition of an alkyl or vinyl radical onto carbon monoxide with formation of an acyl radical intermediate, which can further react with electron-deficient olefins to lead to the polyfunctionalized compounds. ... 

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]. 

Scheme 17 Iron-catalyzed three-component coupling reactions of aldehydes, terminal alkynes, and amines...

Scheme 18 Plausible mechanism of iron-catalyzed three-component coupling of aldehyde,...

Dithioacetal monoxides undergo Michael addition to acrylonitrile. The addition products are easily converted into y-ketonitriles 382 (equation 221). Benzenesulphinyl allylic carbanions 383 derived from the corresponding allylic sulphoxides react selectively at the y-position with a variety of cycloalkenones to give the l,4-adducts " (equation 222). Recently, Nokami and coworkers have synthesized some prostaglandin analogues via a three-component coupling process involving 1,4-addition of phenylsul-phinyl allylic carbanion (equation 223) . ... 

Scheme 2.1 Three-components coupling strategy for 1 by medicinal chemists.

Recently, a Pd/Cu-catalyzed three-component coupling reaction of aryl halides, norbomadiene, and alkynols was reported to generate 2,3-disubstituted norbomenes in high yields in the presence of aqueous NaOH and a phase-transfer catalyst in toluene at 100°C (Eq. 3.39).151... 

Recently, the three-component couplings of a-oxyaldehydes, alkynes, and amines in water were investigated by using gold, silver, and copper... 

The above studies illustrated that sp2-hybridized organozincs underwent direct addition to aldehydes rapidly, thus preventing the desired three-component couplings. However, alkenylzirconium reagents, derived from hy-... 

Scheme 2.15. Three-component coupling of thiolate 2-67, cyclohexenone (2-29a), and imines 2-68.

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. 

Scheme 6/2.24. Rhodium-catalyzed three-component coupling of C6o with diynes and a silane.

The three-component coupling systems explored extensively by Zhu has been used to synthesize tricyclic azaindole derivatives 153 from 150, heptanal 151, and an aryl- or alkylamine 152 (Equation 35) <20050L239>. 

Three-component coupling of methylenecyclopropane 137 with iodoben-zene or 2-bromopropene and malonate anion is catalyzed by a palladium(0)... 

A three-component coupling was used to prepare a series of 1,4-disubstituted-l,2,3-triazoles 129 from the corresponding acetylated Baylis-Hillman adducts 127, sodium azide and terminal alkynes 128 <06TL3059>. This same reaction was also carried out in either water or in... 

Efficient synthesis of highly substituted alkylpyrroles and fused pyrroles has been achieved by three-component coupling of ... 

Bromoalkynes also couple with vinylstannanes readily to result in enynes. Synthesis of protected enynals via cross-coupling of vinylstannanes with 1-bromoalkynes in the presence of a catalytic amount of Pd(II) has been reported (equation 143)252. Hiyama and coworkers extended the Stille methodology for sequential three-component coupling of trimethylstannyl(trimethylsilyl)acetylene with a vinyl iodide in the first step and cross-coupling of the intermediate trimethylsilylethyne with another alkenyl iodide in the presence of tris(diethylamino)sulphonium trimethyldifluorosilicate in the second step to generate a dienyne (equation 144)253. Both steps occur under palladium catalysis, in one-pot, to result in stereodefined l,5-dien-3-ynes. 

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