Heterocyclization gold -catalyzed

Hydroamination of Alkynes The discovery of palladium-catalyzed intramolecular addition of amines to acetylene coupled with the spectacular contribution of Hutchings opened the door for the synthesis of several nitrogen heterocycles. The first study in this field was performed by Utimoto et al., who researched gold catalyzed intramolecular 6-exo-dig hydroamination. Tautomerization of the initial enamines allowed them to obtain imines, which were thermodynamically more stable [111] (Scheme 8.20). 

Floreancig and Hood recently incorporated gold-catalyzed heterocycle formation in the total synthesis of (+)-Andrachcinidine, a natural component extracted from the plant Andrachne aspera, which has medicinal properties. Gold catalysis was required in the last step of the synthesis, as shown in Scheme 8.22 [119]. 

Silver and gold-catalyzed reactions have recently been exploited in approaches to various kinds of heterocycles, including thiophenes. For example, a gold-catalyzed annulation has been utilized in the conversion of the substrate 20 into the benzo[Z>]thiophene 21, involving an interesting silyl migration <070L4081>. 

Gold-catalyzed hydroamination of C-C multiple bonds, particularly, in synthesis of N-heterocycles 06EJO4555. 

Gold-catalyzed reactions of oxo-alk3mes in preparation of O-heterocycles 07ARK(5)6. 

Lipshutz reported the first gold-catalyzed dehydrative cyclization of diols and triols in aqueous medium to the corresponding heterocycles 6 in good to excellent yield at room temperature. The reactions occur in nanoparticle micelles (TPGS-750-M) where the hydrophobic effect drives the dehydration reaction. The addition of salts was also shown to decrease reaction times (140L724). 

An intramolecular gold-catalyzed hydroamination took place upon heating of cyclic dienes bearing a sulfonamide side chain with PhsPAuCl and AgOTf. In this case, 1,4-addition of the amide leads to the formation of hexahydroindoles and related heterocycles. The presence of the bulky phenyl groups in the tether is crucial for... 

Representative procedure for the gold-catalyzed transformation ofhomopropargyl ethers to heterocyclic ketones. l-((2R,6S)-6-((R)-2-Hydroxypentyl)-l-(2-nitrophenylsulfor l)-piperidin-2-yl)propan-2-on ... 

Dudnik, A., Chernyak, N. and Gevorgyan, V. 2010. Copper-, silver-, and gold catalyzed migratory cycloisomerization leading to heterocyclic five-membered rings. Aldrichim. Acta. 43 37-46. 

Jung, H. H. and Floreancig, P. E. 2006. Gold-catalyzed heterocycle synthesis using homo-propargylic ethers as latent electrophiles. Org. Lett. 8 1949-1951. 

Wilckens, K., Uhlemann, M. and Czekehus, C. 2010. Gold-catalyzed cnseven-membered ring heterocycles. Chem. Eur. J. 15 13323-13326. 

Nitrogen nucleophiles have also proven to be suitable nucleophiles in a series of gold-catalyzed reactions, as exemplified by the transformations shown below (Scheme 16.14) [18, 17c]. The great majority of the reactions deal with the formation of nitrogen-containing heterocycles. 

The gold-catalyzed alkynylation of heterocycles allowed the functionalizaticm of the most electron-rich position. Nevertheless, this is a limitation if the synthesis of other alkyne regioisomers is desired. In 2013, Waser and co-workers reported that the C2-selective alkynylation of indoles was possible using a palladium catalyst (Scheme 21) [127]. A current limitation of this approach is the requirement for an alkyl substituent on the nitrogen atom. 

Intramolecular additions of alcohols or amines to olefins are recognized as useful methods to provide heterocyclic compounds. Kozmin and Zhang have achieved a gold-catalyzed synthesis of heterobicyclic alkenes by double cyclization of alcohols or sulfonamides which have a 1,5-enyne moiety [175]. As a typical example, unsaturated alcohol (95) is smoothly converted to 6-oxabicyclo[3.2.1]octane (96) in 90% yield using a 5 mol% of AuCls catalyst (Scheme 18.34). Cyclic ethers are also available from homopropargylic ethers with pendant alcohols through gold-catalyzed... 

Pyrroles almost exclusively add to acetylenes as Ai-centered nucleophiles however, when the acetylene is activated by a strong electron-withdrawing substituent, pyrrole can add to the triple bond as a C-centered nucleophile. " In their gold-catalyzed alkynylation of pyrrole with silyl-protected alkynyl benziodoxolone hypervalent iodine reagent 6, members of the Waser laboratory only saw C-alkynylated products (Scheme 10.2). Using this method, 1/f-pyrrole (1) could be C2-funtionalized to afford 7 in 62% yield, whereas Ai-TIPS pyrrole (8) was selectively transformed into C3-product 9 in 79% yield. In both cases, auration of the heterocycle led to an organogold(III) intermediate that reductively eliminated to afford the alkynylated products. 

Nevado and de Haro later reported a gold-catalyzed arene ethynylation reaction in which both the sp C—H and sp C—H were activated by the gold catalyst. Heterocycles such as Ai-benzyl pyrrole and Ai-benzyl indole were suitable substrates for this reaction but in the former case, ethynylated regioisomers were obtained. 

Chen, Z., Zhang, Y.-X., Wang, Y.-H., Zhu, L.-L., Liu, H., Li, X.-X., Guo, L. (2010). Gold catalyzed diastereoselective cascade allylation/enyne cycloisomerization to construct densely functionalized oxygen heterocycles. Organic Letters, 12, 3468-3471. 

Krause N, Winter C (2011) Gold-catalyzed nucleophilic cyclization of functionalized allenes a powerful access to carbo- and heterocycles. Chem Rev 111(3) 1994-2009 McDonald RI, Liu G, Stahl SS (2011) Palladium(II)-catalyzed alkene functionalization via nucleopalladation stereochemical pathways and enantioselective catalytic applications. Chem Rev 111(4) 2981-3019... 

In 2010, Gouverneur and coworkers reported a novel cascade cyclization-intermolecular alkynylation reactions toward the synthesis of five-membered 0-heterocycles. /i-Alkynyl-y-butenolides 2 could be efficiently prepared from allenoates 1 and terminal alkynes in the presence of a gold catalyst with the use of Selectfluor as an external oxidant (Scheme 12.1) [5]. This process involves a direct C(sp)-H functionalization of terminal alkynes. This novel gold-catalyzed cascade cyclization oxidative cross-coupling process provides a basis for the development of novel cascade reactions combining traditional gold catalysis and intermolecular oxidative alkynylation. 

Interestingly, when the substrate was switched from benzene-1,2-dialkyne 90 to cA-enediyne 95, 6-endo-dig cyclization reaction pathway was observed. Two regioisomeric ort/zo-auroaryl cation intermediates 96 and 98 were proposed via dual gold-catalyzed 6-endo-dig cyclization model, which can be mutual isomerization via aryne-coordinated gold complex 97. Ort/zo-aurophenyl cation intermediates 98 could be trapped by a tethered hydroxy or sulfonamide group to deliver the seven-membered O- or AT-heterocycles 99 (Scheme 12.45) [48]. 

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