Gold(I)-Catalyzed Activation of Alkynes for the Construction of Molecular Complexity

Abstract

1 Introduction 1.1 General Reactivity of Alkyne-Gold(I) Complexes For centuries, gold had been considered a precious, purely decorative inert metal. It was not until 1986 that Ito and Hayashi described the first application of gold(I) in homogeneous catalysis. 1 More than one decade later, the first examples of gold(I) activation of alkynes were reported by Teles 2 and Tanaka, 3 revealing the potential of gold(I) in organic synthesis. Now, gold(I) complexes are the most effective catalysts for the electrophilic activation of alkynes under homogeneous conditions, and a broad range of versatile synthetic tools have been developed for the construction of carbon–carbon or carbon–heteroatom bonds. Gold(I) complexes selectively activate π-bonds of alkynes in complex molecular settings, 4−10 which has been attributed to relativistic effects. 11−13 In general, no other electrophilic late transition metal shows the breadth of synthetic applications of homogeneous gold(I) catalysts, although in occasions less Lewis acidic Pt(II) or Ag(I) complexes can be used as an alternative, 9,10,14,15 particularly in the context of the activation of alkenes. 16,17 Highly electrophilic Ga(III) 18−22 and In(III) 23,24 salts can also be used as catalysts, although often higher catalyst loadings are required. In general, the nucleophilic Markovnikov attack to η2-[AuL]+-activated alkynes 1 forms trans-alkenyl-gold complexes 2 as intermediates (Scheme 1). 4,5a,9,10,12,25−29 This activation mode also occurs in gold-catalyzed cycloisomerizations of 1,n-enynes and in hydroarylation reactions, in which the alkene or the arene act as the nucleophile. Scheme 1 Anti-Nucleophilic Attack to η2-[AuL]+-Activated Alkynes Structurally, Au(I) predominantly forms linear two-coordinate complexes, although higher coordination numbers are also possible. 30 A significant number of alkyne-gold complexes have been characterized 31,32 and studied either in solution 32,33 or theoretically. 34 This selective activation of the alkyne moiety can explain a vast majority of the results experimentally observed for gold(I)-catalyzed cyclization of 1,n-enynes. Nevertheless, complexes of gold(I) with the alkene moiety of the enynes are also formed in equilibrium with the alkyne-gold complexes. 35 Indeed, well-characterized complexes of gold(I) with alkenes have been reported, 36 as well as with allenes 37 and 1,3-dienes. 38 Despite the fact that simple gold salts such as NaAuCl4 or AuCl are active enough to catalyze several transformations, gold(I) complexes bearing phosphines or N-heterocyclic carbenes as ligands have found more wide-ranging applications. 39 The active species are often generated in situ by chloride abstraction from [LAuCl] upon treatment with a silver salt bearing a weakly coordinating anion. Complexes [LAuY] only exist as neutral species when Y– is a coordinating anion (halides, carboxylates, sulfonates, and triflimide). The corresponding complexes with less coordinating anions, such as SbF6 –, PF6 –, or BF4 –, are in most of the cases not stable. Although, species [AuL]+ (also known as “naked gold complexes”) are often suggested in mechanistic proposals, structural proof for their existence as stable, isolable species is still lacking. Here, for the sake of simplicity in mechanistic schemes throughout this review, LAu+ is used as a surrogate of [LAuL′]+ complexes, where L′ states for a relatively weakly bound ligand such as the substrate (alkyne or alkene), product, or solvent molecule. It is important to remark that when the catalytically active species are generated in situ by chloride abstraction from complexes [LAuCl] in the absence of the alkyne or other unsaturated substrate, much less reactive chloride-bridged dinuclear species [LAuClAuL]Y are readily formed. 40 Formation of these dinuclear complexes could explain, at least partly, the erratic results that have been ascribed as the “silver effects” in reactions in which Ag(I) salts are used in situ to activate neutral gold(I) complexes [LAuY]. 41 Often, the most convenient catalysts for the activation of alkynes are complexes [LAuL′]X or [LAuX] bearing weakly coordinating neutral (L′) 42 or anionic ligand (X–). 43 These complexes can enter catalytic cycles by ligand exchange with the unsaturated substrate, which proceed by associative mechanisms as observed for Au(I) and other diagonal d10 metal centers. 44 Thus, large negative activation entropies characteristic of associative mechanisms have been determined for the rate determining ligand exchange reactions of substituted alkyne 45,46 and alkenes 36o on commonly used Au(I) catalysts. Although nitriles are frequently used as weakly coordinating neutral ligands, 1,2,3-triazole 46,47 or other related ligands 48 have also been employed. The properties of gold(I) complexes can be easily tuned sterically or electronically depending on the ligand, consequently modulating their reactivity in the activation of alkynes, alkenes, and allenes. 27,29f,49 Thus, complexes containing more donating N-heterocyclic carbenes (3) are less electrophilic than those with phosphine ligands (4, 5) (Figure 1). 28 Complexes with less donating phosphite ligands (6) and related species are the most electrophilic catalysts. Figure 1 Increase in electrophilicity with decreased donating ligand ability in gold(I) complexes. Gold(I) complexes bearing weak-coordinated ligands such as Me2S, thiodiglycol, or tetrahydrothiophene (tht) have been widely used for the preparation of soluble gold(I) complexes, commonly starting from a gold(III) source. 50 Complex [Au(tmbn)2]SbF6 (tmbn = 2,4,6-trimethoxybenzonitrile), in which gold(I) is supported by two nitrile ligands, can be used for the in situ preparation of a variety of chiral and achiral cationic complexes [LAu(tmbn)]SbF6, including complexes immobilized on a polymeric support. 42a Other immobilized gold(I) complexes have also been prepared. 51 The use of gold complexes bearing chiral ligands has led to the development of efficient asymmetric gold-catalyzed transformations. 52 Less common precatalysts used in gold(I)-catalyzed transformations are gold hydroxo complex IPrAuOH, which is activated in the presence of Brønsted acids, 53 open carbenes, 39c,54 and other related complexes, 55 which give rise to selective catalysts of moderate electrophilicity. Cyclopropenylylidene-stabilized phospenium cations, which behave similarly to classical triaryl- and trialkylphosphines, have also been used as ligands in gold-catalyzed reactions. 56 The effect of the counteranion has been studied in detail for several gold(I)-catalyzed transformations. 57,58 Thus, for the intermolecular reaction of phenylacetylene with 2-methylstyrene catalyzed by [t-BuXPhosAu(NCMe)]Y, it was found that yields increase depending on the counteranion in the order Y = OTf– < NTf2 – < BF4 – < SbF6 – < BARF (BARF = 3,5,bis(trifluoromethyl)phenylborate). By using the bulky and noncoordinating anion BARF, yields are increased by 10–30% compared to those obtained when Y = SbF6 –, probably due to a decrease in the formation of the unproductive σ,π-(alkyne)digold(I) complexes from the initial alkyne. 57 1.2 Scope and Organization of the Review Homogeneous gold(I)-catalysis has experienced an outbreak in the past decade leading to the discovery of a remarkable amount of new synthetically useful transformations. Thus, in recent years many groups have used gold catalysis in key steps of total synthesis taking advantage of the unique catalytic ability of gold to build molecular complexity under mild reaction conditions. Several reviews have been published on gold(I)-catalyzed reactions of alkynes, enynes, and related substrates, 5,7,25−28,59 as well as on gold(I)-catalyzed reactions of allenes 60 and cascade gold-catalyzed reactions. 61 Moreover, specific reviews focused on gold-catalyzed carbon-heteroatom bond formation 62 and on the use of gold catalysis in total synthesis 63 have also been published. In this review, we will cover reactions of alkynes activated by gold(I) complexes, including recent applications of these transformations in the synthesis of natural products. According to the aim of this thematic issue, the main focus is on the application of gold(I)-catalyzed reactions of alkynes in organic synthesis, although reactions are organized mechanistically. Reactions of gold(I)-activated alkenes and allenes, as well as gold(III)-activated alkynes, will not be covered. The discussion has been primarily organized based on the different reactions catalyzed by gold(I) complexes that alkynes can undergo. When possible, inter- and intramolecular processes, as well as the applications in total synthesis, are treated in specific subsections. 2 Addition of Heteronucleophiles to Alkynes 2.1 Addition of O-Nucleophiles to Alkynes The effectiveness of gold(I) complexes for the activation of alkynes toward inter- and intramolecular nucleophilic attack has been demonstrated for a variety of heteronucleophiles. Due to relativistic effects, cationic gold complexes possess, besides a high π-acidity, a low oxyphilicity, 7,8 and therefore they are able to activate unsaturated C–C bonds in the presence of H2O, alcohols, or any other oxygen-containing functional groups. Hence, once the alkyne is activated, the nucleophilic oxygen can attack forming a new C–O bond. 2.1.1 Intermolecular Addition of O-Nucleophiles to Alkynes Hydration and alkoxylation of alkynes are industrially important processes for the synthesis of carbonyl compounds. A well-known method for the addition of water and alcohols to alkynes uses toxic Hg(II) salts under acidic conditions. 64 Other less harmful although expensive transition-metal-based catalytic systems have also been described, 65 including the use of Au(III) salts. 66 The first examples of gold(I)-catalyzed addition of alcohols and water to alkynes were reported by the groups of Teles 2 and Tanaka, 3 respectively, employing air stable gold complexes [AuMe(L)] (L = phosphine, phosphite or arsine), which were activated in situ by protic acids to form acetals such as 7 or ketones 8 and 9 (Scheme 2). Markovnikov-type addition was observed in all cases, being reactive under these reaction conditions both terminal and internal alkynes. Despite its efficiency, this method suffers from several drawbacks, including the use of concentrated solutions of strong acids and relatively high catalyst loadings. Scheme 2 Hydration and Acetalization of Alkynes with Ph3PAuMe and Protic Acids Although the catalytic hydration of alkynes with neutral N-heterocyclic carbene gold(I) chlorides or carboxylates in the presence of B(C6F5)3 was already demonstrated in 2003, 67 later in 2009 it was found that the use of gold(I) complexes bearing bulkier N-heterocyclic carbene ligands allowed to catalyze this process at loadings as low as <10 ppm under acid-free conditions (Scheme 3). 68 This catalytic system showed wide versatility, since both terminal and internal alkynes possessing any combination of alkyl and aryl substituents were suitable substrates. However, the reaction required high temperatures to proceed and for unsymmetrical internal alkynes only moderate regioselectivities were obtained. Alkynes can also be hydrated at room temperature without any acidic cocatalyst in the presence of gold(I)-phosphine complexes. 69 Scheme 3 Hydration of Alkynes with Low-Catalyst Loadings The regioselective hydration of haloalkynes was recently reported to afford α-halomethylketones 12 in excellent yields under very mild reaction conditions (Scheme 4). 70 This procedure was applied on the gram-scale, and the catalyst loading could be decreased up to 2 mol % with little effect on the yield. However, ortho-substituted arylacetylenes provided only trace amounts of the carbonyl compounds. Scheme 4 Hydration of Haloalkynes Cyclic acetals are important building blocks present in many natural occurring biologically active compounds, and, moreover, they are very useful as protecting groups. 71 They are usually obtained by the addition of a diol to the corresponding aldehyde or ketone under Brønsted acid conditions. When diols are added to alkynes in the presence of a gold(I) catalyst, cyclic acetals 13 are regioselectively formed instead of the unprotected carbonyls (Scheme 5). This reaction proceeds with complete regioselectivity in the case of terminal alkynes and with moderate selectivity for internal alkynes, yielding a mixture of cyclic acetals 13/13′. 72 The reaction can also be expanded to the preparation of acetals from 1,5-diols. Scheme 5 Acetalization of Alkynes In a more recent example, α-bromo cyclic and acyclic acetals 14 and 15 were obtained from terminal alkynes and NBS (Scheme 6). 73 The reaction proceeded via formation of bromoacetylenes followed by addition of the O-nucleophiles to the triple bond. Scheme 6 Bromo-Acetalization of Alkynes The role of the anion in the intermolecular alkoxylation of alkynes catalyzed by N-heterocyclic carbene-based gold(I) complexes [(NHC)AuX] (X = BARF–, BF4 –, OTf–, OTS–, TFA–, AcO–) has recently been dissected, with the conclusion that both coordination ability and basicity have a great impact on this transformation. 74 The most important factor seems to be the ability to abstract the proton from the alcohol during the nucleophilic attack, which is directly related to the anion basicity. Gold(I)-catalyzed intermolecular additions of alcohols to alkynes can be coupled with other tandem reactions, therefore increasing the degree of molecular complexity in the final product. 75 The addition of allylic alcohols to alkynes followed by a Claisen rearrangement of the resulting intermediates (16) has recently been developed, leading to the formation of γ,δ-unsaturated ketones 17 in an efficient one-pot procedure from simple starting materials (Scheme 7). 76 Scheme 7 Synthesis of Homoallylic Ketones by Nucleophilic Addition-Claisen Rearrangement 2.1.2 Intramolecular Addition of O-Nucleophiles to Alkynes The high activity of gold(I) salts and complexes for C–O bond formation has been widely exploited intramolecularly to construct oxygen containing heterocycles. In this context, one of the most studied transformations is the intramolecular gold(I)-catalyzed cyclization of unactivated alkynols. 60b,77 As an example, alkynediols 18 underwent a gold(I)-catalyzed cyclization leading to furans 20 after elimination of H2O from intermediate 19 in the presence of very low catalyst loadings (Scheme 8). 78 The alcohol moiety may already be present in the precursor of the gold(I)-catalyzed transformation 79 or may be generated in situ from epoxides by ring opening. 80 Carbonyls can also act the nucleophiles. 81 Thus, alkynyloxiranes 21 were converted into trisubstituted furanes 22, 80b and alk-4-yn-1-ones 23 gave rise to 2,4,5-trisubstituted furans 24 or substituted 4H-pyranes 25 depending on the substitution pattern of the substrate (Scheme 9). 81b Scheme 8 Synthesis of Furans by Cyclization of Alkynediols Scheme 9 Cyclization of Epoxy and Ketoalkynes Furan derivatives were obtained from Z-enynols 26 (Scheme 10). 82 Enynols bearing a secondary alcohol afforded substituted furans 27, and those containing a tertiary alcohol gave dihydrofurans 28. In the presence of gold(I) catalysts bearing N-heterocyclic carbene ligands these substrates were also converted into furan structures allowing the use of low catalyst loadings and very mild reaction conditions. 83 Scheme 10 Synthesis of Furan Derivatives from Z-Enynols Oxazocenones 30 have been recently synthesized via gold(I)-catalyzed 8-endo-dig hydroalkoxylation of alkynamides 29 (Scheme 11). 84 Scheme 11 Synthesis of Oxazocenones The reaction of alkynediols to give bicyclic acetals by gold(I)-catalyzed intramolecular hydroalkoxylation of terminal alkynes using bis-homopropargylic alcohols 31 was first described in 2005, opening a door to an interesting family of strained acetals 32 (Scheme 12). 85 Notably, the addition of methanol to alkene intermediates did not occur under the reaction conditions. Recently, the selective conversion of acetonide-tethered alkynes into bridged acetals through an analogous process using Ph3PAuCl and AgOTf in the presence of water was reported. 86 Scheme 12 Intramolecular Acetalization of Alkynes As described for intermolecular additions of O-nucleophiles, the intramolecular version can also be combined with subsequent tandem reactions in order to increase molecular complexity of the resulting products. One of the simplest examples is the tandem cycloisomerization/hydroalkoxylation of homopropargylic alcohols in the presence of an external alcohol to form tetrahydrofuranyl ethers 33 (Scheme 13). 87 Bishomopropargylic alcohols also react with gold(I) in a similar fashion, giving rise to methylene tetrahydrofuran motifs, which in the presence of an external nucleophile are the entry to a variety of structurally different products. 88 Scheme 13 Tandem Cycloisomerization/Hydroalkoxylation of Homopropargylic Alcohols The formation of bicyclo[3.2.0]heptenes 35 was reported involving an intramolecular addition of an oxygen-containing nucleophile to a cyclopropyl alkyne 34 activated by gold(I) (Scheme 14). 89 The same group also developed an unprecedented gold(I)-catalyzed tandem reaction to form polysubstituted dihydrofurans from acetal-protected propargylic alcohols and carbonyl compounds. 90 Scheme 14 Synthesis of Bicyclo[3.2.0]heptenes by Intramolecular Addition to a Cyclopropyl Alkyne The synthesis of tricyclic cage-like structures was described starting from diyne-diols by trapping the intermediate dienol ether, which results from a double intramolecular hydroalkoxylation with external nucleophiles. 91 The synthesis of 3-alkoxyfurans 37 from acetal-containing propargylic alcohols 36 has recently been reported. 92 Thus, these synthetically useful substrates can be easily prepared in two steps from readily available aldehydes, alcohols, and 3,3-diethoxypropyne (Scheme 15). Scheme 15 Synthesis of 3-Alkoxyfurans from Acetal-Containing Propargylic Alcohols In the case of alkynylketones or esters, the mechanism of the gold(I)-catalyzed hydration or alkoxylation involves the anchimeric assistance of the carbonyl group forming an intermediate that is opened back by one water or alcohol molecule leading to the final carbonyl compounds. 93 Diethynylketones 38 were converted into naphthol derivatives 40 by this ketone-assisted hydration followed by cyclization (Scheme 16). Scheme 16 Synthesis of Naphthol Derivatives from Diethynylketones In the formation of tricyclic spiroketones 44/44′ by tandem hydration/Conia-ene/aldol condensation, 93b the first step also takes place via anchimeric assistance of the carbonyl moiety to give intermediate 42 and not through direct addition of H2O to 41 (Scheme 17). Scheme 17 Synthesis of Tricyclic Spiroketones by Tandem Hydration/Conia-Ene/Aldol Condensation 2-Alkynyl-1,5-diketones 45 undergo intramolecular oxygen transfer in the presence of AuCl via [4 + 2] cycloaddition to form cyclopentenylketones 48 (Scheme 18). 94 The mechanism of this transformation was proposed based on DFT calculations and also demonstrated by isotopic labeling experiments, determining that the reaction proceeds via tandem oxycyclization/[4 + 2] cycloaddition. Scheme 18 Synthesis of Cyclopentenylketones from 2-Alkynyl-1,5-diketones A metal-dependent catalytic method has been developed for the synthesis of cyclohexadienes from enynals 49 and alkenes (Scheme 19). 95 When Cu(OTf)2 was used as the catalyst, 2,4-cyclohexadienes 52 were formed, whereas in the presence of InCl3 or gold(I) complexes, 1,3-cyclohexadienes 53 were obtained instead. The gold(I)-catalyzed transformation proceeds via intramolecular addition of the carbonyl to the alkyne, followed by a Diels–Alder reaction between the resulting pyrylium intermediate 50 and the alkene, and final demetalation. Scheme 19 Catalyst-Dependent Synthesis of 1,3-Cyclohexadienes Cascade-type sequences have also led to the formation of pyrane derivatives. 96 Tricyclic 2,3-benzopyranes 56 were synthesized by a tandem intramolecular hydroalkoxylation/hydroarylation to obtain benzo-fused cyclic ethers. 97 Shortly later, a gold(I)-catalyzed tandem intramolecular hydroalkoxylation/Prins-type cyclization was described, affording oxygen-containing [3.3.2] bicyclic compounds 58 diastereoselectively (Scheme 20). 98 Scheme 20 Synthesis of Oxygen-Containing [3.3.2] Bicyclic Compounds by Cascade Sequences Involving Intramolecular Hydroalkoxylations Spiroketals, which are key structural units in many biologically active natural products, can also be obtained by gold(I)-catalyzed intramolecular hydroalkoxylation of alkynediols and alkynetriols. 79,99 The use of an acetonide moiety to function as a regioselectivity regulator in the spiroketalization process has been proposed to address the possible regioselectivity issues in the formation of monounsaturated spiroketals. 100 The first multicomponent enantioselective gold(I)-catalyzed synthesis of spiroketals 59 has been recently described using a gold-phosphate catalytic system in a three-component coupling between alkynols, anilines, and glyoxylic acid (Scheme 21). 101 More recently, another synthesis of spiroketals has been reported combining a gold(I)-catalyzed cycloisomerization of an alkynol with an inverse-electron-demand hetero Diels–Alder mediated by Y(OTf)3. 102 Scheme 21 Enantioselective Synthesis of Spiroketals by Coupling of Alkynols, Anilines, and Glyoxylic Acid Carboxylic acid derivatives, 103 carbonates, 104 carbamates, 105 sulfoxides, 106 boronic acids, 107 and related O-nucleophiles 108 can also add to alkynes (Scheme 22). Acetylenic carboxylic acids 60 undergo selectively an exo-cyclization providing functionalized γ-lactones 61. 103a Analogously, tert-butyl carbonates derived from homopropargyl alcohols 62 cyclize to afford cyclic enol carbonates 63(104b) and N-Boc propargylamines 64 yield 1,3-oxazin-2-ones 65. 105b Gold(I) also promotes the rearrangement of homopropargyl sulfoxides 66 to give benzothiepinones 67(106a) and the formation of boron enolates 70 from alkynes, which can be further transformed into other derivatives such as diols 71. 107 Scheme 22 Intramolecular Addtion of O-Nucleophiles to Alkynes A gold(I)-catalyzed tandem sequence has been developed for the synthesis of dihydropyridones 76 from homopropargylic carboxamides 72 (Scheme 23). 109 After an intramolecular carbonyl addition of the homopropargylic amide to the alkyne, the formation of a σ-complex of the gold salt with the intermediate oxazine 73 promotes a nucleophilic addition of an external alcohol to form 74 followed by a Petasis-Ferrier rearrangement via 75. Based on this concept, a new protocol for the synthesis of benzyl alcohols has been described generating the benzylating agent upon treatment of N-Cbz-N-benzyl-propargylamine with IPrAuNTf2. 110 This reaction takes place under very mild conditions and eliminates the need of base additives. Scheme 23 Synthesis of Dihydropyridones by Intramolecular Addition of Homorpropargylic Amides to Alkynes 1-Oxo-4-oxy-5-ynes 77 react with gold(I) to form s-trans-methylene(vinyl)oxonium intermediates 78, which in the presence of an external alkene undergo a formal [4 + 2] cycloaddition giving rise to 9-oxabicyclo[3.3.1]nona-4,7-dienes 79 (Scheme 24). 111 Scheme 24 Reaction of 1-Oxo-4-oxy-5-ynes with Alkenes To Form 9-Oxabicyclo[3.3.1]nona-4,7-dienes 2.1.3 Addition of O-Nucleophiles to Alkynes in Total Synthesis The gold(I)-catalyzed formation of O-heterocycles is a powerful tool in the field of total synthesis of natural products. In the synthesis of (−)-atrop-abyssomicin C (82), 112 the bridged bicycle 81 was obtained via intramolecular 6-exo-dig cyclization of alkynol 80 (Scheme 25). Another remarkable example is found in the total synthesis of bryostatin 16 (85), 113 in which a gold(I)-catalyzed oxycyclization of alkynol 83 generates the dihydropyran cycle present in the natural product (Scheme 26). In the formal total synthesis of didemniserinolipid B, a gold(I)-catalyzed 6-endo-dig alkynol-cycloisomerization was considered as the key step to construct the bicyclic acetal skeleton. 114 Another example of gold(I)-promoted cycloisomerization of alkynols was recently reported in the total synthesis of (±)-cafestol. 115 In this work, the furan ring is constructed in a late-stage of the synthesis via intramolecular 5-endo-dig cycloisomerization followed by dehydration. Scheme 25 Synthesis of (−)-atrop-Abyssomicin C Scheme 26 Synthesis of Bryostatin 16 The formation of spiroketal skeletons catalyzed by gold(I) has also been successfully applied in several total syntheses. 116 Okadic acid (86) is a natural occurring polyether containing three spiroketal motifs. The C15–C38 fragment was synthesized taking advantage of the high activity and selectivity of AuCl for the synthesis of spiroketals starting from alkynediols (Scheme 27). 117 Scheme 27 Construction of the Spiroketal Fragments in the Total Synthesis of Okadic Acid The ability of carboxylic acid derivatives to add to alkynes in the presence of gold(I) complexes was exploited in the first total synthesis of neurymenolide A (94) 118 (Scheme 28) and in the synthesis of psymberin (97) 119 (Scheme 29). Scheme 28 Synthesis of Neurymenolide A Scheme 29 Synthesis of Psymberin A gold(I)-catalyzed tandem reaction of 1,7-diynes bearing a propargylic carboxylic acid was developed for the total synthesis of drimane-type sesquiterpenoids, 120 involving a first intramolecular alkoxylation to give a furanone intermediate that undergoes an alkoxycyclization with benzyl alcohol. A similar tandem alkoxylation/alkoxycyclization sequence was also recently used in the synthesis of cladiellins. 121 2.2 Addition of N-Nucleophiles to Alkynes 2.2.1 Intermolecular Addition of N-Nucleophiles to Alkynes Despite the fact that gold(III)-catalyzed hydroamination of terminal alkynes had been known since 1987, 122 it was not until 2003 that Hayashi and Tanaka developed the first gold(I)-catalyzed intermolecular amination of alkynes with anilines to form imines 98/98′ (Scheme 30). 123 Another more recent example was developed using gold(I) complexes bearing 1,2,4-triazole-based N-heterocyclic carbene ligands for the formation of the corresponding ketimines from terminal alkynes and aniline derivatives. 124 A different approach for the formation of imines was based on gold(I)-phosphine complexes bearing a low coordinating bis(trifluoromethanesulfonyl) imidate counterion, namely SPhosAuNTf2. 125 These complexes are active catalysts for the regioselective intermolecular hydroamination of both internal and terminal alkynes under mild reaction conditions, showing a regioselectivity based on electronic rather than steric factors. This electronic control on the regioselectivity of alkyne hydroamination reactions had earlier been reported for the hydroamination of unsymmetrical electron-poor and electron-rich alkynes with anilines (Scheme 31). 126 More challenging hydroaminations of less-reactive internal alkynes an unprotected aliphatic amines could be performed using a novel series of 1,2,3-triazole-based cationic gold(I) complexes, 47a which turned out to have a superior thermal stability than other catalysts previously reported. Scheme 30 Intermolecular Amination of Alkynes to Form Imines Scheme 31 Regioselective Hydroamination of Unsymmetrical Alkynes Nowadays, as happens for the addition of O-nucleophiles to alkynes, gold(I)-catalyzed hydroamination of alkynes is not limited to the synthesis of imine or enamine products by formal addition of N–H reagents onto triple bonds. 123,127 Instead, a number of tandem sequences involving alkyne-hydroamination steps have been reported leading to the formation of more complex structures such as azaflavanones 101(128) or quinoline derivatives 102(129) (Scheme 32). Another example refers to a tandem intermolecular hydroamination/transfer hydrogenation catalyzed by gold(I) combined with a chiral Brønsted acid to form enantioenriched secondary amines 103 (Scheme 33). 130 This methodology tolerates a wide range of aryl, alkenyl, and aliphatic alkynes, as well as a range of anilines with different electronic properties. Scheme 32 Synthesis of Azaflavanones and Quinoline Derivatives Scheme 33 Enantioselective Hydroamination/Transfer Hydrogenation Synthesis of Secondary Amines An enantioselective tandem hydroamination/hydroarylation of alkynes has recently been reported using a gold(I)/chiral Brønsted acid binary system as catalyst. 131 In this transformation, the gold(I)-activated alkynes react with a range of pyrrole-based aromatic amines to give pyrrole-embedded aza-heterocyclic scaffolds bearing a quaternary center. Isoxazoles can also add to ynamides in the presence of gold(I) in a formal [3 + 2] cycloaddition to give polysubstituted 2-aminopyrroles. 132 The gold(I)-catalyzed intermolecular reaction between 2H-azirines and ynamides provides highly substituted pyrroles 105 in a formal [3 + 2] cycloaddition (Scheme 34). 133 Scheme 34 Synthesis of Polysubstituted Pyrroles from 2H-Azirines and Ynamides 2.2.2 Intramolecular Addition of N-Nucleophiles to Alkynes The intramolecular hydroamination of unactivated alkynes is a very useful tool to construct nitrogen-containing heterocycles. An efficient method to obtain pyrroles comes from the intramolecular dehydrative cyclization of amino-3-alkyn-2-ols mediated by gold(I). 78b A similar catalytic system catalyzed a tandem direct amination/cycloisomerization from (Z)-2-en-4-yn-1-ols in the presence of an external amine to give substituted pyrroles under mild reaction conditions. 134 Alkynyl amidoalcohols undergo a gold(I)-catalyzed spiroamidoketalization giving rise to spiro-N,O-ketals with 5- and 6-membered rings presumably via tandem intramolecular 5-exo-dig hydroamidation/intramolecular oxycyclization. 135 Aryl-substituted N-tosyl alkynylaziridines 106 are prone to undergo a gold(I)-catalyzed ring expansion to form 2,5- (107) or 2,4-disubstituted pyrroles (108) depending on the solvent and the counterion of the gold complex (Scheme 35). 136 Similarly, the system Ph3PAuCl/AgOTf is able to catalyze the rearrangement of propargylic aziridines forming trisubstituted and cycloalkane-fused pyrroles. 137 This transformation involves an unusual tandem cyclization-opening/Wagner-Meerweein sequence. The selective formation of 2,5-disubstituted pyrroles catalyzed by the same Au(I)/Ag(I) system from acetylenyl aziridines was also described using THF as solvent, 138 finding that the presence of protic species such as MeOH increased the reaction rate and the yield of the pyrrole products. Scheme 35 Synthesis of 2,5- or 2,4-Disubstituted Pirroles from Aryl-Substituted N-Tosyl Alkynylaziridines A new method for the synthesis of substituted pyrroles 111 based on an intermolecular hydroamination process has recently been reported. 139 The reaction takes place by a tandem process consisting of an initial addition of a gold-acetylide to an acetal moiety to form intermediate 110 followed by a gold(I)-catalyzed 5-endo-dig cyclization and final aromatization (Scheme 36). Scheme 36 Synthesis of Substituted Pyrroles by an Intermolecular Hydroamination The synthesis of N-heterocycles bearing −CN and −CF3 groups at the α-position has been reported by intramolecular hydroamination coupled with the addition of external nucleophiles to the resulting enamine intermediate. 140 Depending on the relative position of the alkyne and the nucleophilic nitrogen, the cyclization can proceed by 5-exo-dig and 6-endo-dig pathways. In general, the electronic properties of the substituent of the alkyne play a crucial role in the control of regioselectivity. The presence of electron-donating substituents on the alkyne tends to favor 6-endo-dig cyclization pathway, whereas electron-withdrawing substituents favor the 5-exo-dig cyclization. One example of this regioselectivity reversal was reported in the cyclization of o-alkynylbenzyl carbamates 112 (Scheme 37). 141 However, other factors such as steric interactions have to be taken into account to predict the regiochemical outcome of intramolecular hydroaminations of internal alkynes having these two competing reaction pathways. In the case of terminal alkynes, most of the heterocyclizations afford 5-exo-dig products as a consequence of the better stabilization of the positive charge on the internal carbon of the triple bond. Scheme 37 Cyclization of o-Alkynylbenzyl Carbamates Another example of exclusive formation of the 6-endo-dig cyclization product gave isoquinoline derivatives by a gold(I)-mediated hydroamination of (2-alkynyl)benzyl carbamates. 142 Moreover, the hydroamination of alkynyl carbamates bearing an acetal or enone was applied to the synthesis of tetracyclic heterocycles such as 119 via a gold(I)-catalyzed tandem hydroamination/cyclization (Scheme 38). Scheme 38 Tandem hydroamination/Cyclization of Alkynyl Carbamates Alkynylureas can also undergo intramolecular hydroamination processes in the presence of gold(I) catalysts. In general, o-ethynylarylureas bearing an internal alkyne lead to N1-attack-5-endo-dig cyclizations, regardless of the gold(I) complex employed. In the case of 3-substituted 1-(o-alkynylphenyl)ureas 120, indole derivatives are formed (Scheme 39). O-Ethynylphenylureas can selectively undergo N3-attack-6-exo-dig cyclization when NHC-stabilized gold(I) complexes are used. 143 In contrast, in a similar gold(I)-catalyzed reaction previously reported, 1-(ortho-ethynylaryl)ureas bearing a terminal alkyne in aqueous media led exclusively to the corresponding indole under microwave heating through N1-5-endo-dig cyclization. 144 This method provided indole-1-carboxamides in moderate yields tolerating a variety of functional groups. 1H-Imidazol-[1,5-a]indol-3(2H)-ones were also prepared in the presence of a gold(I) catalyst starting from urea derivatives. 145 On the other hand, acyclic alkynylureas undergo O-attack-5-exo-dig cyclization in the presence of gold(I). 146 This feature was exploited for the development of an asymmetric three-component tandem reaction from imines, terminal alkynes, and sulfonylisocyanates in which a single gold(I) species can catalyze both the alkynylation of aryl–aryl imines and the subsequent 5-exo-dig cyclization to afford enantioenriched five-membered carbamimidates. Scheme 39 Regiodivergent Cyclization of o-Ethynylarylureas Indenyl-fused and 2,3-disubstituted indoles have been obtained from 2-tosylaminophenylpro-1-yn-3-ols in the presence of gold(I) through a common vinyl gold intermediate. 147 Furthermore, aniline-substituted diethynylarenes 121 give aryl-annulated carbazoles 124 by a hydroamination/hydroarylation cascade in the presence of gold(I) complexes (Scheme 40). 148 Scheme 40 Synthesis of Aryl-Annulated Carbazoles by Hydroamination/Hydroarylation Spiro-N,O-ketals with 5- and 6-membered rings have been recently synthesized under mild conditions via gold(I)-catalyzed spiroamidoketalization of alkynyl amidoalcohols. 149 The analogous intramolecular hydroamidation of the corresponding alkynylamide leading to a seven-membered ring was not successful. 2.2.3 Addition of N-Nucleophiles to Alkynes in Total Synthesis The potential of gold(I) to construct nitrogen containing heterocycles has been demonstrated in several total synthesis. The intramolecular gold(I)-catalyzed alkyne hydroamination reaction provides an efficient entry to tetrahydroisoquinolines, as highlighted in the total synthesis of (−)-quinocarcin (127). 150 In the presence of [JohnPhosAu(MeCN)]SbF6, 125 undergoes regioselectively a 6-endo-dig hydroamination forming the corresponding dihydroquinoline, which after reduction with NaBH3(CN) formed the desired tetrahydrosioquinoline 126 (Scheme 41). In another remarkable example, the key step in the total synthesis of (−)-rhazinicine (132) and (−)-rhazinilam (133) 151 was a gold(I)-catalyzed cascade cyclization of 128 initiated by an intramolecular 6-exo-dig nucleophilic addition of the nitrogen atom of the amide to the gold-activated alkyne to build the highly substituted indolizinone skeleton 131 (Scheme 42). Scheme 41 Synthesis of (−)-Quinocarcin Scheme 42 Synthesis of (−)-Rhazinicine and (−)-Rhazinilam 2.3 Addition of Other Heteronucleophiles to Alkynes The gold(I)-catalyzed addition of heteronucleophiles to alkynes other than oxygen and nitrogen is by far a less developed transformation. Nevertheless, it has been described the attack of the sulfur atom of aryl thioethers to alkynes affording benzothiophenes 135 (Scheme 43). 152 This transformation has also been described in the presence of gold(III). 153 It was shown that aryl thiosilanes 136 can act as both sulfur nucleophiles and silicon electrophiles capturing the vinyl-gold intermediate in the gold(I)-catalyzed intramolecular reaction to afford 3-silylbenzothiophenes 138 (Scheme 44). 154 When enantiomerically pure o-alkynylphenyl-1-aryl ethyl sulfides were used as substrates for this transformation, complete chirality transfer was observed. 155 In an analogous transformation, the gold(I)-catalyzed alkoxyboration of alkynes provides a method for the preparation of O-heterocyclic boronic acid derivatives 140. 156 Scheme 43 Synthesis of Benzothiophenes by Cyclization of Aryl Thioethers Scheme 44 Synthesis of 3-Silylbenzothiophenes and O-Heterocyclic Boronic Acid Derivatives Moreover, in the presence of gold(I) complexes, dithiols can also add to alkynes to form cyclic thioacetals, 72 and homopropargylthiols bearing a propargylic alcohol lead to thiophenes after addition of the thiol to the gold-activated alkyne followed by dehydration. 78 A novel rearrangement was described for propargylic 1,3-dithianes 141 when they were heated in the presence of Ph3PAuCl/AgSbF6. In this transformation, eight-membered dithiosubstituted cyclic allenes 142 were formed with good yields and remarkable stability (Scheme 45). 157 Scheme 45 Synthesis of Eight-Membered Cyclic Allenes N-Heterocyclic carbene gold(I) bifluoride complexes have been shown to be efficient catalysts in the hydrofluorination of symmetrical and unsymmetrical alkynes. 158 This reaction proceeds in good to excellent yields with high stereo- and regioselectivity to afford fluorinated stilbene derivatives and fluorovinyl thioethers. 3 Gold(I)-Catalyzed Reactions of Alkenes with Alkynes 3.1 Cycloisomerization of Enynes 3.1.1 General Mechanistic Aspects Cycloisomerizations of 1,n-enynes are probably one of the most illustrative carbon–carbon bond forming reactions catalyzed by electrophilic metal complexes. These transformations are very useful in synthetic organic chemistry, since they provide access to complex molecular architectures from readily assembled starting materials through mechanistically complex, fully intramolecular processes. The first example of electrophilic activation of enynes was reported back in the 1980s using palladium catalysts, 159 which promoted an intramolecular Alder-ene reaction. The Alder-ene cycloisomerization of enynes requires simultaneous coordination of both the alkyne and the alkene to the metal, followed by a two-electron oxidation of the metal, which is favorable for palladium(II) and also platinum(II). 160 However, the oxidation of gold(I) to form a gold(III) metallacycle is highly improbable under ordinary conditions. 161 In addition, [AuL]+ cations are isolobal to H+, which makes the simultaneous coordination of the alkene and the alkyne highly unlikely. Therefore, in contrast to Pd(II) 159 and Pt(II), 162 gold(I)-catalyzed cycloisomerizations of enynes do not proceed via Alder-ene reaction. Instead, activation of the alkyne by gold(I) forms a (η2-alkyne)metal complex 143 that reacts as an electrophile with the alkene moiety either by 5-exo-dig or 6-endo-dig pathways to form the corresponding cyclopropyl gold carbenes 144 or 145 (Scheme 46), 45,163 which, in the absence of internal and external nucleophiles, evolve by different skeletal rearrangements. It is important to emphasize that these species show highly delocalized structures, which are intermediate between cyclopropyl gold(I) carbenes and gold(I)-stabilized cyclopropylmethyl/cyclobutyl/homoallyl carbocations. In general, π-back-donation from gold(I) to the carbene center is poor, 164,165 although it becomes more significant in complexes [LAuCR2]+ with highly donating N-heterocyclic carbene ligands. 166 Indeed, a few complexes with carbene-like structures showing relatively short Au(I)–C bonds have been structurally characterized. 167 The best-studied gold(I)-catalyzed reactions from a mechanistic point of view are cycloisomerizations of 1,6-enynes, which have often been used as model substrates for the discovery of new reactions and new catalysts activity. According to DFT calculations, the single-cleavage skeletal rearrangement occurs via opening of 144 to form η2-diene 146-gold(I) complexes in a single step by a 1,3-migration of the terminal carbon of the alkene to C(1) of the alkyne. 163b Six-membered ring compounds 147 arise from an alternative endo-type single-cleavage rearrangement in which the internal carbon of the double bond migrates toward C(1) of the alkyne. 168 Although formation of 1,3-dienes by single cleavage in metal-catalyzed cycloisomerization of enynes could also be explained by a conrotatory ring opening of cyclobutene intermediates 148, experimental evidence and theoretical calculations suggest that for enynes with di- and trisubstituted alkenes this transformation takes place by a direct reaction of cyclopropyl gold(I) carbenes bypassing the formation of cyclobutene intermediates. 163b Thus, the rearrangement of 1,6-enynes with two methyl groups at the alkene terminus proceeds smoothly at temperatures as low as −40 to −60° using cationic catalysts [(R3P)Au(MeCN)]SbF6, which would imply an abnormally low activation energy for the hypothetical conrotatory opening of a cyclobutene. 163b Scheme 46 General Pathways for the Cycloisomerization of 1,6-Enynes For the double-cleavage rearrangement, intermediates 144 can evolve by a formal insertion of the terminal carbon of the alkene into the alkyne carbons. These new carbenes 149 undergo α-proton elimination to afford dienes 150. In this process, both the alkene and the alkyne are cleaved in an intramolecular transformation. On the other hand, intermediates 145 from 6-endo-dig cyclization can lead to bicyclo[4.1.0]hept-2-ene derivatives 151 by protodeauration, which are the products of an intramolecular cyclopropanation of the alkene by the alkyne. 161a,169 Alternatively, isomerization of gold(I) carbene 145 by ring expansion of the cyclopropane gives (η2-cyclobutene)-gold(I) complexes 152, which can isomerize to give cyclobutenes 153. Gold(I)-complexes of 152 have been observed by NMR spectroscopy, 170 and a bicyclo[3.2.0]hept-5-ene formed gold(I)-catalyzed by cycloisomerization has been characterized by X-ray diffraction. 163c The opening of these gold(I) complexes can also form complexes 154, which are direct precursors of 1,3-dienes 146, the product of a single cleavage rearrangement. Analogously, 1,5- 171 and 1,7-enynes undergo gold(I)-catalyzed rearrangements through somewhat related pathways. 163b,172 3.1.2 Cycloisomerization of 1,6- and Higher Enynes The pathway followed by a particular enyne is highly influenced by its substitution pattern. DFT calculations 173 support that the formation of 5-membered cyclic compounds is generally kinetically favored for terminal alkynes, while the formation of 6-membered rings becomes preferred for internal alkynes together with the ones with heteroatoms at the tether. Gold(I)-catalyzed single-cleavage rearrangements of enynes proceed under very mild conditions to form 1,3-dienes. 43,161a,163a,163b,174 Hence, enynes 155 bearing a terminal alkyne and a disubstituted alkene undergo a cycloisomerization reaction in the presence of Ph3PAuCl and AgBF4 to give exclusive formation of single-cleavage rearrangement 1,3-dienes 156 (Scheme 47). 163a,163b In most of the cases, these rearrangements are stereospecific processes in which the configuration of the alkene is retained. However, 1,6-enynes such as 157 bearing strongly electron-donating groups at the terminal alkene carbon lead to Z-configured 1,3-dienes 158 regardless the configuration of the starting enynes (Scheme 48). 175 1,6-Enynes 159 containing alkyl-substituted alkynes undergo double-cleavage rearrangements in the presence of Ph3PAuCl and AgBF4 (Scheme 49). 161a,163b Scheme 47 Single-Cleavage Rearrangement of 1,6-Enynes Scheme 48 Single-Cleavage Rearrangement of 1,6-Enynes with Electron-Donating Groups at the Alkene Scheme 49 Double-Cleavage Rearrangement of 1,6-Enynes with Alkyl-Substituted Alkynes 1,6-Enynes bearing a terminal alkene and/or tethered with heteroatoms such as 161 and 164 provide six-membered rings 162 and 165 by endo-type single-cleavage rearrangement as the major products (Scheme 50). 161a 1,6-Enynes boronated at either the alkyne or the alkene react in a similar vein with Ph3PAuCl and AgSbF6. 176 Scheme 50 Endo-Type Single-Cleavage Rearrangement Regarding gold(I)-catalyzed 6-endo-dig cyclizations, when 1,6-enynes are tethered by an ether or a sulfonamide group, oxa- or aza-bicyclo[4.1.0]hept-4-ene derivatives 168 and 171 are formed as the major products as a result of a formal intramolecular cyclopropanation of the alkene by the alkyne (Scheme 51). 161a,177 Scheme 51 Synthesis of Oxa- and Aza-Bicyclo[4.1.0]hept-4-enes by Cycloisomerization of 1,6-Enynes A tandem allylation/cycloisomerization has been developed for the synthesis of 3-oxabicyclo[4.1.0]hept-4-ene derivatives using gold(I) catalysts. 178 The enantioselective synthesis of bicyclo[4.1.0]hept-4-enes has also been described with excellent enantioselectivities using (R)-DTBM-MeO-biphep(AuCl)2/AgOTf 179 (DTBM = 4-MeO-3,5-(t-Bu)2C6H2) or more recently gold(I) complexes with chiral phosphoramidite ligands. 52b,180 NHC-capped cyclodextrins coordinated to AuCl also catalyze the formation of 3-azabicyclo[4.1.0]hept-4-enes, although this catalyst provides only modest enantioselectivities. 181 3-Alkoxy-1,6-enynes in the presence of gold(I) form 1,4-cycloheptadienes by a nucleophilic attack of the alkoxy group onto the alkyne presumably followed by a [3,3]-sigmatropic rearrangement. 182 O-Tethered 1,6-enynes 172 that contain a strained ring react with gold(I) by cycloisomerization followed by a 1,2-alkyl carbocationic shift resulting in ring expansion (Scheme 52). 183 A two-step method involving this transformation was developed for the synthesis of ketomacrolactones 174, which are scaffolds present in several natural products. The tricyclic skeleton of natural products crotobarin and crotogoudin has very recently been obtained via a 1,6-enyne gold(I)-catalyzed cycloisomerization followed by intramolecular trapping of the resulting gold(I) carbene by a carboxylic acid. 184 Scheme 52 Cycloisomerization Followed by a 1,2-Alkyl Carbocationic Shift A gold(I)-catalyzed polycyclization of linear dienediynes 175 has been developed for the construction of fused 5,7,6-tricyclic ring systems 177 in one step with high diastereocontrol (Scheme 53). 185 The polycyclization takes place through gold(I)-catalyzed intramolecular cyclopropanation of the diene with the diyne followed by Cope rearrangement to give strained allene intermediate 176, which subsequently undergoes a C–H activation, followed by 1,2-H and G- (H- or AcO) shifts. Scheme 53 Polycyclization of Dienediynes To Form 5,7,6-Tricyclic Ring Systems The skeletal rearrangements of 1,7-enynes have been much less studied than those of 1,5- and 1,6-enynes. Gold(I) complexes are in general the best catalysts for the cycloisomerization of these substrates, leading to 1,3-dienes 179 through a single-cleavage process (Scheme 54). 172 Related enynes bearing aryl substituents at the alkene give mixtures of products of single-cleavage along with seven-membered ring compounds by an endo-type single-cleavage rearrangement. 186 Scheme 54 Single-Cleavage Rearrangement of 1,7-Enynes Gold(I) complexes also catalyze Conia-ene reactions, which can be considered as cyclizations of 1,6-enynes via the corresponding enol tautomers (Scheme 55). 187 Thus, cyclopentane derivatives 180 were obtained in excellent yields and good diastereoselectivities. The reaction has also been efficiently carried out using a gold catalyst bearing a bulky phosphine ligand 188 or a catalyst generated in situ from a cyclic thiourea-AuCl complex and a silver salt. 189 The cyclization of aldehydes with alkynes in the presence of secondary amines proceeds analogously via the corresponding enamines generated in situ. 190 Scheme 55 Formation of 5-Membered Rings by Conia-Ene Cyclization Silyl enol ether derivatives react with alkynes in a similar way. 191 Substrates featuring a 1,6- or 1,7-relationship between the silyl enol ether and the alkyne such as 181 undergo an exo-cyclization to form five- (182) or six-membered rings (183), respectively (Scheme 56). 192 However, it was found that it is possible to tune the exo- or endo-selectivity by changing the ligand on gold. 193 Thus, gold(I) complexes containing very bulky phosphine ligands favor the 6-endo-dig cyclization, whereas complexes with NHC ligands lead to 5-exo-dig cyclization products preferentially. Enantioselective versions of this reaction have been developed using chiral gold(I) complexes. 194 Scheme 56 Exo-Cyclization of Silyl Enol Ethers with Alkynes Conia-ene cyclizations have also been performed starting from 1,6-diynes that react first with methanol of another alcohol in the presence of gold(I) to form in situ the corresponding enol ethers, which then undergo the cycloisomerization process to afford the corresponding 5-membered-ring products. 195 An analogous process has been developed by the intramolecular addition of other nucleophiles such as carboxylic acids or nitrogen nucleophiles to 1,6-diynes. 196 Gold(I)-complexes with a semihollow-shaped triethynylphosphine ligand promote a 7-exo-dig cyclization of 1,7-enynes bearing silyl enol ethers. 197 Related 1,8-enynes also give seven-membered-ring products in the presence of this catalyst as a result of a 7-exo-dig cyclization. 198 The 8-endo-dig pathway to form eight-membered carbocycles could be promoted by using a modified triethynylphosphine-based ligand. 1,7-Enynes 184 also undergo a formal gold(I)-catalyzed 8-endo-dig cyclization to give benzoxocines 187 (Scheme 57). 199 It has been proposed that the reaction proceeds through a 7-endo-dig cyclization, followed by ring expansion to form the benzylic carbocation 186 that after elimination and protodeauration leads to the final product. As a proof of this mechanism, tricyclic compounds deriving from the protodeauration of 185 have been isolated in some cases as the minor products. Scheme 57 Synthesis of Benzoxocines by Cyclization of 1,7-Enynes Certain 7-aryl-1,6-enynes undergo gold(I)-catalyzed cycloisomerization reactions leading to bicyclo[3.2.0]hept-6-enes. 163c,169c,170,200 In the case of 7-aryl-1,6-enynes 188 having an amide or an ester at the tether, gold(I) promotes the exclusive formation of cyclobutenes 189 that result from a formal [2 + 2] cycloaddition between the alkene and the alkyne followed by isomerization of the double bond (Scheme 58). 201 It has been recently found that, when these reactions are carried out in the presence of air, tricarbonyl compounds 190 are formed instead. 202 Scheme 58 Formal [2 + 2] Intramolecular Cycloaddition Between Alkene and Alkyne 1,6-Ene-ynamides undergo highly diastereoselective gold(I)-catalyzed cycloisomerizations forming cyclobutanones or carbonyl compounds containing a 2-azabicyclo[3.1.0]hexane subunit, depending on the substitution pattern. 203 1,7- 163b and 1,8-enynes 204 also form cyclobutene derivatives in the presence of gold(I) catalysts. In the case of 1,9-enyne 191, 10-membered-ring 192 was obtained in the presence of large amounts of gold(I) (Scheme 59). 205 Scheme 59 Synthesis of a 10-Membered-Ring Compound by Cycloisomerization of a 1,9-Enyne The macrocyclization of higher 1,n-enynes (n = 10–16) affords benzene-fused 9- to 15-membered rings incorporating a cyclobutene ring as a result of a formal [2 + 2] cycloaddition (Scheme 60). 206 Scheme 60 Macrocyclization of 1,n-Enynes 3.1.3 Cycloisomerization of 1,5-Enynes In general, 1,5-enynes react by endocyclic pathways. This tendency can be rationalized in terms of the more favorable formation of a bicyclo[3.1.0]hexane system in the endo-cyclization, which is less strained than the bicyclo[2.1.0]pentane system that would result from the exo-cyclization. 244b The first example of a cyclization of 1,5-enynes was described for the gold(III)-catalyzed synthesis of pyridines from ketones and propargyl amines via in situ generated enamine. 207 1-Alkynyl-2-alkenylbenzenes 195 in the presence of gold(I) mainly undergo endo-dig cyclizations affording substituted naphthalenes 196 (Scheme 61). 208 The formation of products 197 through exo-cyclization becomes more relevant when R1 = H or I. 208a In an analogous reaction, (Z)-hexa-1,3-dien-5-ynes lead to highly substituted benzene derivatives through a gold(I)-catalyzed endo-cyclization followed by a 1,2-alkyl shift. 209 Scheme 61 Synthesis of Naphthalenes by endo-dig Cyclization of 1,5-Enynes The selectivity of the cyclization of 2-(alkynyl)-α-methylstyrenes could be switched from 6-endo-dig to 5-exo-dig by adding an alcohol to the reaction media. 210 Moreover, 2-alkynylstyrenes disubstituted at the β-position of the styrene moiety selectively afford 1H-indene derivatives via 5-endo-dig cyclization. An enantioselective cycloisomerization of 2-alkynylstyrenes 198 has been described using a chiral dinuclear gold(I) catalyst with the (S)-3,5-xylyl-MeO-biphep ligand. 211 In this particular case, only exo-cyclization products were observed, providing access to 1-alkenyl-1H-indenes 199 in excellent yields and with good enantioselectivities (Scheme 62). Scheme 62 Enantioselective Cycloisomerization of 2-Alkynylstyrenes Nitrogen-tethered 1,5-enynes have been used to form N-heterocycles. The synthesis of 4-aryl-2-pyridones was reported by gold(I)-catalyzed endo-cyclization of 1,5-enynes bearing an amide at the tether. 212 Analogously, azaanthraquinones 201 were assembled from N-propargylaminoquinones 200 (Scheme 63). 213 The same strategy was later employed for the synthesis of pentacyclic pyrido[4,3,2-mn]acridin-8-ones. 214 Alkyne-tethered dihydropyrimidones undergo an endo-cyclization in the presence of AuCl yielding pyridopyrimidones. 215 Scheme 63 Synthesis of Azaanthraquinones from N-Propargylaminoquinones Alkyl- and aryl-substituted 1,5-enynes undergo gold(I)-catalyzed endo-dig cycloisomerization to afford bicyclo[3.1.0]hexene derivatives 202 in a stereospecific manner (Scheme 64). 216 Under these reaction conditions, substrates bearing a quaternary center at the propargylic position evolve differently. Thus, cycloalkyl-substituted enyne 203 undergoes a ring expansion by 1,2-alkyl shift to give tricyclic compound 205, whereas 204 bearing a larger cycloalkyl substituent goes through C–H bond insertion to afford tetracyclic compound 206 (Scheme 65). 217 Scheme 64 Synthesis of Bicyclo[3.1.0]hexenes by endo-dig Cycloisomerization of 1,5-Enynes Scheme 65 endo-dig Cycloisomerization of 1,5-Enynes Followed by Ring Expansion and C–H Insertion In the presence of gold(I), 1,5-enynes 207 bearing a cyclopropylidene moiety undergo an enantioselective ring-expanding cycloisomerization providing bicycle[4.2.0]octanes 210 (Scheme 66). 218 Scheme 66 Enantioselective Ring-Expanding Cycloisomerization of Cyclopropylidene 1,5-Enynes The gold(I)-catalyzed cycloisomerization of 3-hydroxylated-1,5-enynes may follow divergent reaction pathways depending on their substitution pattern (Scheme 67). 219 The reaction of nonprotected 3-hydroxy-1,5-enynes with gold(I) gives bicyclo[3.1.0]hexan-3-ones 211, whereas those benzyl-protected give the analogous product 212 together with the product of skeletal rearrangement 213. Boc-protected 3-hydroxy-1,5-enynes form cyclohex-4-ene-1,2-diol derivatives 214. 220 Gold(I) complexes also catalyze formation of benzene derivatives 215 from 3-hydroxy-1,5-enynes, 221 which can also be generated in situ by the addition of allylsilanes to alkynals. 222 Scheme 67 General Pathways for the Cycloisomerization of 3-Hydroxylated-1,5-Enynes The gold(I)-catalyzed cyclization of 3-silyloxy-1,5-enynes proceeds with concomitant semipinacol rearrangement leading to carbonyl compounds. 223 6-Silyloxy-1,5-enynes such as 216 and 218 react with AuCl by an endo-pathway to give 1,4- (217) or 1,3-cyclohexadienes (219) depending on the substitution at the propargylic position (Scheme 68). 171 Analogously, chiral 1,5-enynes were used to construct tricyclic structures bearing a spirofused 1,3-cyclohexadiene ring. 224 Scheme 68 endo-dig Cycloisomerizations of 6-Silyloxy-1,5-enynes Propargyl cyclopropenes react with gold(I) to form substituted benzene derivatives (Scheme 69). 225 In this transformation, the substituents in the cyclopropane ring have a crucial effect on the reaction pathway and therefore on the regiochemical outcome. Thus, cyclopropenes bearing larger substituents such as aryl groups (220) lead to rearranged products in which neither the alkene nor the alkyne is cleaved (222). In contrast, those cyclopropenes bearing smaller hydrogen or alkyl groups (221) favor a double cleavage pathway. According to DFT calculations, the mechanism of this reaction involves an unprecedented two consecutive 1,3-cationic alkylidene migrations of nonclassical carbocation intermediates. 226 Scheme 69 Synthesis of Substituted Benzenes by Cycloisomerization of Propargyl Cyclopropenes Alkynylcyclopropanes 224 undergo a gold(I)-catalyzed rearrangement to afford alkynyl cyclohexadienes 226 and 227 (Scheme 70). 227 The mechanism of this rearrangement has been recently revised experimental and theoretically, giving clear evidence for the involvement of η1-allylic gold(I) cationic intermediate 225. 228 Scheme 70 Synthesis of Alkynyl Cyclohexadienes by Rearrangement of Alkynylcyclopropanes Enols such as 229 deriving from β-keto esters can also participate in gold(I)-catalyzed 1,5-enyne cycloisomerizations, namely Conia-ene carbocyclizations (Scheme 71). 229 Silyl enol ether derivatives react similarly with alkynes. 191 As for 1,6-enynes, enantioselective versions of this reaction have been described. 194 Bicyclo[m.n.1]alkenone frameworks 232 with a bridged ketone were synthesized through a Conia-type reaction of 1,5-enynes 231 (Scheme 72). 230 Scheme 71 Conia-Ene Carbocyclizations of β-Keto Esters Scheme 72 Synthesis of Bicyclo[m.n.1]alkenone Frameworks by Conia-type Cyclization 3.1.4 Cycloisomerization of 1,n-Enynes in Total Synthesis Cycloisomerizations of 1,n-enynes, generally coupled with tandem reactions, allow for an increase of molecular complexity in one step under very mild conditions. Therefore, these transformations have been widely used in the field of total synthesis. 63 The total synthesis of sesquiterpene ventricosene 236 was accomplished through a key gold(I)-catalyzed cyclization of 1,6-enyne 233, which proceeds with concomitant ring expansion via 234 to form cyclobutanone 235 (Scheme 73). 231 Scheme 73 Synthesis of Ventricosene The total syntheses of hyperforin (239) and papuaforins A-C (240-242) have been achieved by using a gold(I)-catalyzed Conia-type reaction from 1,5-enynes 237 (Scheme 74). 232 Similar cyclizations were used in the syntheses of the alkaloids (+)-lycopladine A (245) 233 and (+)-fawcettimine (249) (Scheme 75), 234 as well as in the total synthesis of platencin. 235 This reaction has also been applied to the cyclization of 1,7-enynes in the total synthesis of the marine sesquiterpene (±)-gomerone C 252(236) and also in the total synthesis of Daphniphyllum alkaloid daphenylline 255 (Scheme 76). 237 Scheme 74 Syntheses of Hyperforin and Papuaforins A–C Scheme 75 Synthesis of Alkaloids (+)-Lycopladine and Fawcettimine Scheme 76 Syntheses of the Sesquiterpene (±)-Gomerone C and Alkaloid Daphenylline The cyclization of 3-silyloxy-1,5-enyne 256 followed by semipinacol rearrangement was used to construct the hexahydro-1H-inden-4(2H)-one core of (+)-sieboldine A (259), which contains an unprecedented N-hydroxyazacyclononane ring (Scheme 77). 238 Scheme 77 Synthesis of (+)-Sieboldine A 3.2 Intermolecular Reactions of Alkenes with Alkynes Gold(I)-catalyzed intermolecular reactions between alkenes and alkynes constitute a real challenge since all the conceivable products are by themselves potential substrates for gold(I), which in consequence may compete with the initial alkene leading to oligomerization products. 59 The first reaction developed in this area was a formal [2 + 2] cycloaddition between terminal alkynes and substituted alkenes that led to the formation of cyclobutenes 261 (Scheme 78). 239 The regiochemical outcome of this process is in agreement with a reaction pathway through highly distorted cyclopropyl gold(I) carbenes 260 that finally undergo a ring expansion. Scheme 78 [2 + 2] Cycloaddition of Alkynes with Alkenes Interestingly, the intermolecular reaction of propiolic acid with alkenes does not form cyclobutenes. Instead, this reaction leads to 1,3-dienes (262) or lactones (263) depending on the nature of the alkenes (Scheme 79). 240 Asymmetrically substituted alkenes lead to the formation of lactones by attack of the carboxylic acid to the most substituted carbon of the alkene. On the other hand, alkenes with two electronically identical or very similar substituents afford stereospecifically 1,3-dienes by 1,3-migration, following a pathway that is similar to the one occurring in the single-cleavage rearrangement of 1,6-enynes. Scheme 79 Formation of Lactones or Dienes by Reaction of Propiolic Acid with Alkenes Propiolic esters 241 and sulfonylacetylenes 242 react in a different manner with allylic ethers to provide 1,4-dienes by nucleophilic addition of the ether oxygen onto the alkynes, followed by [3,3]-sigmatropic rearrangement. The presence of α-substituents in the allyl ether promotes a competing [1,3]-sigmatropic rearrangement concomitant with the [3,3]-rearrangement. Terminal ynamides react intermolecularly with enol ethers in the presence of gold(I) to give enamines 264 as a result of a [2 + 2 + 2] cycloaddition (Scheme 80). 243 Arylynamides react intermolecularly with alkenes forming a cyclopropyl gold(I) carbene, which is opened by a Friedel–Crafts attack of the aryl group forming 1,2-dihydronaphthalenes. 243 Scheme 80 [2 + 2 + 2] Cycloaddition between Ynamides and Alkenes 3.3 Addition of Heteronucleophiles to Enynes Gold(I) complexes catalyze the addition of amines, alcohols, or water to enynes leading to products of amino-, alkoxy-, or hydroxycyclization under much milder conditions than other metal catalysts. 161a,163a,211,244 The overall process is an anti-addition of an electrophile (alkyne-gold(I) complex) and a heteronucleophile to a double bond in a stereospecific process. 3.3.1 Intermolecular Addition of Heteronuclephiles to Enynes In the presence of an external heteronucleophile, the cyclopropyl gold(I) carbenes generated as intermediates in the cycloisomerization of 1,n-enynes are opened by attack to the cyclopropane ring. These additions take place following the Markovnikov regiochemistry, giving rise to products of exo-trig (266) or endo-trig cyclization (268) (Scheme 81). 161a,163a Similar results have been obtained using NHC-gold(I) or gold(III)-complexes as catalysts. 174a,244a,245 The enantioselective hydroxy- and alkoxycyclization of 1,6-enynes catalyzed by a chiral biphosphine-gold complex 246 or by NHC-gold(I) complexes 247 proceeds with moderate to good enantioselectivities. 1,5-Enynes also react with alcohols or water in the presence of gold(I) catalysts to give the corresponding adducts. 244c The hydroxy- and alkoxycyclization of 1,7-enynes takes place similarly. 172 It is remarkable that the hydroxycyclization process is usually much faster than the direct addition of water to terminal alkynes to form the corresponding methyl ketones. Scheme 81 Alkoxycyclization of 1,6-Enynes 7-Substituted-1,6-enynes 269 bearing a fused aromatic ring at the tether undergo predominantly gold(I)-catalyzed hydroxycyclization by a 6-endo-dig pathway instead of the 5-exo-dig pathway usually observed for 1,6-enynes with trisubstituted alkenes to afford bicyclic compounds 270 (Scheme 82). 248 Scheme 82 Alkoxy or Hydroxycyclization of 1,6-Enynes by 6-endo-dig Pathway The reaction of allylsilylalkynes such as 271 catalyzed by gold(I) in the presence of external alcohols gives vinylsilanes. 249 Depending on the choice of the nucleophile, either cyclic or acyclic vinylsilanes were obtained (Scheme 83). DFT calculations suggest that this transformation takes place through silicenium cations 272 formed by a pericyclic reaction of the allylsilylalkynes coordinated to gold(I). 250 The attack of methanol to these intermediates gives cyclic vinylsilanes 273, whereas the attack of a weaker nucleophile such as phenol takes place at the silicon leading to acyclic vinylsilanes 274. Scheme 83 Synthesis of Vinylsilanes from Allylsilylalkynes Propargyl vinyl ethers in the presence of gold(I) and water or alcohols undergo a Prins-type reaction affording dihydropyrans. 251 Furthermore, N-heteronucleophiles such as carbamates and anilines also react intermolecularly with 1,6-enynes to form amino-functionalized carbo- or heterocycles 275 (Scheme 84). 252 Scheme 84 Aminocyclization of 1,6-Enynes 1,6-Enynes also react with aldehydes to give products of formal [2 + 2 + 2] cycloaddition 276 together with a metathesis-type reaction of the enyne with the aldehyde that forms 1,3-dienes 277 (Scheme 85). 253 1,7-Enynes also undergo a [2 + 2 + 2] cycloaddition with carbonyl compounds in the presence of gold(I) giving rise to analogous heterocyclic products. 254 Scheme 85 [2 + 2 + 2] Cycloaddition of 1,6-Enynes with Carbonyl Compounds and Formation of Metathesis-Type Products Cyclopropenones react with enynes in a ring-expanding spiroannulation incorporating a molecule of water to afford spirocyclic cyclopentenones 278 by a mechanistically related process (Scheme 86). 255 Scheme 86 Reaction of 1,6-Enynes with Cyclopropenones 1,6-Enynes bearing a monosubstituted alkene react with aldehydes and ketones in a different way, presumably via trapping of the rearranged carbene that results from the enyne to give intermediate 279, followed by Prins reaction, to afford tricyclic compounds 281 (Scheme 87). 256 In a similar vein, 1,5-enynes also undergo intermolecular reactions with carbonyl compounds. 253 Scheme 87 Reaction of 1,6-Enynes with Carbonyl Compounds via Rearrangement 3.3.2 Intramolecular Addition of Heteronuclephiles to Enynes The alkoxycyclizations can also take place intramolecularly starting from hydroxyl-1,6-enynes, 161a,244d and the resulting adducts may further evolve increasing molecular complexity. As an example, the synthesis of 4-oxa-6-azatricyclo[3.3.0.02,8]octanes 285 was reported by a complex gold-catalyzed cycloisomerization of alkynyl hydroxyallyl tosylamides 282 in the presence of Ph3PAuCl and AgSbF6 (Scheme 88). 257 Scheme 88 Synthesis of 4-Oxa-6-azatricyclo[3.3.0.02,8]octanes from Alkynyl Hydroxyallyl Tosylamides The intramolecular amino- or alkoxycyclization of amino- or hydroxyl-1,5-enynes 286 yields spirofused heterobicyclic compounds 287 (Scheme 89). 258 1,5-Enynes bearing carbamates 259 or carbonates 260 also undergo gold(I)-catalyzed tandem cyclizations in a mechanistically related transformation. The analogous reaction of 1,6-enynes bearing a carboxylic acid leads stereospecifically to lactones. 244d,261 Phenols can also add to 1,5-enynes in substrates of type 288 with a gold(I) catalyst to give tricycles 289 stereospecifically (Scheme 90). 262 The enantioselective version of the addition of phenols to 1,6-enynes has also been described. 261 Similarly, the intramolecular reaction of hydroxypropargyl vinyl ethers 290 catalyzed by a trinuclear gold(I)-oxo complex leads to 5,6- and 6,6-spiroketals 291 and 292 with good stereocontrol (Scheme 91). 251 This transformation constrasts with the reactivity previously shown for propargyl vinyl ethers, which in the presence of the same trinuclear gold(I)-oxo complex underwent a Saucy-Marbet rearrangement giving rise to allenes. 263 Scheme 89 Intramolecular Amino- or Alkoxycyclization of 1,5-Enynes Scheme 90 Intramolecular Addition of Phenols to 1,5-Enynes Scheme 91 Synthesis of 5,6- and 6,6-Spiroketals from Hydroxypropargyl Vinyl Ethers Oxo-1,6-enynes such as 293 also react in the presence of gold(I) complexes to give oxatricyclic compounds 295 by a tandem sequence in which two C–C bonds are formed together with one C–O bond (Scheme 92). 264 This formal [2 + 2 + 2] alkyne/alkene/carbonyl cycloaddition proceeds by attack of the carbonyl to the cyclopropyl gold carbene intermediate followed by Prins cyclization to give 294, which forms the final oxatricyclic derivative after deauration. Oxo-1,5-enynes also undergo an intramolecular reaction to give tricyclic derivatives. 265 Scheme 92 Cyclization of Oxo-1,6-enynes by [2 + 2 + 2] Alkyne/Alkene/Carbonyl Cycloaddition Terminal alkynes and oxoalkenes undergo an analogous [2 + 2 + 2] cycloaddition reaction by intermolecular cyclization of the alkyne and the alkene followed by intramolecular attack of the carbonyl group to form 8-oxabicyclo[3.2.1]oct-3-enes 296 (Scheme 93). 266 Scheme 93 Intermolecular [2 + 2 + 2] Cycloaddition of Terminal Alkynes with Oxoalkenes Dienynes with a methoxy or other OR group at the propargylic position such as 297 react with gold(I) by an intramolecular 1,5-OR migration to form tricyclic compounds 299 (Scheme 94). 267 Substrates substituted with other OR groups at the propargyl position also undergo this 1,5-migration. Scheme 94 Cyclization of 1,6-Enynes via 1,5-OR Migration 3.3.3 Addition of Heteronucleophiles to Enynes in Total Synthesis Gold(I)-catalyzed intramolecular [2 + 2 + 2] alkyne/alkene/carbonyl cycloadditions 264 have been exploited for the synthesis of several oxygen-bridged sesquiterpenoids. Ketoenyne ( E )-300 in the presence of gold(I) reacted intramolecularly to give oxatricyclic compound 301, which was converted into (+)-orientalol F (302) in three additional steps (Scheme 95). 268 The key step of the synthesis of pubinernoid B (304) proceeded analogously starting from ( Z )-300. Scheme 95 Syntheses of (+)-Orientalol F and Pubinernoid B The stereospecific [2 + 2 + 2] alkyne/alkene/carbonyl cycloaddition was also applied to the synthesis of antitumor sesquiterpene (−)-englerin A (309) in two independent syntheses (Scheme 96). 269 It is remarkable that in both approaches an unprotected aldol subunit could be used as the substrate for the gold(I)-catalyzed reaction. Scheme 96 Synthesis of (−)-Englerin A The formation of alkenylsilanes from allylsilylalkynes in the presence of an external alcohol 249 was used in the total synthesis of (−)-amphidinolide V. 270 Gold(I)-catalyzed reaction of 1,6-enyne 310 by cyclization followed by 1,5-acetoxy migration from 312 forms an α,β-unsaturated carbene 314, 267 which reacts intermolecularly with alkene 311 to afford 315 with only 5% loss of enantiomeric excess (Scheme 97). 271 This transformation was reported as part of the total synthesis of antiviral sesquiterpene (+)-schisanwilsonene A (316). It is interesting that the cyclization/1,5-acetoxy migration is faster than the alternative 1,2-acyloxy migration, which would lead to racemization. Scheme 97 Synthesis of (+)-Schisanwilsonene A The total syntheses of three sesquiterpenes, namely (−)-4β,7α-aromadendranediol (320), (−)-epiglobulol (321), and (−)-4α,7α-aromadendranediol (322), have been accomplished by a stereodivergent gold(I)-catalyzed reaction from a single precursor 317 (Scheme 98). 272 The reaction can take place intramolecularly by 1,5-migration of OBn giving 318 or intermolecularly in the presence of allyl alcohol as an external nucleophile, obtaining allyl ether 319. Scheme 98 Synthesis of Aromadendrane Sesquiterpenes 3.4 Addition of Carbonucleophiles to Enynes 3.4.1 Cyclopropanation of Enynes The gold(I)-catalyzed cyclization of dienynes 323 leads stereoselectively to tetracyclic compounds 325 by cyclopropanation of intermediate gold(I) carbenes 324 (Scheme 99). 163a,169a These intramolecular cyclopropanations afford very complex ring systems when the starting dienynes are cyclic substrates. 273 Intramolecular cyclopropanations of 1,5-enynes take place similarly through an endo-carbene. 274 Scheme 99 Intramolecular Cyclopropanation of 1,6-Enynes Intermediate cyclopropyl gold carbenes resulting from the cyclization of 1,6-enynes can also be trapped intermolecularly by cyclic or acyclic alkenes to form adducts 326 stereoselectively (Scheme 100). 275 Scheme 100 Intermolecular Cyclopropanation of 1,6-Enynes 1,6-Enynes bearing a terminal alkene react by a different mechanism through rearrangement of the initially formed cyclopropyl gold(I) carbene 327 to form 328, which reacts with an external alkene to afford 329 (Scheme 101). Scheme 101 Intermolecular Cyclopropanation of 1,6-Enynes via Rearrangement In the presence of gold(I), 7-alkynylcyclohepta-1,3,5-trienes generate highly fluxional barbaralyl gold(I) cations 330, which can be intercepted intramolecularly with alkenes to form 331a–b (Scheme 102). 276 These two species are in equilibrium by Cope rearrangement both in the solid state and in solution. Scheme 102 Intramolecular Cyclopropanation from 7-Alkynylcyclohepta-1,3,5-trienes 3.4.2 Friedel-Craft Arylation of Enynes Electron-rich aromatic and heteroaromatic compounds such as indoles can undergo a stereospecific intermolecular addition to 1,6-enynes in the presence of gold(I) catalysts (Scheme 103). 252,265,277 This transformation proceeds by opening of the intermediate cyclopropyl gold(I) carbene in a process mechanistically related to the hydroxy- and alkoxycyclization of 1,6-enynes. The enantioselective version of this reaction has also been reported. 278 The enantioselective intramolecular addition leads to enantiomerically enriched complex ring systems in a single step. 261 Scheme 103 Intermolecular Addtion of Indole to 1,6-Enynes 1,6-Enynes bearing an aryl substituent at the alkyne such as 333 react stereospecifically with gold(I) in a formal [4 + 2] cycloaddition reaction under very mild reaction conditions (Scheme 104). 169b,244a,279 This reaction proceeds via initial exo-cyclization followed by opening of the cyclopropyl gold(I) carbene by a Friedel–Crafts-type reaction to provide 334. Related 1,6-enynes with 1-thienyl and 1-indolyl groups at the alkyne also undergo formal [4 + 2] cycloadditions catalyzed by gold(I) complexes bearing bulky biphenyl phosphine ligands. 280 In the presence of chiral phosphine gold(I) complexes 281 or gold(I) phosphite complexes 282 these [4 + 2] cycloadditions can be performed enantioselectively. Related cyclizations of alkynes with allenes 283 and diynes 284 have also been described. The endo-cyclization also takes place in certain cases, being the major pathway in the platinum(II)- or gold(I)-catalyzed cycloaddition of related arylalkynes bearing enesulfonamides or enamines. 285 Scheme 104 Intramolecular [4 + 2] Cycloaddition of Arylalkynes with Alkenes 1,5-Enynes 335 with an aryl substituent at the alkyne react with gold(I) to form dihydrobenzofluorenes 339 in a formal [3 + 3] cycloaddition by a 1,2-H shift in intermediate 337, followed by a Friedel–Crafts alkylation (Scheme 105). 286 Scheme 105 Synthesis of Dihydrobenzofluorenes by Cycloisomerization and Friedel-Crafts Alkylation 3.4.3 Addition of Other C-Nucleophiles 1,3-Dicarbonyl compounds can add to 1,6-enynes as C-nucleophiles through their enol tautomers, although some of them such as cyclohexane-1,3-dione and 2-oxocyclohexanecarboxaldehyde behave as O-nucleophiles. 277a In the presence of 1,3-diketones, N-tethered 1,6-enynes bearing an internal alkyne afford tetrahydropyridines 340 as a result of an endo-cyclization (Scheme 106). In contrast, analogous 1,6-enynes bearing a terminal alkyne undergo an exo-cyclization and in the presence of the nucleophile giving adducts 341 and/or 342 depending on the nature of the gold(I) catalyst (Scheme 107). Products 341 are favored with the most electrophilic gold(I) catalysts, whereas less electrophilic complexes with more donating ligands favor the formation of 342. Gold(I) complexes also catalyze the addition of allylic silanes to 1,6-enynes. 277a Scheme 106 Addition of 1,3-Diketones to 1,6-Enynes by endo-Cyclization Scheme 107 Ligand-Controlled Addtion of 1,3-Diketones to 1,6-Enynes 1,3-Dien-8-ynes undergo a formal intramolecular gold(I)-catalyzed [4 + 2] cycloaddition reaction. 287 Dienynes 343 cyclize similarly in the presence of gold(I) and heating by microwave irradiation to form stereoselectively hydrindanes 344 (Scheme 108). 169b,244a,288 Scheme 108 Intramolecular [4 + 2] Cycloaddition of 1,3-Dien-8-ynes 4 Gold(I)-Catalyzed Reactions of Propargylic Carboxylates 4.1 Reactions of Propargylic Carboxylates Propargylic carboxylates react with gold(I) complexes undergoing 1,2- or 1,3-acyloxy migrations through 5-exo-dig or 6-endo-dig cyclizations to form α-acyloxy-α,β-unsaturated carbenes 345 or allene-gold complexes 347, which are in equilibrium (Scheme 109). 46,289 Similar transformations have been described for propargyl acetals, 290 as well as by using other metal catalysts. 291 Scheme 109 General Pathways in the Isomerization of Propargylic Carboxylates Species 348 have been trapped in intermolecular reactions with alkenes, 52a,292 ynamides, 293 carbon nucleophiles, 294 imines, 295 and sulfides. 296 Although the reaction of intermediates 348 with alkenes usually affords vinylcyclopropanes, in the case of propargyl acetals such as 349, products of [3 + 2] cycloaddition 352 are obtained (Scheme 110). 290b,290c In this transformation, gold(I) carbene 351 is formed by 1,2-OMe shift. Intermediate 351 undergoes an intermolecular cyclopropanation with vinyl acetate to form 350, which reacts with 351 in a Michael-type addition, followed by a Prins cyclization to form 352. Scheme 110 [3 + 2] Cycloaddition of Propargyl Acetals with Alkenes The gold(I)-catalyzed synthesis of benzopyrans 356 has been described from propargyl carboxylates 353 by intramolecular trapping of gold(I) carbenes 354 by an ether group followed by rearrangement of the resulting allylic oxonium ylides 355 (Scheme 111). 297 The synthesis of substituted naphthalenes has been reported from propargylic esters by a gold(I)-catalyzed sequence involving a 1,3-acyloxy migration followed by a 1,2-alkyl or aryl migration and subsequent hydroarylation. 298 Scheme 111 Synthesis of Benzopyrans from Propargyl Carboxylates Gold allenic intermediates 347 derived from 1,3-acyloxy migration (see Scheme 109) can be trapped by other functional groups to give of a range of different compounds. 299 In situ generated ketone-allene substrates 358 were used as substrates for a gold(I)-mediated tandem oxacyclization/[4 + 2] cycloaddition cascade to afford highly substituted oxacycles 359 with excellent stereocontrol (Scheme 112). 300 Nucleophilic allenes have also been generated in situ by a gold(I)-catalyzed rearrangement of propargylic esters and then used for intermolecular C(sp3)–C(sp2) bond formation reactions. 301 Scheme 112 Tandem Oxacyclization/[4 + 2]-Cycloaddition from in Situ Generated Ketoallene Substrates In the presence of AuCl, ω-hydroxy propargylic acetates undergo a 1,3-acetoxy migration to form allenyl acetate 360, which is trapped intramolecularly to form tetrahydropyranes 361 containing an exocyclic enolacetate (Scheme 113). 302 This transformation proceeds with remarkable high Z-selectivity in the final alkenes and the retention of the configuration of diastereomerically pure substrates. 1,6-Diyne esters also react with gold(I) forming allenyl gold(I) intermediates, which can react with the pendant alkyne giving a variety of cyclized products. 303 Scheme 113 Synthesis of ω-Hydroxy Propargylic Acetates via 1,3-Acetoxy Migration The gold(I)-catalyzed acyloxy migration has been applied to the synthesis of 1-acetoxy-1H-indenes. 304 The mechanism of this transformation involves a 1,3-migration to form the allenyl intermediate that undergoes an intramolecular hydroarylation, followed by another final 1,3-acyloxy migration to generate a more stable substituted indene. The same reaction in the presence of water leads to α,β-unsaturated ketones. Terminal halo-substituted propargyl carboxylates 362 react with Ph3PAuNTf2 in anhydrous CH2Cl2 to form 1-halo-2-carboxy-1,3-dienes 363 by 1,2-migration of the ester (Scheme 114). 289f It has been recently reported that the same substrates in the presence of Ph3PAuCl/AgSbF6 and H2O undergo a regioselective hydration to give α-acyloxy α′-halo ketones 364. 305 Scheme 114 Migration or Hydration of Halo-Substituted Propargyl Carboxylates Gold(I) catalyzes the formation of alkenyl enol esters or carbonates from trimethylsilylmethyl-substituted propargyl esters/carbonates with excellent E-selectivity. 306 Alkynyloxiranes 365 bearing a propargylic ester rearrange to form divinyl ketones 366 (Scheme 115). 307 The mechanism of this transformation seems to proceed via anchimeric assistance of the propargyl ester moiety, although DFT calculations predict a complex mechanism involving several equilibriums. Scheme 115 Synthesis of Divinyl Ketones from Alkynyloxiranes Bearing a Propargylic Carboxylate α-Iodoenones can be accessed by 1,3-migration of propargylic acetates in the presence of gold(I) and NIS. 308 α-Trifluoromethyl enones have been synthesized by a tandem 1,3-acyloxy migration/trifluoromethylation from 1-arylpropargyl esters with excellent stereoselectivity. 309 Propargylic 3-indoleacetates undergo a gold(I)-catalyzed tandem [3,3]-rearrangement/[2 + 2] cycloaddition to afford 2,3-indoline-fused cyclobutanes. 310 Other structures have also been accessed by reactions of propargyl carboxylates with gold(I), such as dihydrofurans, 311 aromatic ketones, 312 allenes, 313 or polyconjugated δ-diketones. 314 4.2 Cycloisomerizations of Enynes Bearing Propargylic Carboxylates Enynes bearing propargylic α-acyloxy substituents can react with gold(I) by two parallel pathways, depending on the order of attack of the acyloxy group or the alkene onto the alkyne in complexes 367 (Scheme 116). This transformation is known as the Ohloff-Rautenstrauch (or simply Rautenstrauch) rearrangement, following the original discovery of the reaction catalyzed by zinc(II) or palladium(II). 315 If the alkene reacts first, then the cyclopropyl gold carbene 369 can suffer an intramolecular attack of the acyloxy group on the carbene, followed by elimination of AuL+ to give 370. On the other hand, the acyloxy group can first undergo a 1,2-migration to form carbene 368, which leads to 370 by intramolecular cyclopropanation. Annulations of enynes 367 may also proceed via the acyloxy allene formed by 1,3-migration. 316 Scheme 116 Parallel Reaction Pathways of Enynes Bearing Propargylic Carboxylates The gold(I)-catalyzed cyclization of 1,5-enynes containing propargylic carboxylates affords bicyclic structures 373, which form the corresponding ketones 374 after methanolysis (Scheme 117). 317 The cyclization of 1,7- and 1,8-enynes with propargylic acetates affords analogous products by a tandem 1,2-acyloxy migration/cyclopropanation. 318 This process allows the enantioselective synthesis of 7- and 8-membered-ring compounds by using chiral gold(I) catalysts. 319 Scheme 117 Synthesis of Bicyclo[3.1.0]hexan-2-ones by Cyclization of 1,5-Enynes with Propargylic Carboxylates In a mechanistically related transformation, 1,4-enynes 375 bearing propargylic carboxylates in the presence of gold(I) form cyclopentenones 376 via 1,2-acyloxy migration (Scheme 118). 320 In this Rautenstrauch rearrangement, enantiomerically enriched propargyl carboxylates give enantioenriched cyclopentenones. The cycloisomerization of 1,6-enynes with acyloxymethyl substituents at the alkyne also proceeds by 1,2-migration to produce bicyclic derivatives with an exocyclic enol acetate group. 321 Scheme 118 Synthesis of Cyclopentenones from 1,4-Enynes with Propargylic Carboxylates 1,3-Enynes bearing propargylic carboxylates also lead to cyclopentenones in the presence of gold(I). 322 This transformation takes place through 1,3-migration of the carboxylate followed by a Nazarov-type cyclization. 289d Propargylic acetates 377 also react via 1,3-acyloxy migration to afford bicyclo[3.1.0]hexenes 378 (Scheme 119), which can be converted into cyclopentenones (R2 ≠ H) or cyclohexenones (R2 = H) by methanolysis. 316,323 Scheme 119 Synthesis of Cyclopentenes from 1,3-Enynes with Propargylic Carboxylates The gold(I)-catalyzed cycloisomerization of 1,6-dien-8-yne carbonates and esters 379 has been reported to yield cis-cyclohepta-4,8-diene-fused pyrrolidines 381 by a tandem process involving a 1,2-acyloxy migration/cyclopropanation to form 380 and a final [3,3] sigmatropic rearrangement (Scheme 120). 324 Scheme 120 Synthesis of cis-Cyclohepta-4,8-diene-Fused Pyrrolidines from 1,3-Dien-8-yne Carbonates and Esters Trienyne 382 cyclizes following a 5-endo-dig pathway through cyclopropyl gold(I) carbene 383, which gives 384 by 1,2-acyloxy migration followed by a Cope rearrangement to afford hydrozulenic derivative 385 (Scheme 121). 325 Scheme 121 Synthesis of Hydroazulenes by Cycloisomerization of 1,5-Enynes and Cope Rearrangement N-Tethered 1,7-enyne benzoates such as 386 bearing a substituent at the alkyne react with gold(I) by 1,3-acyloxy migration to form azabicyclo[4.2.0]oct-5-enes 388 by a formal [2 + 2] cycloaddition of the alkene with the in situ generated 1-acyloxyallene 387 (Scheme 122). 326 Scheme 122 Synthesis of Azabicyclo[4.2.0]oct-5-enes from N-Tethered 1,7-Enyne Benzoates Enynes 389 form hydroxy dicarbonyl compounds 391 in wet dichloromethane (Scheme 123). 327 This reaction presumably proceeds by two consecutive 1,2-acyloxy migrations, followed by a 1,3-dipolar cycloaddition of the carbonyl ylide to form acetal 390, and final hydrolysis. A similar mechanism is involved in the gold(I)-catalyzed reaction of propargylic esters tethered to cyclohexadienones. 328 Scheme 123 Synthesis of Hydroxy Dicarbonyl Compounds by Two 1,2-Acyloxy Migrations Cyclopropyl alkynyl acetates without any substituent at the alkyne undergo a gold(I)-catalyzed rearrangement to form cyclohexenones with high degree of enantiospecificity through gold-stabilized carbocations. 329 Cyclopropyl alkynyl acetates with a substituent at the alkyne terminus react differently by a 1,3-acyloxy shift, whereas the ones substituted at the internal position of the alkene follow a different reaction pathway to give cyclohexenones disubstituted at the 4-position. 330 1,n-Enynes 392 with a conjugated enone react by a different mechanism involving a 1,3-acyloxy migration to form acyloxyallenes 393, which undergo a Michael addition to form cyclic products 394 (Scheme 124). 331 Scheme 124 Cyclization of 1,n-Enynes by 1,3-Acyloxy Migration and Michael Addition α,β-Unsaturated ketones can be efficiently prepared by a gold(I)-catalyzed Meyer-Schuster-like rearrangement from propargyl carboxylates 332 or alcohols. 333 In contrast, γ-hydroxy-α,β-acetylenic esters in the presence of alcohols undergo a gold(I)-catalyzed alkoxylation/lactonization to form 4-alkoxy-2(5H)-furanones. 334 The gold(I)-catalyzed reaction of alkynylcyclopropanols and cyclobutanols proceeds through ring expansion to give α-alkylidene cyclobutanones. 335 4.3 Reactions of Propargylic Carboxylates in Total Synthesis The gold(I)-catalyzed Meyer-Schuster rearrangement was applied in the total synthesis of (+)-anthecotulide 396 (Scheme 125). 336 Scheme 125 Synthesis of Anthecotulide The cyclization of an acetoxy-1,6-enyne by 1,3-acyloxy migration, followed by a Nazarov-type electrocyclization, was used in the total synthesis of the marine triquinane sesquiterpene capnellene 399 (Scheme 126). 337 Scheme 126 Synthesis of Capnellene 5 Hydroarylation and Hydroheteroarylation of Alkynes 5.1 Cyclizations of Arylalkynes Electrophilic metal catalysts form, upon coordination to an alkyne, electrophilic complexes that undergo electrophilic aromatic substitution reactions with arenes. Gold(I)-complexes generally promote reactions according to this pathway. 338 The direct auration of electron-rich arenes and heteroarenes by gold(I) 339 and gold(III) 340 is a well-known process, but the resulting aryl-gold complexes are apparently not involved in subsequent C–C bond forming reactions with alkynes. The auration of electron-deficient arenes has also been achieved. 341 Aryl-gold(I) complexes only react with alkynes in the presence of a palladium(0) catalysts, or a palladium(II) precatalyst, to afford products of carboauration. 341c The gold-catalyzed intermolecular hydroarylation of alkynes leads to 1,1-disubstituted alkenes or 1,2-disubstituted derivatives in the case of alkynes bearing electron-withdrawing groups. 342 According to experimental and computational work on the cyclization of arylalkynes catalyzed by platinum(II), two pathways with very similar activation energies compete in intramolecular hydroarylations: a Friedel–Crafts alkenylation and a reaction proceeding through metal cyclopropyl carbenes. 343 However, comparing the results obtained for platinum(II)-catalyzed hydroarylation reactions such as the cyclization of N-propargyl-N-tosyl anilines, better yields and milder reaction conditions are obtained with cationic gold(I) catalysts (Scheme 127). 344 A detailed theoretical analysis of the cycloisomerization of phenyl propargyl ethers catalyzed by a Au38 cluster has recently been reported. 345 N-Butynyl anilines also form 1,2-dihydroquinolines by 6-exo-dig cyclization followed by a proton-catalyzed isomerization of the exocyclic double bond. 346 These products could be rearranged into functionalized indole derivatives under photochemical conditions. The intramolecular hydroarylation of N-propargyl-N′-phenylhydrazines gives cinnoline derivatives. 347 Scheme 127 Synthesis of 1,2-Dihydroquinolines from N-Propargyl Anilines N-Aryl-2-alkenylpyrrolidine derivatives 402 formed in situ give rise to pyrrolo[1,2-a]quinolones 403 through a tandem sequence involving the attack to an external alkyne followed by an intramolecular hydroarylation (Scheme 128). 348 Unprotected propargylic and homopropargylic aniline derivatives in the presence of terminal alkynes undergo a tandem hydroamination/hydroarylation to give dihydroquinolines or quinolones. 129a,349 Scheme 128 Synthesis of Pyrrolo[1,2-a]quinolones by Intramolecular Hydroarylation The hydroarylation of iodo-substituted propargyl anilines 404 gives selectively 4-iododihydroquinolines 405 with more electrophilic gold(I) complexes, whereas 3-iododihydroquinolines 406 are obtained with more electron-rich gold(I) catalysts bearing NHC ligands (Scheme 129). 350 The cyclization of bromo- and iodopropargyl aryl ethers with IPrAuNTf2 also proceeds with 1,2-halogen migration to give 3-halo-2H-chromenes. 351 Scheme 129 Hydroarylation of Iodo-Substituted Propargyl Anilines The cyclization of propargyl aryl ethers takes place analogously yielding 2H-chromenes, even in the cases in which the aromatic ring bears electron-withdrawing groups. 163a,343,344b,344c,352 However, in the case of substrates containing both a 1,6-enyne and an aryl propargyl ether, the enyne cycloisomerization is favored, and no hydroarylation takes place. 353 Aryl alkynoate esters 407 afford coumarin derivatives 408 in the presence of gold(I) by intramolecular hydroarylation under anhydrous conditions (Scheme 130). 342b,344b,354 It has been recently reported that the same substrates under the same reaction conditions swapping from anhydrous to wet solvent undergo a gold(I)-catalyzed spirocyclization under mild conditions, giving spirolactones 409 in high yields. 355 Spiro[4.5]cyclohexadienones have been also obtained by a gold(I)-catalyzed carbocyclization of phenols with a terminal alkyne via intramolecular ipso-Friedel–Crafts. 356 Aryl alkynylphosphonates also undergo intramolecular gold(I)-catalyzed hydroarylation to give phosphacoumarins. 357 Scheme 130 Synthesis of Coumarins or Spirolactones from Aryl Alkynoate Esters The intramolecular hydroarylation has also been applied in a complex transformation initiated by a rhodium(II)-catalyzed intramolecular cyclopropanation of α-aryldiazo ketones with alkenes to give products 411 that react with silver(I) to form alkynylhydrofurans 412, which in the presence of gold(I) afford benzo-fused dihydrofurans 413 (Scheme 131). 358 Alkynylaziridines with an aryl group rearrange in the presence of gold(I) to form spiro[isochroman-4,2′-pyrrolines] via allenylidene intermediates. 359 Scheme 131 Synthesis of Benzo-Fused Dihydrofurans from Alkynylhydrofurans The cyclization of o-alkynyl biphenyl derivatives with gold(I), as happens with gold(III), platinum(II), and other metal catalysts, 360 proceeds preferentially by the endo-pathway leading to phenanthrenes 414. The use of a new strongly π-acidic phosphine-bound gold(I) catalyst has allowed to broaden the scope of this transformation, leading to excellent yields in short reaction times, even for 4,5-disubstituted phenanthrenes (Scheme 132). 361 Scheme 132 Synthesis of Phenanthrenes from o-Alkynyl Biphenyls Interestingly, o-haloalkynebiaryls react with AuCl to give phenanthrenes in which the halide has suffered a 1,2-shift. 360c This type of transformation has been applied to the synthesis of 5,8-diiodo- and 6,13-diiodobenzo[k]tetraphenes 415 (Scheme 133), 362 as well as to the synthesis of benzo[a]phenanthridines from 3-alkynyl-4-arylisoquinolines. 363 It has been proposed that the most favored reaction pathway features an initial 6-endo-dig hydroarylation of the alkyne followed by 1,2-H shift and formation of a gold-carbene intermediate, which then undergoes a 1,2-halogen shift to finally give the rearranged product after deauration. 364 The reaction of (o-arylphenyl)alkynylselenides in the presence of gold(I) and gold(III) affords rearranged phenanthrenyl selenides very efficiently by migration of the selenide from the terminal to the internal position of the alkyne. 365 Scheme 133 Synthesis of Diiodobenzo[k]tetraphenes Gold(I)-catalyzed 6-exo-dig hydroarylation reactions are much less common. The synthesis of substituted anthracenes in the presence of gold(I) by exo-cyclization was achieved from o-alkynyldiarylmethanes. 366 In a mechanistically related transformation, the synthesis of functionalized phenanthrenes 416 has been described from o-propargylbiaryls (Scheme 134). 367 Dibenzocycloheptatrienes were obtained by a related transformation through a 7-exo-dig hydroarylation. 368 Scheme 134 Synthesis of Phenanthrenes by 6-exo-dig Hydroarylation The gold(I)-catalyzed hydroarylation of alkyne-tethered fluorenes was applied to the synthesis of fluoranthenes and more complex polyarenes. 22 A gold(I)-catalyzed formation of benzofurans has been coupled with intramolecular hydroarylations to form polyaromatic ribbons. 369 5.2 Cyclizations of Heteroarylalkynes 5.2.1 Reactions of Indoles with Alkynes The reaction of N-propargyl tryptophans or tryptamines 417 catalyzed by gold(I) or gold(III) leads to seven- and eight-membered rings, respectively (Scheme 135). 370 Eight-membered-ring products 419 are formed by an 8-endo-dig process, a type of cyclization that had not been observed in any other hydroarylation of alkynes or cyclization of enynes. These cyclizations have been coupled with other tandem reactions to obtain polycyclic indole-based structures. 371 Scheme 135 Formation of Seven- and Eight-Membered Rings from Alkynyl Indoles by 7-exo-dig or 8-endo-dig Cyclization The intermolecular reaction of indoles with (Z)-pent-2-en-4-yn-1-ols gives intermediate (Z)-3-(pent-2-en-4-ynyl)indoles, which undergo a similar cyclization to afford seven-membered-ring products. 372 Tetracyclic indole derivatives were synthesized enantioselectively by coupling a organocatalytic process with a gold(I)-catalyzed 7-endo-dig cyclization. 373 Indoles with the alkynyl chain tethered at the 2-position can undergo a gold(I)-catalyzed cyclization to form carbazoles. 374,375 The formation of indoles in situ by intramolecular hydroamination coupled with an intramolecular hydroarylation has been applied to the preparation of benzo-fused carbazoles, 148a,376 1,2,3,10-tetrahydroazepino[3,4-b]indoles, and related cyclic compounds. 148b Other gold(I)-catalyzed transformations that yield functionalized carbazoles are the gold(I)-catalyzed deactylative cyclization of 3-acylindole/ynes 377 and the tandem hydroarylation/6-endo-dig cyclization of alkynes with 2-alkynylindoles. 378 In the case of indoles bearing a nucleophilic functional group, either at the 3-position (420) or on the alkynyl chain (422), the reaction leads to tetracyclic indolines (Scheme 136). 371,379 Other cascade processes initiated by cyclizations of indoles with alkynes have also been reported. 380 Scheme 136 Synthesis of Tetracyclic Indolines by Hydroarylation and Intramolecular Nucleophilic Addition An Ugi four-component reaction of propargylamines with 3-formylindoles, acids, and isonitriles can be coupled with a gold(I)-catalyzed cyclization of the resulting adducts 424 to furnish substituted spiroindolines 425 (Scheme 137). 381 Scheme 137 Synthesis of Substituted Spiroindolines from Ugi Four-Component Adducts The intramolecular gold(I)-catalyzed hydroarylation of alkynes with indole-3-carboxamides 426 proceeds by 1,2-acyloxy shift to form dihydroindoloazepinones 428 (Scheme 138). 382 An unusual 1,2-indole migration has been observed in the gold(I)-catalyzed reaction of 3-propargylindoles. 383 Scheme 138 Synthesis of Dihydroindoloazepinones from Indole-3-carboxamides The intermolecular reaction of homopropargyl alcohols with indoles in the presence of gold(I) catalysts proceeds differently forming first 2,3-dihydrofurans, which undergo the addition of two equivalents of the indole to the resulting enol ether to give bis(indolyl)alkanes 429 (Scheme 139). 384 Scheme 139 Intermolecular Reaction of Homopropargyl Alcohols with Indoles 5.2.2 Reactions of Furans with Alkynes In contrast to the usual Friedel–Crafts type reaction of arenes with alkynes, furans usually undergo gold(I)- or gold(III)-catalyzed intramolecular reactions with alkynes to form phenols in good to excellent yields (Scheme 140). 91,385 According to experimental and theoretical studies, the phenol synthesis proceeds initially by a mechanism similar to that of the cyclization of 1,n-enynes from furans 430 giving intermediates 431 that evolve by ring opening, cyclization of the resulting carbene, demetalation, and final rearrangement to afford phenols 432. 385f,385g,385p,385s,386 Scheme 140 Intramolecular Phenol Synthesis from Alkynyl Furans Furans generated in situ from endiynes also undergo cyclization with alkynes to form phenols that feature the hydroxyl group at the meta position with respect to the ring junction. 387 The first example of synthesis of phenols by intermolecular reaction of a furan with an alkyne was reported using cationic binuclear complex [(Mes3PAu)2Cl]BF4 as the catalyst, albeit the reaction is very slow and the resulting phenol was obtained in low yield. 388 Later it was reported that phenols 433 can be obtained by intermolecular reaction of furans and alkynes using gold(I) complexes bearing NHC ligands (Scheme 141). 389 Scheme 141 Intermolecular Phenol Synthesis from Alkynyl Furans Furan-yne systems 434 with aromatic tethers react with gold(III) to form phenol derivatives. However, in the presence of gold(I) these substrates react to form indene derivatives 435 by exo-cyclization followed by 1,4-furanyl migration and cyclization. 390 It has been recently described that the same substrates undergo an endo-selective cyclization with concomitant 1,5-migration of the furan group in the presence of unactivated molecular sieves to yield trisubstituted alkenes 436 (Scheme 142). 391 Scheme 142 Divergent Reactions of Furan-ynes To Form Indenes or cis-Stilbene-Type Derivatives Arylated (Z)-enones 440 are obtained by intramolecular reaction of in situ formed intermediates 438 to give 439, which undergo ring opening and final aromatization (Scheme 143). 392 A related transformation leads to functionalized fulvenes with an enone or an enal moiety starting from furanynes with a two-carbon tether between the furan and the triple bond. 393 Scheme 143 Synthesis of Arylated (Z)-Enones from Furanyl Z-1,3-Enynes Furans 441 containing an alkynyl ether moiety in the presence of gold(I) undergo a furan-yne cyclization by a different reaction pathway by which, instead of phenols, tetracycles 443 containing two heteroatoms and two new stereocenters are formed (Scheme 144). 394 A more complex gold-catalyzed process initiated by an intermolecular reaction between 1,6-diyn-4-en-3-ols and furans leads to phenanthrene derivatives. 395 Scheme 144 Furan-yne Cyclization and Friedel-Crafts Annulation The gold(I)-catalyzed reaction of 4-silyloxy-4-furyl alkynes leads to benzofurans by a Friedel–Crafts mechanism. 396 This cyclization has been expanded for the synthesis of substituted benzo[b]-furans 445 by reaction with various external nucleophiles (Scheme 145). 397 Similarly, propargylic alcohol-tethered furans are converted into benzofuran derivatives in moderate yields. 398 Scheme 145 Synthesis of Benzofurans by Friedel-Crafts Reaction of 4-Silyloxy-4-furyl Alkynes Internal alkynes 446 tethered to a furan through a protected benzylic alcohol react with gold(I) giving protected 1-naphthol derivatives 448 via formation of a cationic intermediate 447, followed by ring-opening of the furan ring and aromatization (Scheme 146). 399 It was recently reported that, when furan-ynes 449 bearing a propargylic alcohol moiety were subjected to an analogous reaction, an additional 1,2-rearrangement takes place, leading to substituted 1-naphthols 451 bearing an enal or enone moiety at the C-4 position. 400 Scheme 146 Synthesis of Naphthols by Furan-yne Cyclization 5.2.3 Reactions of Pyrroles with Alkynes The gold(I)-catalyzed intramolecular post-Ugi hydroarylation of internal alkynes with pyrroles was developed for the synthesis of pyrrolopyridinones. 401 In the presence of platinum(II)-catalysts this reaction affords selectively pyrroloazepinones. Ugi-adducts 452 bearing a terminal alkyne give pyrrolopyridines 454 by 5-exo-dig cyclization followed by 1,2-shift under very mild reaction conditions (Scheme 147). 402 Scheme 147 Synthesis of Pyrrolopyridines by Intramolecular Hydroarylation of Pyrroles The one-pot asymmetric synthesis of annulated pyrroles 455 has recently been reported combining cinchona-alkaloid-derived primary amine and gold(I) catalysts (Scheme 148). 403 Scheme 148 Synthesis of Annulated Pyrroles via Hydroarylation The analogous intramolecular reaction for β-yne-pyrrole derivatives provides access to fused cycloheptapyrroles in the case of internal alkynes and six-membered-ring fused pyrroles in the case of terminal alkynes via endo- and exo-selective cyclizations, respectively. 404 The intermolecular reaction of alkynes with pyrroles was also developed to form functionalized pyrrole derivatives 457 or 458 depending on the nature of the alkyne substituent, which could be useful scaffolds for additional annulation processes (Scheme 149). Scheme 149 Intermolecular Hydroarylation of Pyrroles A new synthesis of indoles 459 proceeds by formal gold(I)-catalyzed intermolecular [4 + 2] cycloaddition between 1,3-diynes and pyrroles (Scheme 150). 405 This reaction involves the hydroarylation of one of the alkyne moieties of the diyne with the pyrrole, followed by intramolecular hydroarylation to give 4,7-disubstituted indole. Carbazoles could also be obtained when indoles were used as the nucleophiles instead of pyrroles. Scheme 150 Synthesis of Indoles by Cycloaddition between 1,3-Diynes and Pyrroles 5.3 Hydroarylation and Hydroheteroarylation Reactions in Total Synthesis An application of the formation of 2H-chromenes by intramolecular hydroarylation is found in the synthesis of the tetracyclic core of berkelic acid (462) (Scheme 151). 406 Scheme 151 Synthesis of the Tetracyclic Core of Berkelic Acid The cyclization of aryl propiolates gives coumarin derivatives, including the natural products pimpinellin (464), fraxetin, and purpurasol (Scheme 152). 407 Scheme 152 Synthesis of Pimpinellin The cyclization of alkynylindoles bearing a nucleophile at the 3-position has been used in the formal total synthesis of the indole alkaloid minfiensine. 379a The gold(I)-catalyzed synthesis of carbazoles has recently been applied to the first total synthesis of naturally occurring alkaloid karapinchamine A 466 (Scheme 153). 375b Scheme 153 Synthesis of Karapinchamine A An intramolecular gold(I)-catalyzed hydroarylation of a 3-substituted furan is used as the key step of the total synthesis of furanosesquiterpenes crassifolone and dihydrocrassifolone. 408 6 Oxidative Reactions 6.1 Oxidative Reactions of Alkynes The inter- or intramolecular oxidation of alkynes has been described using sulfoxides, 409 pyridine N-oxides, 410 nitrones, 411 nitroso- and nitrobenzenes, 412 as well as epoxides, 413 as the oxidizing agent. These processes have been proposed to proceed via α-oxo gold(I) carbenes 468, 414 although most likely gold(I) carbenoids 469 are involved by attack of the nucleophile to the highly reactive gold(I) carbene (Scheme 154). 415 The reaction of alkynes with pyridine-N-amidines to give 2,4,6-oxazoles has also been proposed to proceed through α-oxo gold(I) carbenes. 416 Nevertheless, a mechanism involving β-alkoxy alkenylgold(I) intermediates of type 467 rather than α-oxo gold(I) carbenes has been proposed in some of these oxidative reactions of alkynes. 417 Scheme 154 Generation of α-Oxo Gold(I) Carbenes and Gold(I) Carbenoids by Oxidation of Alkynes In the case of terminal alkynes, the gold(I) carbene is always positioned at the terminal carbon of the alkyne. However, regioselectivity becomes a major challenge with internal alkynes. A highly regioselective oxidation of internal alkynes to α,β-unsaturated ketones was developed using IPrAuNTf2 as the catalyst and 8-isopropylquinoline N-oxide as the oxidant. 410c The intermediate α-oxo gold(I) carbenes can be trapped intramolecularly by a nucleophile present in the starting alkyne increasing the molecular complexity of the final products. As an example, propargyl aryl ethers 470 in the presence of gold(I) and a pyridine N-oxide presumably form α-oxo gold(I) carbene 471, which undergoes an intramolecular Friedel–Crafts-type reaction to afford chroman-3-ones 472 (Scheme 155). 418 In a related transformation, propargylic and homopropargylic alcohols react with gold(I) in the presence of pyridine N-oxides to give dihydrofuranones and oxetan-3-ones, respectively. 419 The related oxidative reaction of o-ethynylanilines gives 3-oxyindoles by intramolecular trapping of the intermediate gold(I) carbene. 420 Scheme 155 Synthesis of Chroman-3-ones by Oxidative Cyclization The strong electrophilicity of the α-oxo gold(I) carbene also allows its intermolecular trapping. 2,5-Disubstituted oxazoles 474 were obtained by a formal [2 + 2 + 1] annulation using nitriles as the solvent via intermediates 473. 421 When carboxamides were used as the nucleophilic partners, 2,4-disubstituted oxazoles 476 were obtained by a formal [3 + 2] annulation between terminal alkynes via intermediates 475 (Scheme 156). 422 Carboxylic acids are also suitable trapping agents for the in situ generated α-oxo gold carbenes, giving rise to carboxymethyl ketones. 423 Scheme 156 Synthesis of 2,5- and 2,4-Disubstituted Oxazoles by Oxidative Cyclization The intermolecular trapping of α-oxo gold(I) carbenes by external nucleophiles such as indoles and anilines in aqueous media has been reported, revealing that water can dramatically suppress the undesired overoxidation of the alkyne. 424 A gold(I)-catalyzed tandem cycloisomerization/intermolecular trapping of an in situ generated α-oxo gold(I) carbene involving this transformation has been described to form functionalized indoles 477 from o-alkynyl anilines and ynamides (Scheme 157). 425 In this transformation, gold(I) serves dual catalytic roles to mediate both the cycloisomerization of o-alkynyl anilines and the intermolecular oxidation of ynamides. Scheme 157 Synthesis of Indoles from o-Alkynyl Anilines and Ynamides Diynes bearing one terminal and one triarylmethyl-substituted alkyne were converted into benzofluorenone derivatives via a one-pot process involving a gold(I)-catalyzed generation of an α-oxo carbenoid at the terminal alkyne, followed by a photocyclization/oxidation. 426 6.2 Oxidative Cyclizations of Enynes The oxidative cyclization of 1,5-enynes in the presence of gold(I) and a range of oxidants is a well documented process. Thus, the reaction of 3,5-dien-1-ynes with pyridine N-oxides leads to cyclopropa[a]inden-6(1H)-ones 478(427) or cyclopentadienyl aldehydes 479(428) depending on the structure of the starting substrate or the particular oxidant used (Scheme 158). In a similar cyclization, N-allylyamides are converted into 3-aza-bicylo[3.1.0]hexan-2-ones. 429 Scheme 158 Oxidative Cyclization of 3,5-Dien-1-ynes The gold(I)-catalyzed reaction of 3,5- and 3,6-dienynes (480) with 8-alkylquinoline N-oxides results in an oxidative cycloaddition in which a quinoline framework is activated (Scheme 159). 430 The mechanism of this transformation probably involves an intermediate α-oxo pyridinium ylide 481, which undergoes a concerted [3 + 2] cycloaddition with the tethered alkene to form 482. Cycloalkanone-fused cyclopropanes have been recently obtained by a gold(I)-catalyzed oxidative cyclization from 1,5-ene-ynes. 431 Scheme 159 Synthesis of Quinoline Frameworks by Oxidative Cycloaddition Sulfoxides can also be employed in oxidative cyclization of enynes to afford rearranged products bearing a carbonyl moiety via gold(I)-carbenoid intermediates. 432 Enantiomerically enriched bicyclo[3.1.0]hexan-2-ones have recently been obtained by a tandem alkyne oxidation/cyclopropanation in the presence of gold(I) complexes bearing a chiral phosphoramidite ligand. 433 Similarly, an enantioselective alkyne oxidation/cyclopropanation sequence of 1,5-enynes by gold(I) complexes bearing a P,N-bidentate ligand affords bicyclic cyclopropane products. 434 The intramolecular additions of azides to alkynes are somewhat mechanistically related transformations that give rise to pyrroles 486 (Scheme 160). 435,436 This reaction proceeds by nucleophilic attack of the azide in 483 to form intermediates 484, which loses N2 in a processs reminiscent of the Schmidt reaction to form cationic α-imino gold(I)-carbene 485. Final 1,2-H shift and tautomerization lead to substituted pyrroles. In a similar reaction, 2-alkynyl arylazides have been converted into indoles, 437 whereas similar substrates bearing propargylic carboxylates give quinolines. 438 Scheme 160 Synthesis of Pyrroles by Acetylenic Schmidt Reaction o-(Azido)ynamides 487 were efficiently converted into indoloquinolines 489 in the presence of gold(I) via α-imino gold(I)-carbenes 488 (Scheme 161). 439 Ynamides bearing a simple alkene instead of an allyl silane gave cyclopropane-fused derivatives. Scheme 161 Synthesis of Indoloquinolines from o-(Azido)ynamides 6.3 Oxidative Reactions in Total Synthesis An intramolecular oxidation of 490 through its N-oxide forms 4-piperidone 491, an intermediate in the total synthesis of the alkaloid (±)-decinine 492 (Scheme 162). 440 Scheme 162 Synthesis of (±)-Decinine The gold(I)-catalyzed synthesis of optically active γ-lactams by tandem cycloisomerization/oxidation of homopropargyl amides was applied in the synthesis of (−)-bgugaine. 441 A similar strategy has been used in the total synthesis of (−)-irniine. 442 Interestingly, 3-coumaranones such as 493 can also be obtained by gold(I)-catalyzed oxidative cyclization of o-ethynylanisoles, which has been applied in the total synthesis of sulfuretin (494) (Scheme 163). 443 Scheme 163 Synthesis of Sulfuretin The gold(I)-promoted regioselective oxidation of alkynes 410c was applied on the total synthesis of alkaloids (−)-citrinadin A (497) 444 and (+)-citrinadin B (500) (Scheme 164). 445 Scheme 164 Total Syntheses of (−)-Citrinadine A and (+)-Citrinadine B The gold(I)-catalyzed oxidative cyclization of 1,5-enynes 427 has been recently used as the key step for a concise enantioselective total synthesis of the sesquiterpene (−)-nardoaristolone B (504) by reaction of dienyne 501 with IPrAuNTf2 in the presence of 3,5-dichloropyridine N-oxide to form enone 502, along with the product of cycloisomerization 503 (Scheme 165). 446 Scheme 165 Synthesis of (−)-Nardoaristolone B by Oxidative Cyclization 7 Conclusions Work carried out during the past decade has demonstrated that gold(I) complexes and, in particular, cationic complexes bearing bulky phosphines and NHC ligands are the most active and selective catalysts for the activation of enynes, even in complex polyfunctional settings. Mechanistically, reactions catalyzed by gold(I) are similar to those catalyzed by other electrophilic metal complexes or even Brønsted acids and resemble carbocation-mediated processes. However, gold(I) provides unique control on complex transformations by very selectively activating alkynes and by stabilizing the key carbocationic intermediates by weak, but still significant, metal to carbene π-back-donation. Although many gold-catalyzed reactions of alkynes and, in particular, enynes appear to proceed through gold(I) carbene-like species, the implication of α-oxo gold(I) carbenes in oxidative cyclizations has been recently questioned in several contexts. Further work on the mechanism of these reactions should shed light into the structure of the species involved in these transformations. Most of the work has been carried out in intramolecular processes leading to five- or six-membered ring compounds, although smaller or larger ring systems can also be accessed by using gold(I)-catalysis. However, the regiochemical control in many cases is still essentially dependent on the substrate substitution pattern and not on the ligands on the gold(I) catalyst. Additionally, the structural characteristics of linear two-coordinated gold(I) complexes, in which the ligand is very distant from the nucleophilic addition site to the π-bound substrate, explains the slow development of general enantioselective transformations of alkynes. Finally, the developing of broad-scope intermolecular reactions of alkynes for the formation of carbon–carbon bonds still remains an important challenge in homogeneous gold(I) catalysis,