Synthesis, trisubstituted aromatic

The co-operative effect of 1,3-interrelated directing groups is a powerful strategy in synthesis. This allows the otherwise difficult preparation of 1,2,3-trisubstituted aromatic compounds. Hence the lithiation of the aromatic compound 129 is directed by both the methoxy and secondary amide groups (1.118). Two equivalents of the... 

An interesting example of a triple electrophilic aromatic substitution between an oxonium ion, generated from a trisubstituted dihydrofuran, and phloroglucinol was exploited for the total synthesis of the C3-symmetric xyloketal A, as depicted in the scheme below C06OL1427 06JOC1620>. 

Ethylene and styrene derivatives react with various propargylic silyl ethers in the presence of zirconocene(II) to afford allenic products in high yield (Scheme 5.7). For example, substrate 67 was transformed into the trisubstituted allene hydrocarbon 68 in 93% yield under the reaction conditions [20]. In the synthesis of various tetraalkylated allenes, in which several of the alkyl substituents also contained triple bonds, allowing these substrates to be cydized intramolecularly into aromatic com-... 

Oximes can be also used for the imidazole ring synthesis. Thus, reaction of a-amino-oximes 122 and orthoesters leads to imidazole Af-oxides 123 (equation 53) . Interaction of a-ketooxime 124 with triazinanes also afforded imidazole Af-oxides 125 in good yields (equation 54) . Similarly, a-ketooximes in the system NH3/H20/aromatic aldehyde afforded trisubstituted 1-hydroxyimidazoles . ... 

Nondestructive reactions of trisacetylacetonates of chromium(lll), cobalt(lll), and rhodium(lll) are reviewed. Halogenation, nitration, thiocyanation, acylation, formylation, chloromethylation, and aminomethylation take place at the central carbon of the chelate rings. Trisubstituted chelates were obtained in all cases except acylation and formylation. Unsymmetrically and partially substituted chelates have been prepared. Substitutions on partially resolved acetylacetonates yielded optically active products. NMR spectra of unsymmetrically substituted, diamagnetic chelates were interpreted as evidence for aromatic ring currents. Several groups were displaced from the chelate rings under electrophilic conditions. The synthesis of the chromium(lll) chelate of mal-onaldehyde is outlined. 

The trisubstituted amidinothioureas (98) required as precursors of the thiadiazolines are obtained by the interaction of isothiocyanate esters and s-diarylguanidines,115 or by the action of aromatic amines on dithiazolidines (102).117 The former reaction might conceivably yield the isomeric amidinothioureas (98a) instead if so, however, oxidation and isomerization would give rise to a 2-(diphenylguanidino)benz-thiazole (100a) isomeric with, but different from, the product (100) actually obtained. The structure of this product is confirmed by synthesis from 2-aminobenzthiazole (101) and carbodiimides.115... 

The [3 + 2] addition of type llbd is a significant method for synthesis of both simple and complex pyrrole derivatives. One manifestation of this pattern is seen in the base-catalyzed condensation of tosylmethyl isocyanide with alkenes having strong electron-accepting substituents. The aromatization by elimination of the arenesulfinic add occurs under the reaction conditions (equation 117) (72TL5337). This reaction can be applied to the synthesis of 2,3,4-trisubstituted pyrroles by using C-alkylated tosylmethyl isocyanides or AT-tosyl-methyl-S- methylthioimidates <77H(7)77, 81JHC1127). 

The use of nitro aromatics as dipolarophiles in cycloaddition reactions has shown great utility in heterocyclic synthesis. The reaction of 3-substituted-4-nitroisoxazoles (299) with trisubstituted oxazolium 5-oxides (300) affords an intermediate adduct (301) which eliminates carbon dioxide and nitrous acid to afford 3,4,6-trisubstituted pyrrolo[3,4-r/]isoxazoles (302) (Scheme 56) <93G633>. 

A three component coupling reaction of A-acetyl-2-azetine, aromatic imines and aromatic amines allows a rapid stereoselective entry to 2,3,4-trisubstituted tetrahydroquinolines, via fused tricyclic azetidines 1 <02CC444>. Fused heterocycles 1 were formed through an aza Diels-Alder reaction between aromatic imines and A-acetyl-2-azetine, which acts as an enamide substrate. This strategy has been used for the formal synthesis of luotonin A <02TL5469>. 

Traceless solid-phase synthesis of 2,6,9-trisubstituted purines from resin-bound 6-thiopurines <02T7911>, and microwave assisted solid-phase synthesis of 2,6,9-trisubstituted purines <02TL6169> have been described. A resin-capture and release strategy toward combinatorial libraries of 2,6,9-trisubstituted purines has been reported <02JCO183>. Alkylated purines chlorinated at the 6,8- or 2,6,8-positions can be captured onto a solid support and further elaborated by aromatic substitution or via palladium catalyzed crosscoupling reactions <02JA1594>. 

A classic illustration of scaffold decoration is the trisubstituted 1,3,5-triazine. The starting material trichloro-l,3,5-triazine is inexpensive, and the halogens can be displaced by nucleophilic aromatic substitutions one by one. Such chemistry was well precedented in pre-combinatorial days, and used on a large scale for the synthesis of colour-fast reactive dyes. The overall reaction sequence has an appeal in its simplicity, and both academic and industrial practitioners have reported a steady trickle of such triazine-based libraries over the last 20 years. Novelty will come either from the particular set of nucleophiles employed or the assay targets. 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

Polymer-supported peracids are also used effectively for the epoxidation of di-and trisubstituted olefins. The ratio of the stereoisomers is similar to that for the products of the reaction of the monomer with aromatic peracids. MCPBA epoxidation of homoallyl phosphonates has led to the preparation of 3,4-epoxyalkane phosphonates 39 in addition to the 1,2- and 2,3-epoxy derivatives.Stereospecific peracid oxidation is one of the preparative methods employed in the synthesis of the structurally varied cyclic polyoxirane isomers, which are of interest from a biological aspect. ... 

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