Coupling, four-component

It is supposed that the nickel enolate intermediate 157 reacts with electrophiles rather than with protons. The successful use of trimethylsilyl-sub-stituted amines (Scheme 57) permits a new carbon-carbon bond to be formed between 157 and electrophiles such as benzaldehyde and ethyl acrylate. The adduct 158 is obtained stereoselectively only by mixing nickel tetracarbonyl, the gem-dibromocyclopropane 150, dimethyl (trimethylsilyl) amine, and an electrophile [82]. gem-Functionalization on a cyclopropane ring carbon atom is attained in this four-component coupling reaction. Phenyl trimethyl silylsulfide serves as an excellent nucleophile to yield the thiol ester, which is in sharp contrast to the formation of a complicated product mixture starting from thiols instead of the silylsulfide [81]. (Scheme 58)... 

Recently, four-component coupling reactions of aldehydes, alkynes, dienes, and dimethylzinc catalyzed by a nickel complex have been reported (Equation (78)).435 Similarly, l,c< -dienynes react with carbonyl compounds and dimethylzinc in the presence of an Ni catalyst to afford the corresponding cyclized products. 

A four-component coupling reaction proceeds, forming a cyclopentane ring through sequential selective addition and cyclization, although the product is obtained as a mixture of stereoisomers (Scheme 40).202... 

In this section I refer to a number of cycloadditions which cannot be categorized into the above-described types. For example, Murai and colleagues reported the four-component coupling of alkyne, hydrazone, hydrosilane and CO. Here, the [Ir4(CO)i2]-catalyzed reaction proceeded under pressurized CO conditions at high temperature, whereby a seven-membered nitrogen heterocycle was obtained (Scheme 11.37) [48]. 

Seike H, Sorensen EJ (2008) A synthesis of the tricyclic core structure of FR901483 featuring an Ugi four-component coupling and a remarkably selective elimination reaction. 

Mukund Sibi of North Dakota State University has developed (J. Am. Chem. Soc. 2004,126,718) a powerful three-component coupling, combining an a,(5-unsaturated amide 9, a hydroxylamine 10, and an aldehyde 11. The hydroxylamine condenses with the aldehyde to give the nitrone, which then adds in a dipolar sense to the unsaturated ester. The reaction proceeds with high diastereocontrol, and the absolute configuration is set by the chiral Cu catalyst. As the amide 9 can be prepared by condensation of a phosphonacetate with another aldehyde, the product 12 can be seen as the product of a four-component coupling, chirally-controlled aldol addition and Mannich condensation on a starting acetamide. 

Free-radical-mediated four-component coupling reactions are rare. However, when an allyltin-mediated radical carbonylation is conducted in the presence of electron-deficient alkenes, four-component coupling reactions take place efficiently to give good yields of p-functionalized <5,fi-unsaturated ketones [40]. The wide scope of this four-component coupling reaction is noteworthy Primary, secondary, and tertiary alkyl bromides and iodides can be used as well as aromatic and vinylic halides. A variety of electron-deficient alkenes, such as methyl vinyl ketone, ethyl acrylate, acrolein, acrylonitrile, and vinyl sulfone, can be used as the acyl radical trap (Scheme 6.23). Fluorous allyltin compounds can also be used in four-component coupling reactions [41]. 

This synthesis featured a four-component coupling involving an oxidative dimerization process. Treatment of homochiral acyl silane 56 with vinyl lithium at low temperature, followed by the addition of half an equivalent of iodine to the reaction mixture, furnished tetraene 58 in high yield and with a very high level of stereoselectivity. The TBS ether was then converted to its triflate equivalent 59 in a... 

Kobayashi S, Akiyama R, Moriwaki M, Three-component or four-component coupling reactions leading to 6-lactams, Facile synthesis of y-acyl-6-lactams from silyl enolates, a, /l-unsaturated thioesters, and imines or amines and aldehydes via tandem Michael-imino aldol reactions, Tetrahedron Lett., 38 4819—4822, 1997. 

Fully substituted triazoles were synthesized via the four-component coupling reaction of the unactivated silylacetylenes 50, two equivalents of allyl carbonates 5b, and trimethylsilyl azide 42 in the presence of a Pd(0)-Cu(I) bimetallic catalyst (Scheme 18) [54], Various trisubstituted 1,2,3-triazoles were obtained in good yields. The reaction most probably proceeds through the formation of alkynylcopper species 52, which on cross-coupling reaction with the 7r-allylpalladium complex 53 gives the products 51. 

Ahmed MSM, Kobayashi K, Mori A (2005) One-pot construction of pyrazoles and isoxa-zoles with palladium-catalyzed four-component coupling. Org Lett 7 4487-4489... 

Andreana and co-workers [188] developed a one-pot method for generating molecular diversity via a multicomponent coupling reaction under microwave irradiation. The initially formed Ugi four-component coupling products gave rise to three structurally distinct scaffolds depending on the solvent effects and sterics the 2,5-diketopiperazines 137, the 2-azaspiro[4.5]deca-6,9-diene-3,8-diones 138, and the thiophene-derived Diels-Alder tricyclic lactams 139 (Scheme 107). 

DiMauro EF, Kennedy JM (2007) Rapid synthesis of 3-amino-imidazopyridines by a microwave-assisted four-component coupling in one pot. J Org Chem 72 1013-1016... 

Four-component coupling of a terminal alkyne, hydroxylamine, carbon monoxide, and an aryl iodide in the presence of a palladium catalyst allowed the regioselective preparation of 3,5-diarylisoxazoles 428. The reaction proceeds at room temperature and an ambient pressure of CO in an aqueous solvent system (Equation 68) <2005OL4487>. 

The stereoselectivity of these four-component coupling reactions were remarkable in most cases. Similar Ugi reactions were studied using per-O-pivaloylated L-fucopyranosylamine as... 

The total synthesis of (+)- -onocerin via four-component coupling and tetracyclization steps was achieved in the laboratory of E.J. Corey. The farnesyl acetate-derived acyl silane was treated with vinyllithium, which brought about the stereospecific formation of a (Z)-silyl enol ether as a result of a spontaneous Brook rearrangement. In the same pot, the solution of I2 was added to obtain the desired diepoxide via oxidative dimerization. 

Tandem sequences have also yielded some interesting pyrazole structures. Four-component coupling of terminal alkynes 37, hydrazines 38, carbon monoxide and aryl iodides furnished pyrazoles 39 in the presence of palladium catalyst <05OL4487>. Fully substituted 1/f-pyrazoles 42 were prepared from the condensation/fragmentation/cyclization/extrusion reactions of thietanone 40 with 1,2,4,5-tetrazines 41 <05JOC8468>. Reactions of isocyanides 43 and dialkyl acetylenedicarboxylates 44 in the presence of 1,2-diacylhydrazines 45 led to highly-functionalized pyrazolines 46 <05TL6545>. 

More recently, chemists seem to be able to invent multi-component reactions almost at will. An outstanding example is this four-component coupling catalysed by ruthenium. Three component, surely, do we hear you say The fourth component is the bromide ion.33... 

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