Gold-catalyzed reactions of oxo-alkynes

Gold (I) and gold (III) complexes show unique catalytic activities toward alkynes; both inter and intramolecular addition of nucleophiles to alkynes is promoted in the presence of gold catalysts. This review focuses on the gold catalyzed reactions of alkynes tethered with carbonyl groups along with their interesting mechanistic aspects


Introduction
The formation of C-C and C-X bonds by the use of transition metal catalysts is one of the most interesting and intriguing subjects in organic chemistry.The formation of these bonds by using various transition metals such as Pd, Ni, Ru, Rh has been extensively investigated and documented in the literature. 1 The catalysis of organic reactions by gold compounds has recently been shown to be a powerful tool in organic synthesis. 2This chemistry is also valuable in constructing complex molecules.Although gold is considered as an expensive metal, the unique catalytic properties exhibited by the various gold complexes have encouraged organic chemists to explore the viability of these complexes as catalysts.Likewise other transition metals, gold salts are capable of forming several bonds in one pot, without isolating any intermediates, commonly referred as domino 3 or tandem reactions.It is obvious that this type of reactions would allow the minimization of waste elements and most importantly the reaction can be performed with high atom economy. 4Over the decades the usefulness of gold catalyst has been realized and has drawn the attention of numerous research groups, which has been reflected in a number of research publications in the literature.Cationic gold (I) and gold (III) show unique activities toward alkynes, promoting the nucleophilic addition of a variety of functional groups both inter-and intramolecularly.As a part of continuing interest on gold catalysis, we were interested in summarizing the gold catalyzed processes of alkynals, alkynones and alkynoates since the products obtained through these processes are valuable building blocks.This review focuses on the gold catalyzed reactions of alkynes tethered with carbonyl groups (Fig 1) along with their interesting mechanistic aspects.
A plausible mechanism for the AuCl 3 -catalyzed formal [4 + 2] benzannulation is shown (Scheme 1).The coordination of the triple bond of 1 to AuCl 3 enhances the electrophilicity of alkyne and the subsequent nucleophilic attack of the carbonyl oxygen to the electron-deficient alkyne would form the intermediate auric ate complex 5. 6 The Diels-Alder type [4 + 2]  cycloaddition of 5 with an alkyne 2 would occur as shown in 6 to form the intermediate 7. The subsequent bond rearrangement, as shown in 7 with arrows, would afford the naphthalene derivatives 3 and regenerate AuCl 3 .

Scheme 2
The application 9 of this methodology has also been reported recently by Dyker et al. for the total synthesis of rac-heliophenanthrone 15 (eq 4).It was found that gold catalyst gave lower yield (34%) for the benzannulation of 16, however, the use of PtCl 2 proved beneficial giving the product in 71% yield.The benzannulation product 17 thus obtained was converted into heliophenanthrone 15.
An innovative extension of the above approach by Oh and coworkers involved the synthesis of [6,7,n] tricyclic compounds 19 via [3+2] cycloaddition of 18 (eq 5). 10 It is interesting to note that only trace amounts of [4+2] benzannulation products were obtained in each case.Since the main structural feature distinguishing 18 from 10 is the gem-ester group, the author argued that Thorpe-Ingold effect might be playing some role in favoring the formation of the five membered ring products via intermediate 20.We have reported [4+2] benzannulation between the pyrylium intermediates, formed by the nucleophilic attack of carbonyl oxygen to gold-coordinated alkyne in 1, with carbonyl compounds 21. 11 Functionalized naphthalenes 22 or 23 were obtained in good to high yields by heating the substrates at 100 °C in 1,4-dioxane in the presence of AuBr 3 (eq.6).
A plausible mechanism for the present benzannulation is shown in Scheme 3. The gold ate complex 5 was generated from 1 as described previously.The reverse-electron-demand-type Diels-Alder reaction of 5 with the enol 24, derived from 21, followed by dehydration would generate the intermediate 26 through 25.The subsequent bond rearrangement, as shown in 26 with arrows, would afford the naphthyl ketone derivative 22 or 23 with regeneration of AuBr 3 .

Scheme 3
Toste et al. developed 12 Au(I) catalyzed synthesis of cyclopentenones 28 by the rearrangement of 1-ethynyl-2-propenyl pivaloates 27 (eq.7).The reactions are tolerant of substitutions at the acetylenic and olefinic positions (except for Z-olefins) providing access to a wide range of cyclopentenones under exceptionally mild conditions.One of the important features of this reaction is that enantio-enriched cyclopentenones could be prepared by cyclization of enantiomerically enriched propargyl alcohols.The high degree of chirality transfer in these rearrangements was observed.

28
Mechanistically the reaction is quite interesting (Scheme 4).Intramolecular 1,2-addition of the ester oxygen onto the alkyne, induced by coordination of the alkyne to a cationic gold(I) complex, affords the vinyl gold species 28.This cyclization of 28 produces the cationic intermediate 30 via the transition state 29, which upon elimination of cationic gold(I) affords the diene 31.Finally, the cyclopentadiene 31 is hydrolyzed to the cyclopentenone 28.

Scheme 4
Zhang reported the synthesis of highly functionalized 2,3-indoline-fused cyclobutanes 33 from 32 catalyzed by cationic gold (eq 8). 13It was proposed that the catalyst played dual role for activating both propargylic esters and the in situ generated allenylic esters.

33
The proposed mechanism for the formation of the cyclobutane 33 is shown in Scheme 5. Activation of the C-C triple bond in propargylic ester 32 by [Au(PPh 3 )] + promotes a 3,3rearrangement of the indole-3-acetoxy group, which leads to the formation of allenylic ester 37.The allene moiety of 37 was further activated by the cationic Au(I) complex, resulting in the formation of oxonium ion 38.The cyclobutane 33 is produced via the C-C bond formation between the oxonium carbon of 38 and the C-3 carbon of the indole ring, followed by intramolecular trapping of the iminium with the alkenylgold(I).A recent report by the same author described gold catalyzed highly efficient synthesis of cyclopentenones 41 from propargylic esters 40 via tandem 3,3-rearrangement and the Nazarov reaction (eq 9). 14 40 41 The mechanism of the reaction is presented in Scheme 6.The allenylic acetate 42 generated in situ via cationic Au(I)-catalyzed [3,3]-rearrangement of the corresponding propargylic acetate is further activated by the Au(I) catalyst leading to pentadienylic cation 43.4π-Electron closure of 43 forms the Au-containing cyclopentenylic cation 44, which is in resonance with Au carbenoid species 45. [1,2]-Hydride shift in 45 gives 46 after subsequent elimination and regeneration of the cationic Au(I) catalyst.Furstner et al. described the AuCl 3 catalyzed rearrangement of propargylic acetates for the synthesis of terpene derivatives (eq 10). 15Complexation of gold catalyst to alkyne renders alkynes susceptible to attack the carbonyl oxygen to form gold carbene 52 through intermediate 50 and 51.The insertion of carbene 52 was then took place into the tethered alkene to form the product 49.

Issue in
Recently, Toste has developed a gold(I)-catalyzed cyclopropanation of olefins 54 using propargyl esters 53 as gold-(I)-carbene precursors (eq 11). 16The attack of carbonyl oxygen to the gold coordinated alkyne would produce intermediate 57 via 56, which on subsequent rearrangement as shown by the arrow would provide gold carbene complex 58.The carbene complex 58 thus formed could then be inserted into the olefin to provide cyclopropanation products.The highest enantioselectivity of 85% was achieved using DTBM-SEGPHOS-gold (I) catalyst.The chemistry has also been applied by Porco for the synthesis of various azaphilones, which are known to be a component of many natural products.Gold catalyzed cycloisomerization of O-alkynylbenzaldehydes 59 into 2-benzopyrylium salts and subsequent oxidation by using IBX in conjunction with phase transfer catalyst provided products 60 in high yields (eq 12). 17

Issue in
The reaction of propargyl ketones such as 61 in the presence of 0.1 mol.% AuCl 3 gave the furan 62 in essentially quantitative yield (eq 13). 18On the other hand, with palladium as a catalyst, 100 °C temperature is needed in order to proceed the reaction.A novel cascade cyclization of the propargyl ketone 63 in the presence of AuCl 3 was also reported (eq.14).The author proposed the intermediacy of 64 for this cascade cyclization.Recently, Larock reported an entirely new approach for the novel cyclization of 2-(1alkynyl)-2-alken-1-ones 66 with nucleophiles in the presence of catalytic amounts of AuCl 3 which led to the formation of highly substituted furans 67 (eq 15). 19An example of nucleophiles includes alcohol, activated methylene and electron rich arenes such as N,N-dimethylaniline and N-methyl indole.
66 67 The mechanism of the reaction is depicted in Scheme 7. The coordination of the triple bond of 66 to AuCl 3 enhances the electrophilicity of the triple bond, and subsequent nucleophilic attack of the carbonyl oxygen on the electron-deficient triple bond generates carbocation 69.Intermolecular nucleophilic attack on the carbocation and subsequent protonation of the carbongold bond afford furan 67 and regenerate the catalyst AuCl 3 .The authors ruled out the possibility of an alternative mechanism wherein AuCl 3 first acts as a Lewis acid, forming a complex with the carbonyl oxygen thereby facilitating Michael addition since 1% AuCl 3 failed to catalyze the 1,4-addition of methanol to 2-cyclohexenone and methyl vinyl ketone under the standard conditions.Recently, Hashmi and coworkers reported gold catalyzed synthesis of 2,5-disubstituted oxazoles 72 from the corresponding propargylcarboxamides 71 (eq 16). 20The addition of amide oxygen to gold co-ordinated alkyne is highly stereospecific as shown is 73 to form the vinyl gold species 74 which on protonation and regeneration of catalyst gave products 72.The gold catalyzed rearrangement of propargylic tert-butyl carbonates 75 and 77 into 4alkylidene-1,3-dioxolan-2-ones 76 and 78 was described by Gagosz and Buzas (eqs 17 and 18). 21 variety of cyclic carbonates were synthesized under these milder conditions.
In summary, we have discussed the gold catalyzed reactions of carbonyl compounds tethered with alkynes.Other transition metals are also known to activate alkynes allowing the nucleophilic attack of carbonyls to metal co-ordinated alkynes.However, gold is now becoming more popular because of its efficiency in performing reactions at lower catalyst loading and at room temperature.