Gold-catalyzed heterocyclic syntheses through α-imino gold carbene complexes as intermediates

Enrique Aguilar * and Javier Santamaría*
Instituto Universitario de Química Organometálica “Enrique Moles”, Departamento de Química Orgánica e Inorgánica, Universidad de Oviedo, C/Julián Clavería, 8., 33006, Oviedo, Spain. E-mail:;; Fax: +34-985103446

Received 14th February 2019 , Accepted 15th March 2019

First published on 20th March 2019

Gold carbene complexes have been recognized as common intermediates in gold-catalyzed organic syntheses. In this field, α-imino gold carbene complexes, in the last few years, have emerged as valuable intermediates toward the synthesis of N-heterocycles. This review is dedicated toward formulating a comprehensive compilation of the different methodologies for heterocyclic synthesis, postulating the participation of α-imino gold carbene complexes as intermediates. In addition to the scarce examples involving the direct formation of α-imino diazo compounds from gold decomposition, the use of nitrogenated nucleophiles, through an initial attack on gold-activated alkynes followed by gold retrodonation and expulsion of a leaving group, constitutes the most commonly employed strategy for achieving this target. This review has been divided into different sections as follows according to the type of N-nucleophile used: azides, aza-ylides, 2H-azirines, isoxazoles and their derivatives, indazoles, and triazapentalenes. A large number of heterocycles, ranging from five- to seven-membered rings, have been efficiently synthesized following this methodology.

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Javier Santamaría (left) and Enrique Aguilar (right)

Enrique Aguilar was born in Noreña (Asturias) and received his PhD from the Universidad de Oviedo under the supervision of Prof. J. Barluenga and Prof. S. Fustero in 1991. After his postdoctoral research with Prof. A. I. Meyers at Colorado State University (1991–1994), he returned to the Universidad de Oviedo as a Researcher, being promoted to Assistant Professor in 1996 and to Associate Professor in 2002. He has been a Visiting Scientist at the University of Colorado (1996, with Prof. G. A. Molander). His current research interest is centered toward the development of synthetic organic methodology, homogeneous catalysis, and organometallic chemistry.

Javier Santamaría was born in Villaviciosa, Asturias (Spain). He received his PhD (1997) from the University of Oviedo (Spain), working in the group of Professor J. Barluenga. After a postdoctoral stay (1997–1999) at the Skaggs Institute for Chemical Biology (Scripps Research Institute, La Jolla, USA) with Professor Julius Rebek, Jr., he returned to the University of Oviedo. He was appointed as Assistant Professor in 2000 and Associated Professor in 2009. He has been a Visiting Scientist at the University of Florida in 2001. Currently, he is involved in the development of new gold-catalyzed organic reactions.

1. Introduction

The activation of C–C multiple bonds by transition metal complexes to enhance and control their reactivity has been a long-standing strategy in organic chemistry.1 Besides the paramount role played by palladium, both late and early transitions metals have been used in either stoichiometric or catalytic conditions to promote relevant synthetic transformations involving the different types of C–C multiple bonds. The usually accepted Dewar, Chatt, and Duncanson model for π-bonding in organotransition metal complexes, involving both σ and π interactions, describes the relationship between the metal and C–C multiple bonds in donor–acceptor terms,2,3 and it has served as an inspiration for the development of novel reactive species and synthetic strategies. More recently, in a seminal review, Fürstner and Davies defined the concept of π-acid as “any metal fragment that binds to a carbon–carbon multiple bond and thereby deprives it of a part of its electron density”.4 Therefore, by employing π-acids, the corresponding C–C multiple bond is rendered more electrophilic due to the net loss of electron density in the donation–retrodonation balance. In this regard, metals of several groups of the periodic table,5 and, among them, gold and other coinage metals,6 have already shown this mode of action.

The behavior as a π-acid is intricately linked with the concept of carbophilicity, which defines the strong preference of a gold catalyst moiety for C–C multiple bonds over other functional groups present in the reactants. In the last two decades, gold has been, by far, the most active metal in this sense, showing a special π-acid behavior attributed to relativistic effects, because of the contraction of the 6s orbital and expansion of the 5d orbitals.7,8

All the species bearing C–C multiple bonds (alkenes, allenes, or alkynes) may be activated by gold coordination in the initial step of the catalytic process, but higher affinity toward alkyne activation has been clearly established; therefore, the concept of alkynophilicity has also been coined to describe such a behavior.8 Therefore, when both double or triple C–C bonds are present, the reaction is usually initiated by the coordination to the triple bond.

After coordination, a nucleophilic attack could take place, and crucial issues, such as regioselectivity (in all the cases) and chemoselectivity (for allenes), should be addressed to achieve an effective control over the reaction (Fig. 1; top). The slippage of the metal moiety along the axis of the bound double or triple bond accompanies activation and results in a redistribution of the internuclear electron density upon nucleophilic attack onto the C–C multiple bond (Fig. 1; bottom).

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Fig. 1 Metal activation and nucleophilic addition to different C–C multiple bonds (top) and “slippage” (bottom).

Among them, alkynes have been, by far, the most prolific substrates for gold-catalyzed electrophilic additions, and there has been some controversy about the carbocation or carbene nature of the intermediates partaking in such reactions.9 Indeed, such a dual character can be illustrated by the two resonant structures shown in Fig. 2, which depicts gold bound to a divalent carbon atom. In this review, the notation [Au] will be used to denote the combination of the gold atom {either Au(I) or Au(III)} and the ligand (L) employed in each case to modulate its reactivity {[Au] = Au(L)}.

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Fig. 2 Resonance structures that illustrate the dual carbene and carbocation character of gold bound to a divalent carbon atom.

Fürstner and Davies compared the interaction and bonding in gold(I) carbene complexes with that of group 6 Fischer carbene complexes.4 For this type of compounds, the [M]–C bond is explained by an interaction between a carbene carbon in the singlet state with σ-donation from the carbene ligand to the metal, together with a π-back donation from the metal to the ligand (Fig. 3); therefore, the pair of electrons in the π-bonding MO resides mainly on the metal, inducing electrophilic behavior to this type of carbene complexes. Gold(I) carbene complexes are indeed electrophilic and also highly thermodynamically stable as they can be prepared from group 6 Fischer carbene complexes by carbene transfer.10

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Fig. 3 Dominant orbital interactions and bonding in Fischer carbene complexes.

More recently, based on theoretical calculations and experimental results, Goddard and Toste presented a model for the chemical bond in gold(I) carbene complexes. They concluded that three sets of orbital interactions partake in such bonding: a three-centre four-electron σ-bond due to donation to the empty 6s orbital of gold from the occupied orbitals at the ligand and the carbene carbon atom, as well as two orthogonal π-electron density back-donations from filled gold 5d orbitals to π-acceptor orbitals in the carbene carbon atom and on the ligand (Fig. 4). As a result, they suggested “that the reactivity in gold(I)-coordinated carbenes is best accounted for by a continuum ranging from a metal-stabilized singlet carbene to a metal-coordinated carbocation”.11 The nature of the ligand and that of the carbene substituents are crucial in the determination of the position of a given gold species in such a continuum. In addition, it should be pointed out that the bond order in gold(I) carbene complexes is typically close to one (or even less), and therefore, the [Au][double bond, length as m-dash]C representation is not accurate, although it may be convenient mainly for mechanistic purposes.

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Fig. 4 Goddard–Toste bonding model for gold(I) carbene complexes.

With regard to the intermediates partaking in gold(III) catalysis, the available information is more limited. Although the reactions are initiated by alkyne coordination, only a few alkyne adducts of gold(III) have been characterized because of their lability. Then, alkyne slippage occurs, facilitating C–C triple bond polarization,12 concomitantly to the regioselective attack of the nucleophile and formation of a gold carbene complex. Remarkably, the only example of a gold(III) carbene complex that has been isolated and characterized from a reaction of a gold(III) salt with an alkyne is a non-nitrogen-containing six-membered mesoionic species, as reported by Bertrand et al.13

As stated above, both the nature of the ligand and the substituents of the divalent carbon atom play a decisive role in the determination of the predominant carbocation or carbene nature of the reaction intermediates. Therefore, on the one hand, the behavior of the gold catalyst can be sterically or electronically modulated for a specific chemical transformation by changing the ligand (employing more or less bulky ligands and/or switch from more electron-rich N-heterocyclic carbenes to less electron-rich phosphites).14

On the other hand, from the point of viewpoint of reactivity, the substitution at the carbene complexes also exerts a considerable influence on their chemical behaviors. Hence, the presence of an electron-withdrawing group at the α-position renders α-oxo and α-imino gold carbene complexes (αIGCCs) even more electrophilic (Fig. 5). In this regard, α-oxo carbene complexes can be prepared from π-alkyne gold complexes with N-oxides or sulfoxides, or alternatively, from α-diazo carbonyl compounds with gold(I) precursors using a very efficient and generic route.15 In fact, using this strategy, a reactive tricoordinate α-oxo gold carbene complex was isolated for the first time by Bourissou and co-workers.16

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Fig. 5 Gold carbene complexes bearing oxo or imino substituents at the α-position.

αIGCCs are less common than their oxygenated analogues, even though they display increasingly versatile chemistry, as outlined in this review. In general, the synthesis of αIGCCs involves the addition of a N-nucleophile to a gold-activated alkyne, where the nitrogen atom is also linked to a good leaving group (LG) by a readily labile bond. Therefore, after this addition and under the reaction conditions, such a bond undergoes breaking, leading to the formation of αIGCC species, which may evolve in different ways depending on its chemical environment to produce the final N-heterocycles (Fig. 6).

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Fig. 6 General strategy for the gold-catalyzed synthesis of N-heterocyclic compounds through the intermediacy of αIGCCs.

In a similar manner to what happens for α-oxo gold carbene complexes, an alternative route to αIGCCs has been developed from α-diazo-imino compounds with gold(I) precursors, although, so far, it has more limited scope.

When comparing α-oxo and α-imino gold carbene complexes, the following major differences are distinctly perceived. First, because of structural reasons, α-oxo GCCs produce O-heterocycles, while αIGCCs form N-heterocycles. The second one can be attributed to their chemical behaviors; because of the higher electronegativity of oxygen vs. nitrogen, αIGCCs are less electrophilic than their oxygenated analogs. A third relevant difference, which would involve both chemical behavior and structural features, is the possibility of placing a substituent at the imino group, which would help to control and modulate the reactivity in terms of sterics and/or electronics and offer an additional point of diversity (and even of reactivity).

However, even though αIGCCs have been proposed as reactive key intermediates in many transformations and their involvement has been predicted by DFT calculations, as far as we are aware, their isolation and/or spectroscopic characterization remains elusive. This difference between α-oxo and α-imino gold carbene complexes should be neutralized in the future.

On the other hand, despite the increasing attention received by gold-catalyzed synthesis involving αIGCCs as intermediates in the last few years, only a thematic review focused on isoxazoles as nucleophiles17 and a more generic revision, although with scarce diffusion,18 (both published in 2017) have accompanied the excellent 2015 manuscript by Davies and Garzón.19 Our intention is to fill this existing gap with a comprehensive review on this topic.

When describing the postulated mechanisms for each transformation, we focused our attention on the proposed αIGCC intermediates, and they have been depicted as suggested by the authors independent of the gold(I) or gold(III) nature of the catalyst.

Our revision is completely devoted to heterocyclic chemistry, and therefore, the reactions that have been proposed to occur through α-imino gold carbene complexes, but yielding non-heterocyclic compounds, are out of the scope and have not been included in this review. Nevertheless, they may be eventually mentioned when they provide support to processes that generate heterocycles.

We have organized our manuscript focusing on the type of nucleophile reacting with π-acid-coordinated alkynes to generate αIGCCs. A comprehensive representation of all the current approaches to fabricate αIGCCs is shown in Fig. 7, with an indication of the section of this review in which the reactivity of each one of these systems is described.

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Fig. 7 General overview of nucleophiles, and α-imino-diazo compounds, employed in the generation of αIGCCs, with counterclockwise indication of the section where their chemistry is covered.

For the sake of simplicity and to facilitate reading of this manuscript, we have decided to include in Fig. 8 all the catalysts and ligands that appear in the schemes, according to the order in which they are mentioned in the text and schemes.

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Fig. 8 Gold catalysts and ligands mentioned in the manuscript.

2. Results and discussion

The discussion has been divided into eight sections according to the compounds employed as α-imino gold carbene precursors.

2.1. From azides: pioneering work and other contributions

The first reported example of a gold-catalyzed heterocyclic synthesis, invoking the participation of α-imino gold carbene complexes, can be attributed to Toste and co-workers in 2005.20 In this pioneering work, the authors reported the use of homopropargyl azides 1 acting as nitrene transfer reagents (Scheme 1). Therefore, the intramolecular attack of the nitrogen atom to gold π-activated alkyne 3 would generate alkenyl gold intermediate 4 through a 5-endo-dig cyclization process. Next, this intermediate could evolve toward the participation of α-imino gold carbene complex 5, as retrodonation from gold is facilitated by the expulsion of the nitrogen molecule. Finally, a 1,2-hydrogen shift, followed by a tautomerization step, could explain the formation of pyrroles 2. This seminal result opened the door to a new catalytic field in the synthesis of nitrogenated heterocycles. However, for several years, it remained the sole example of gold catalysis that followed this methodology.
image file: c9qo00243j-s1.tif
Scheme 1 First reported example and mechanistic proposal.

Later on, several examples have been reported that employed this strategy involving the use of azides in the synthesis of different families of heterocycles. Gagosz21 and L. Zhang22 independently published the synthesis of indole derivatives 7 from ortho-alkynylphenyl azides 6 (Scheme 2). In these examples, after the formation of proposed α-imino gold carbene complexes 8 from an intramolecular azide attack and nitrogen removal, these intermediates 8 could be captured by an external nucleophile leading to indole derivatives 7.

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Scheme 2 General overview for the synthesis of indoles.

Gagosz's group focused its work on the addition of allylic alcohols to form indolin-3-ones 10. Therefore, after the nucleophilic attack of alcohol to α-imino carbene 8, the reaction could evolve through a gold-catalyzed Claisen rearrangement from intermediate 11 (Scheme 3).

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Scheme 3 Gold-catalyzed formation of indolinones 10 from alkynylphenyl azides 9.

On the other hand, L. Zhang and co-workers employed electron-rich arenes or heteroarenes, such as xylenes, naphthalenes, anisoles, pyrroles, or indoles, as carbon-nucleophiles (Scheme 4).

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Scheme 4 Nucleophile scope for the capture of carbene intermediates.

Several other examples have been reported using 2-alkynyl aryl azides, presumably involving the participation of α-imino gold carbene intermediates, followed by their capture with diverse types of nucleophiles. In this sense, the use of propargyl alcohols 13 as nucleophiles, as reported by Gong, L. Zhang, and co-workers,23 yielded a family of pyrroloindolone derivatives 14 (Scheme 5). Hence, after the intramolecular azide addition and formation of carbene intermediate 15, this species could undergo a nucleophilic attack by propargylic alcohol 13. Next, the gold activation of the alkyne moiety could facilitate a Saucy–Marbet rearrangement on intermediate 16,24 followed by a gold-catalyzed intramolecular hydroamination of allenyl intermediate 18, leading to pyrroloindolones 14.

image file: c9qo00243j-s5.tif
Scheme 5 Synthesis of pyrroloindolones 14.

Following this methodology, the use of enantiopure (S)-3-butyn-2-ol allowed the synthesis of optically active pyrroloindolones with high enantiomeric excesses (up to >99% ee). These results reveal a high degree of chirality transfer from propargylic alcohol to pyrroloindolones, although low diastereoselectivity was observed.

In a similar approach, X. Zhang and Rao described the synthesis of [1,3]dioxino[5,4-b]indoles 21, invoking a formal [4 + 2] cycloaddition of 3-indolylidene gold carbene intermediate 22 with aldehyde 20 (Scheme 6).25 The reaction presumably takes place due to the presence of a hydroxyl group in 3-(2-azidophenyl)prop-2-yn-1-ols 19, which are used as the starting material. On the other hand, the presence of electron-withdrawing groups, such as 3,5-dichloro or 3-cyano, in the phenyl ring facilitates this reaction, avoiding a competitive initial aldehyde attack on the gold-activated alkyne.

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Scheme 6 Preparation of [1,3]dioxino[5,4-b]indole derivatives 21.

The presence of an additional triple bond in the starting material allowed the formation of more complex heterocycles. Hence, Uchiyama, Ohno, and co-workers recently reported the synthesis of annulated carbazoles using pyrroles, indoles, or electron-rich arene derivatives as nucleophiles.26 Furthermore, after the attack of the nucleophile to α-imino gold carbene intermediate 27, the reaction could evolve through a second nucleophilic attack over gold-activated alkyne 28, yielding several types of aryl-annulated[c]carbazoles. Scheme 7 shows the reaction conditions and mechanistic proposal for the synthesis of benzene-fused carbazoles 26. The use of other nucleophiles, such as pyrroles or indoles, also yielded good results.

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Scheme 7 Gold-catalyzed access to benzo-fused carbazoles 26.

This approach has also been employed in cascades involving two consecutive intramolecular reactions of 2-alkynylphenyl azides with a nucleophile pending at the end of the alkyne functionality. In this sense, Qiu, Xu, and co-workers recently reported the synthesis of a family of indole-fused derivatives 30[thin space (1/6-em)]27 from 2-alkynylphenyl azides 29 bearing a benzyl alcohol functionality attached to the alkyne (Scheme 8). As a mechanistic proposal, after the initial formation of imino gold carbene 31, the reaction could evolve through an insertion of the carbene functionality in the O–H bond, yielding tetracyclic indole derivatives 30. In addition, this methodology has also worked satisfactorily for nitrogen or aryl nucleophiles.

image file: c9qo00243j-s8.tif
Scheme 8 O–H insertion on carbene intermediate 31.

The same approach was followed by Li, Ye et al. in the synthesis of oxazino- and pyrazinoindoles 33.28 For this purpose, phenylazides 32 with a ynamide group at the ortho position were selected (Scheme 9). The imino carbene intermediate was captured by a heteroatom attached to the ynamide moiety, forming a new ring.

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Scheme 9 Synthesis of oxazino- and pyrazinoindoles 33.

Similarly, Fujii, Ohno, and co-workers prepared several types of indoloquinolines,29 taking advantage of the presence of different groups in the molecule, such as olefins, allylsilanes, or arenes, acting as nucleophiles. Among them, it is noteworthy that the intramolecular cyclopropanation by α-imino carbenes 36 resulted in the formation of polycyclic compounds 35 (Scheme 10).

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Scheme 10 Intramolecular cyclopropanation.

The use of alkynyl propargyl ynamides 37 led to the formation of pyrrolo[2,3-b]indoles 38, as described by Ye et al.30 (Scheme 11). The authors invoked a mechanistic proposal involving an alkyne attack to carbene complex 39. This evolution, which could be facilitated by the presence of an arene ring, resulted in the formation of allenyl intermediate 40. Next, 40 would undergo a nucleophilic addition of water, yielding pyrrolo[2,3-b]indole 38.

image file: c9qo00243j-s11.tif
Scheme 11 Synthesis of pyrrolo[2,3-b]indoles 38.

Finally, Scheme 12 shows the intramolecular additions of azides to gold-activated alkynes and the formation of gold indolylidene intermediates described by Zhang et al.31 For this reaction, the mechanistic proposal could involve an intermolecular gold-catalyzed cyclopropenation reaction. Next, the gold-catalyzed regioselective opening of cyclopropene intermediate 45 would result in the formation of new gold carbene complex 46. Finally, the C–H insertion of carbene 46 over an arene ring followed by oxidation results in the formation of arene-fused carbazole derivatives 43.

image file: c9qo00243j-s12.tif
Scheme 12 Intermolecular cyclopropanation.

This methodology was also extended to the synthesis of benzofuran-fused carbazoles or 13H-dibenzo[a,h]carbazoles in moderate yields by an appropriate choice of azides.

In 2012, L. Zhang et al. reported the synthesis of five-membered heterocycles invoking a different reactive pattern in the formation of α-imino carbene complexes. Therefore, the use of alkynyl azides 47, with an additional carbon atom, resulted in the generation of dihydropyrrolizines 48 (Scheme 13).32 The reaction would involve a gold-catalyzed 5-exo-dig cyclization process in the formation of α-imino gold carbene intermediate 49. Subsequently, an intramolecular conjugated nucleophilic attack on the carbene complex would drive the reaction toward 2,3-dihydropyrrolizines 48.

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Scheme 13 α-Imino gold carbene complexes from 5-exo-dig cyclization.

On the other hand, the gold dihydropyrrolyl methylidene intermediate could also react in an intermolecular fashion.33 Therefore, when the gold-catalyzed reaction is performed using nitrile 51 as the solvent, α-imino gold carbene intermediate 53 could be captured by the solvent (Scheme 14). As a result of the nucleophilic attack of the nitrogen atom of the nitrile, followed by a closure of the five-membered ring, several pyrroloimidazoles 52 were synthesized.

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Scheme 14 Nitrile capture of carbene intermediate 53.

In addition to α-imino gold carbene complexes supporting an indole skeleton in their structure, other heterocyclic carbene intermediates have also been described. Scheme 15 outlines the gold-catalyzed intramolecular reaction of 2-alkynyl benzyl azides 54 to form isoquinoline derivatives 55. In the study by He, Ye et al.,34 the mechanistic proposal postulates the participation of 4-isoquinolidinylidene gold complex 56 formed via a 6-endo-dig cyclization process. Finally, an intramolecular nucleophilic attack of the alcohol or sulfonylimide moiety would drive the reaction to the formation of tricyclic compounds 55.

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Scheme 15 α-Imino gold carbene complexes from 6-endo-dig cyclization.

In a similar approach, the groups of Chiba and Gagosz reported the synthesis of oxazine derivatives 58, presumably involving the intramolecular formation of oxazinylidene gold complex 59 (Scheme 16).35 Intermediate 59 would evolve toward 2H-1,3-oxazine 58 by [1,2]-hydrogen migration.

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Scheme 16 Synthesis of 2H-1,3-oxazines 58.

In addition to the intramolecular reactions, scarce examples have been reported until now in relation to the intermolecular generation of α-imino gold carbene intermediates.36 Moreover, to the best of our knowledge, in all the examples, the reaction requires the presence of highly polarized alkynes as ynamides.

The first reported example in this field was described by Lu, Ye et al., describing the synthesis of valuable heterocycles such as indoles from benzyl azides and N-phenyl ynamides.37 As outlined in Scheme 17, gold carbene intermediate 63, which could be formed by the nucleophilic addition of benzyl azides 61 to activated ynamides, would react in an intramolecular fashion with the aromatic ring of the ynamides. Finally, after the corresponding C–H insertion and tautomerization steps, indoles 62 were obtained.

image file: c9qo00243j-s17.tif
Scheme 17 Synthesis of indoles 62 from intermolecular access to imino carbenes.

The use of indolomethyl azides 64 in their gold-catalyzed reaction with ynamides 65 follows a similar behavior and results in the formation of 3-amino-β-carbolines 66. Therefore, due to the high nucleophilicity of the indole ring, the reaction would progress through the heterocyclic attack to carbene intermediate 67. As a result of this evolution, 3-amino-β-carboline derivatives 66 were obtained by a pathway that would imply consecutive C–H insertion and oxidation steps (Scheme 18).

image file: c9qo00243j-s18.tif
Scheme 18 β-Carboline synthesis from indolomethyl azides 64.

Surprisingly, when the reaction was performed starting from 3-indolomethyl—instead of 2-indolomethyl—azides, 3-amino-β-carbolines 66 were also obtained (Scheme 19).38 In this case, carbene intermediate 69 intramolecularly reacted with the indole ring to form intermediate 70. Next, a 1,2-alkyl migration reaction from C3 to C2 of the indole skeleton of 70 occurred. The final protodeauration and aromatization steps could result in the formation of similar β-carboline derivatives 66 as that obtained when starting from regioisomeric indoles 64.

image file: c9qo00243j-s19.tif
Scheme 19 β-Carboline synthesis from regioisomeric indolomethyl azides 68.

Finally, the formation of pyrrole derivatives 73 from enynamides 71 is noteworthy. The study by Lu, Ye et al.39 is closely related to the intramolecular version reported by other authors in 2012.32 Proposed gold carbene intermediate 74, similar to complex 49 (see Scheme 13), could evolve through an aza-Nazarov-type reaction, resulting in the synthesis of pyrroles 73 (Scheme 20).

image file: c9qo00243j-s20.tif
Scheme 20 Formal [4 + 1] heterocycloaddition.

2.2. From aza-ylides (aminides and sulfilimines)

Azides are not the only nucleophilic compounds that can act as nitrene transfer reagents since other nitrogenated systems have also been employed. Among them, aminides (pyridine aza-ylides) can be considered as nitrogenated analogues to pyridine oxides, which are widely used in reactions that postulate the participation of α-oxo gold carbene complexes as intermediates.15b,e,g–i

The first reported example for the use of these compounds in reactions invoking the participation of α-imino gold carbene complexes was proposed by L. Zhang et al.,40 although acyclic products were obtained. However, the application of this methodology in the field of heterocyclic synthesis has been mainly developed by Davies and co-workers. In this sense, in 2011, these authors reported a gold-catalyzed synthesis of oxazoles in a formal [3 + 2] dipolar heterocycloaddition process, from aminides and ynamides.41 As an analogy to the proposed mechanism for the formation of α-oxo gold carbene complexes, after the nucleophilic attack of aminides 75 to the gold-activated ynamide, α-imino gold carbene 79 could participate as an intermediate (Scheme 21). Finally, an intramolecular attack from the carbonyl oxygen to the carbenic centre could explain the formation of oxazole derivatives 77. However, a direct 4-π ring-closing electrocyclization reaction through a synchronic mechanism, with elongation of the pyridine N–N bond before total pyridine elimination, could not be ruled out by the authors. The reaction has also been extended to ynol ethers.

image file: c9qo00243j-s21.tif
Scheme 21 Synthesis of oxazoles 77 from aminides 75 and ynamides 76.

Two years later, the same authors42 were able to perform this reaction using electron-rich alkynes instead of ynamides. Therefore, the reaction involving the formation of oxazole derivatives 82 could also be achieved using 3-indolyl, 4-anisolyl, or 4-anilinylalkynes that can conjugate the lone electron pair of the heteroatom to gold-activated alkynes. The procedure required a bulkier gold(I) catalyst and harsher reaction conditions. As a representative example, Scheme 22 outlines the high-yield synthesis of 4-(3-indolyl)oxazole 82.

image file: c9qo00243j-s22.tif
Scheme 22 3-Alkynyl indoles 81 as highly polarized alkynes in gold catalysis.

This methodology, employing N-nucleophilic 1,3-N,O dipole equivalents facilitating acyl nitrene transfers, has been widely extended by the authors with the publication of the synthesis of a plethora of different 4-aminooxazoles.43 In this work, in addition to the preparation of a large number of aminides to extend the study, the influence of ynamide substitution patterns and aminide nature have been extensively studied. This methodology has been demonstrated to be tolerant with a wide number of functional groups, allowing access to a large family of 4-aminooxazoles.

Following this strategy, alkynyl thioethers 83 also react with aminides 75 to form the corresponding 4-thiooxazoles44 (Scheme 23). As a relevant behavior, the reaction products were synthesized as a mixture of regioisomers, where 84 was the major oxazole: a regioisomer opposite to the one obtained in the reaction with ynamides. After the nucleophilic attack to the gold activated alkyne, the formation of the major isomer could be explained via a stabilizing interaction between sulfur and gold atoms in intermediate 86 (Scheme 23; bottom).

image file: c9qo00243j-s23.tif
Scheme 23 Regioselective cycloaddition with alkynyl thioethers 83.

The use of aminides as nitrene transfer reagents in gold catalysis was also applied for the synthesis of other heterocycles. In this sense, the use of pyridinium N-(pyridinyl or diazyl)aminides 87 as N-nucleophilic 1,3-N,N dipole equivalents in their reaction with ynamides 76 resulted in the formation of a family of fused imidazolopyridines and imidazolodiazines 88.45 The mechanistic proposal, which is outlined in Scheme 24, resembles the one previously reported for the formation of 4-aminooxazoles (see Scheme 21).

image file: c9qo00243j-s24.tif
Scheme 24 Synthesis of imidazolopyridines and imidazolodiazines.

After the nucleophilic attack from aminide 87, intermediate 89 could evolve either through a direct ring closure in a 4π synchronic electrocyclization process or be transformed into α-imino gold carbene complex 90, which undergoes a nucleophilic attack from the nitrogen of pyridine or diazine ring. A DFT study, by X. Zhang et al., for the mechanism of this reaction46 reveals a near-synchronous 4π electrocyclization process with the elimination of the pyridine ring, although carbene intermediate 96 was not considered in the study.

The use of 3-indolyl alkynes also drives the reaction toward the formation of the corresponding imidazolo-fused heterocycles.

More recently, this methodology was extended to the preparation of more complex polyfused heterocycles, such as fused imidazolo[2,1-b]-benzoxazoles and benzothiazoles, among others (Scheme 25).47 These results, emerging from a careful selection of appropriate aminides 91, allowed the preparation of a wide variety of valuable compounds that were structurally closely related to biomedically active compounds. A formal [3 + 2] dipolar heterocycloaddition through nitrene transfer has been proposed by the authors.

image file: c9qo00243j-s25.tif
Scheme 25 Generalization of the reaction to other polyheterocycles.

In addition to the use of pyridine aza-ylides, very recently, Hashmi et al. reported the use of sulfur aza-ylides, such as sulfilimines 93, as a new type of nitrene transfer reagents.48 Their work resembles the reported use of sulfonium ylides as carbene transfer reagents.49 Following this methodology, several heterocycles could be efficiently synthesized, such as indoles 95 or bicyclic compounds 96 (Scheme 26). The mechanistic proposal implies a nucleophilic attack from the nitrogen atom of sulfilimine 93 to the gold-activated ynamide, followed by the formation of α-imino carbene intermediate 94 triggered by the cleavage of the dialkyl sulfide moiety. Next, carbene complex 94 could evolve toward either the formation of indoles 95 through C–H insertion or the cyclopropanation of an allylic group attached to the imide.

image file: c9qo00243j-s26.tif
Scheme 26 α-Imino gold carbene complexes 94 from sulfilimines 93.

The use of pyridinyl sulfilimines, among others, allowed the same group to extend this methodology to the synthesis of imidazole-fused heterocycles.50 Scheme 27 shows the synthesis of a large family of pyridine[1,2-a]imidazoles 98 through the gold-catalyzed reaction of sulfinimines 97 and ynamides 76. Therefore, after the presumable formation of α-imino carbene complex 99, this intermediate could undergo cyclization through the nucleophilic attack of the nitrogen atom of the pyridine ring to the carbene moiety, forming pyridine imidazoles 98.

image file: c9qo00243j-s27.tif
Scheme 27 Synthesis of imidazo[1,2-a]pyridines 98 from sulfilimines 97.

2.3. From 2H-azirines

In 2014, 2H-azirines emerged as efficient counterparts for the synthesis of heterocycles in their reaction with gold-activated alkynes. This type of reaction is invoked to involve azirines acting as nitrene transfer agents and α-imino gold carbene complexes as intermediates. The first reported example of this methodology was published by Gagosz et al., who described the synthesis of pyridines 101 from 2-propargyl 2H-azirines 100 (Scheme 28).51 The mechanistic proposal for the formation of pyridines 101 implies an initial step of intramolecular nucleophilic attack of the azirine nitrogen atom to the gold-activated alkyne, resulting in a 5-endo-dig cyclization process leading to 102. Next, the opening of the cyclopropane ring favored by the electron retrodonation from the gold moiety could afford α-imino gold carbene intermediate 103. Finally, [1,2]-hydrogen shift and aromatization could drive the reaction toward pyridine derivatives 101.
image file: c9qo00243j-s28.tif
Scheme 28 Intramolecular pyridine synthesis from propargyl azirines 100.

Other mechanistic proposals, without the participation of carbene complex 103, could be envisaged. In this sense, an almost concerted three-membered ring fragmentation and [1,2]-hydrogen migration has also been considered by the authors. The reaction mechanism for this synthesis was explored by a DFT study by Wu, Zhao et al.52 These authors analyzed the two abovementioned reaction pathways along with other alternatives. As a result of the consequent computational study, the sequential pathway involving α-imino gold carbene intermediate 103 seemed to be the energetically more favored one.

A similar reaction of the formation of pyridine derivatives 105 initiated by an intramolecular reaction of homopropargyl azirines was reported by Khlebnikov et al.53 (Scheme 29). In this work, the procedure involves double iron-gold catalysis as propargyl azirine 106 was synthesized in situ from propargyl isoxazoles 104 in an iron-catalyzed process.

image file: c9qo00243j-s29.tif
Scheme 29 Double iron-gold catalysis.

Huang and co-workers published the first intermolecular version of this reaction54 using highly polarized alkynes, such as ynamides, as counterparts. Therefore, the reaction of 2H-azirines 107 with ynamides 76 resulted in the formation, under mild conditions, of 2-aminopyrroles 108 in a formal [3 + 2] gold-catalyzed cycloaddition reaction. The mechanistic proposal is outlined in Scheme 30, and it is initiated by an attack from azirine 107 to the gold-activated ynamide to form alkenyl gold intermediate 109. Next, 109 could evolve through the formation of α-imino gold carbene complex 110 favored by the electronic back-donation from the gold complex and opening of the three-membered ring. Finally, cyclization, protodeauration, and aromatization steps afforded 2-amino pyrroles 108.

image file: c9qo00243j-s30.tif
Scheme 30 Intermolecular reaction between 2H-azirines 107 and ynamides 76.

A few months later, R.-S. Liu and co-workers55 described the use of vinyl azides 112 in their gold-catalyzed reaction with ynamides 76 for the synthesis of pyrrole derivatives 108 (Scheme 31). Although an azide derivative was used as the starting material, the presumable formation of α-imino carbene intermediate 110 would occur through a previous transformation of vinyl azide 112 into 2H-azirine 107, which would attack the gold-activated ynamide. Finally, evolution from the carbene intermediate would explain the formation of 2-aminopyrroles 108. Similar results were also published afterward by Huang et al.56

image file: c9qo00243j-s31.tif
Scheme 31 Synthesis of pyrroles 108 from alkenyl azides 112 via 2H-azirine 107.

Interestingly, the presence of electron-donating groups, such as methyl or methoxy, in the aromatic ring of the ynamides allows the formation of benzoazepine derivatives in a formal [4 + 3] heterocyclization process, although a carbene intermediate is not postulated.55

2.4. From decomposition of diazo compounds

The decomposition of diazo compounds in the synthetic procedures involving the participation of α-oxo gold carbene complexes has been widely employed.15c,d,f However, in this field, to the best of our knowledge, a single result by Park et al.57 has described their nitrogenated analogues, namely, α-imino gold carbenes, as intermediates. Taking advantage of this methodology, two families of five-membered heterocyclic rings have been synthesized through the formal [3 + 2] gold-catalyzed cycloaddition reactions and invoking the participation of the same type of carbene intermediates. Scheme 32 shows the synthesis of pyrroles 115 from α-diazo oxime ethers 113 and enol ethers 114. The mechanistic proposal could involve, in addition to the gold decomposition of the diazo compound, a cyclopropanation reaction followed by the ring expansion of cyclopropyl oxime intermediate 117 and aromatization.
image file: c9qo00243j-s32.tif
Scheme 32 α-Imino gold carbene complexes from α-imino diazo compounds 113.

On the other hand, when the reaction is performed in the presence of nitriles instead of enol ethers (Scheme 33), carbene complex 120 could undergo a nucleophilic attack by nitrile 51, forming intermediate 121. Next, the oxygen atom of the carbonyl group would add to the triple bond, closing the ring. A final aromatization step would give rise to the formation of isoxazoles 119.

image file: c9qo00243j-s33.tif
Scheme 33 Intermolecular capture of carbene intermediate 120 by nitriles 51.

2.5. From isoxazoles, anthranils, and 1,2-benzoisoxazoles

Taking advantage of the lability of the N–O bond, isoxazoles, 2,1-benzoisoxazoles (anthranils, benzo[c]isoxazoles), and 1,2-benzoisoxazoles (benzo[d]isoxazoles) have also served as nucleophiles in gold-catalyzed electrophilic cyclizations, yielding different heterocyclic skeletons. Although the mode of reactivity of all these substrates is similar, it is worth mentioning that the aromatic properties of isoxazoles are completely lost during the reaction, while the aromaticity is retained in the benzene ring for benzoisoxazoles. In most of these reactions, highly polarized electron-rich alkynes, such as ynamides, have been employed as electrophilic counterparts. In addition, it should be pointed out that a partial revision of this type of reaction from a different perspective has been recently published.17

In their pioneering work, Ye and co-workers reported the use of isoxazoles 122, unsubstituted at position 4, as nucleophiles in gold-phosphite-catalyzed reactions with ynamides 76, yielding 2-amino-4-acylpyrroles 123 (Scheme 34). After the initial gold complexation of ynamide 76, a nucleophilic attack by isoxazole 122 takes place, leading to alkenyl gold species 124, which could evolve by the breakage of the labile N–O bond to form the α-imino gold carbene complex 125. Then, a sequence involving cyclization and deauration accounts for the formation of the reaction products.58 Overall, this is an atom-economic formal [3 + 2] cycloaddition process for the preparation of a wide scope of synthetically useful tetrasubstituted pyrroles.

image file: c9qo00243j-s34.tif
Scheme 34 4-Acylpyrroles 123 from isoxazoles 122.

A highly related transformation occurs when starting isoxazoles 126 are fully substituted; in this case, 2-aminopyrroles 127, non-acylated at position 4, are formed as unique reaction products in moderate to excellent yields58 (Scheme 35; top). According to the DFT calculations, both transformations (Schemes 34 and 35; top) follow a common mechanism (Scheme 35; bottom) through imino carbene complex 128, which undergoes 1,5-cyclization to yield Au(I)-ligated 3H-pyrrole 129. Then, intermediate 129 is released by ligand exchange with another unit of ynamide; the nature of the substituent at position 4 of the pyrrole is the primary factor that determines the evolution of this intermediate. Hence, isomerization takes place when position 4 is unsubstituted (R4 = H), leading to the formation of 4-acyl-2-aminopyrroles 123, while deacylation occurs for R4 ≠ H to produce 2-aminopyrroles 127.

image file: c9qo00243j-s35.tif
Scheme 35 Synthesis of pyrroles and divergent evolution from intermediate 130.

An additional outcome has been observed for the gold-catalyzed reaction between oxazolidinone-derived ynamides 131 and fully substituted isoxazoles 132: N-acyl fully substituted pyrroles 133 are formed as the major products in addition to tetrasubstituted pyrroles 134, analogous to the ones mentioned in the previous scheme, which are the minor components59 (Scheme 36). In this case, the evolution of 3H-pyrrole intermediate 136, formed from α-imino gold carbene complex intermediate 135 via 1,5-cyclization, generates tetrasubstituted pyrroles 134 and N-acyl fully substituted pyrroles 133 (the authors suggest the intermolecular migration of acyl group for this compound). The relatively weak electron-withdrawing character of the oxazolidinone group, as compared to the sulfonyl groups present in other ynamides, would explain the different evolution of this type of 3H-pyrroles 136.

image file: c9qo00243j-s36.tif
Scheme 36 Synthesis of pyrroles from ynamides 131 derived from 2-oxazolidinone.

A combination of π-acid (gold) and Lewis acid (copper) catalysis allowed the synthesis of 5-amino 2H-pyrroles 139 from isoxazoles 138 and ynamides 137 under mild conditions (Scheme 37). The two-step reaction sequence is assumed to involve α-imino gold carbene intermediates 140, which should lead to isolable 5-amino 3H-pyrroles 141. Treatment with a copper salt results in the deacylation and migration of the PMB group. Scalability, moderate to good chemical yields, and limited functional group tolerance are the main features of this transformation, which appears to be influenced by the nature of the substituents.60

image file: c9qo00243j-s37.tif
Scheme 37 Synthesis of 2H pyrroles 139.

In a similar manner to previously discussed reactions, 7-acyl indoles 143 have been efficiently synthesized by Hashmi and co-workers by a gold-catalyzed reaction between ynamides 76 and anthranils 142 (Scheme 38).61 Soft reaction conditions, flexibility due to several points of diversity, and atom economy are the main features of this formal [3 + 2] approach. In the proposed mechanism, intermediate 144 formed by anthranil addition to the gold-activated alkyne should evolve by benzoisoxazole ring opening to α-imino gold carbene complex 145. An intramolecular ortho-aryl C–H insertion, due to the high electrophilicity of gold carbene, should lead to the reaction products (Scheme 38).

image file: c9qo00243j-s38.tif
Scheme 38 Synthesis of 7-acylindoles 143.

It has also been shown that aryl ynol ether 146 is reactive toward unsubstituted anthranil 147 under standard conditions to produce 7-formyl-2-aryloxyindol 148 in fairly good yields (Scheme 39; top). On the other hand, nonpolarized or low-polarized alkynes 149 require the addition of 10 mol% MsOH (presumably to facilitate the deauration process), higher temperatures, longer reaction times, and higher excesses of alkynes. In this manner, 2-substituted indoles 151 (R2 = H) are regioselectively formed from terminal alkynes, and 2,3-disubstituted indoles 151 (R2 ≠ H) are formed from symmetrical internal alkynes, both with reasonable yields (Scheme 39; middle). An example of an unsymmetrically alkyl/aryl-substituted alkyne leads to the formation of 2-alkyl-3-aryl indole 152 as the only regioisomer (Scheme 39; bottom). Besides being the pioneering work in which anthranils are employed as nucleophiles, this research represents the first example62 that postulates an intermolecular formation of an α-imino gold carbene complex using nonpolarized or low-polarized alkynes.

image file: c9qo00243j-s39.tif
Scheme 39 Reactivity of anthranils with ynol ethers and nonpolarized alkynes.

R.-S. Liu and co-workers have shown that besides alkynamides, isoxazoles react under gold-catalyzed conditions with other types of alkynes such as 1,4-diyn-3-ols 153. Hence, a gold-catalyzed [4 + 1] annulation reaction takes place between isoxazoles 154 and bispropargyl alcohols 153, leading to tetrasubstituted pyrroles 155 (Scheme 40).63 The reaction is highly (i) regioselective (the nucleophilic attack of the isoxazole takes place at the Csp linked to the substituent); (ii) chemoselective (in most cases, the attack is preferential toward the more accessible triple bond as compared to the other; for instance, the initial attack occurs at the cyclopropyl-substituted triple bond instead of that at the phenyl-substituted triple bond); and (iii) stereoselective (see below). Only the nitrogen atom from the isoxazole unit is incorporated into the pyrrole skeleton and bears, as substituents, an enal or enone moiety depending on the substitution of the starting isoxazole. The diastereoselectivity of the new double bond of the enal or enone goes from >4/1 up to >20/1 for the Z-isomer for R1 ≠ H, while only the E-isomer is formed for terminal alkynes (Scheme 40; top). Substituted isoxazoles also partake in this reaction (Scheme 40; middle). The reaction is proposed to occur via α′-hydroxy α-imino gold carbene complex 158, which undergoes a 1,2-alkyne migration reaction to form propargyl gold species 159, which should evolve to the final products (Scheme 40; bottom).

image file: c9qo00243j-s40.tif
Scheme 40 Gold-catalyzed synthesis of pyrroles through 1,2-migration of alkynes.

The reaction was extended to use anthranils 160 as the source of nitrogen atoms, yielding N-aryl pyrroles 161 (Scheme 41; top). In addition, 1,4-diyn-3-ol 162 bearing a tertiary alcohol has been demonstrated to be a suitable partner, leading to the formation of N-aryl pyrrole 163 with an acetyl group at position 3 of the pyrrole ring (Scheme 41; bottom).

image file: c9qo00243j-s41.tif
Scheme 41 Synthesis of N-aryl pyrroles.

A similar reaction satisfactorily takes place between anthranils 165 and 4-methoxy-1,2-dienyl-5-ynes 164, where a terminal allene unit replaces one of the triple bonds. Although a large excess (4 equiv.) of anthranil component 165 and semi-stoichiometric amounts of silver trifluoroacetate are required, 3-acyl-1-aryl-2,5-disubstituted pyrroles 166 are obtained in moderate to good yields (Scheme 42). The reaction is inhibited if the terminal allene unit is disubstituted.64

image file: c9qo00243j-s42.tif
Scheme 42 Gold-catalyzed synthesis of aryl pyrroles 166 from allenyl alkynes 164.

Following this strategy, pyrrolo[1,2-a]quinolines 169 can be prepared in moderate to good yields, when ethyl 5-methoxy-2,3-dienyl-6-ynecarboxylates 167 (that is, internal allene units bearing a terminal ester group) are employed (Scheme 43). The optimized conditions consisted on a one-pot two-step protocol for the dehydration of aldol adduct 170, which was isolated in one case, readily performed by DBU at room temperature at the last stage.

image file: c9qo00243j-s43.tif
Scheme 43 Preparation of pyrrolo[1,2-a]quinolines 169.

In these gold-catalyzed transformations of 1,2-diene-5-yne moieties, a 1,2-migration reaction of the allenyl fragment (analogous to the 1,2-alkyne migration described previously, see Scheme 40) is proposed to take place on α-imino carbene intermediate 171, leading to alkyl gold species 172. Intermediate 172 would evolve by a sequence involving the migration of Au, activation of allene (Au-π-allene species) to undergo intramolecular electrophilic addition, and cyclization to form gold-containing intermediate 173. The preferred evolution of this type of intermediates (173) would depend on the nature of R: (i) for terminal allenes (R = H), protodeauration should take place to yield pyrroles 166, while (ii) for internal allenes (R = CO2Et), the more stable enolate should partake in an aldol reaction to generate intermediate 174 and finally pyrrolo[1,2-a]quinolines 169 (Scheme 44).

image file: c9qo00243j-s44.tif
Scheme 44 Mechanistic proposal involving 1,2-migration of allenes.

In addition, unsubstituted isoxazole 154 affords 3,8-dicarbonylimidazo[1,2-a]pyridines 176 in a trimolecular reaction that includes two units of isoxazoles and one unit of propiolate ester (Scheme 45; top).65 Pyrroles 177 are always obtained as byproducts. Four equivalents of isoxazole 154 are required for this transformation, which involves two α-imino gold carbene complex species as intermediates in the proposed mechanism. After the addition and ring opening of oxazoles, carbene complex 178 is formed and undergoes ring closure to yield intermediate 179. Then, a [4 + 2] cycloaddition reaction takes place with another unit of oxazole 154, followed by the opening of the seven-membered ring of 180 and elimination of H2O, leading to the formation of new α-imino gold carbene complex 181, which bears a pyridine moiety in its structure. The nucleophilic attack by the pyridine nitrogen atom to the carbene would explain the formation of the reaction products (Scheme 45; bottom). Overall, the cascade sequence can be labeled as a formal [2 + 2 + 1]/[4 + 2] cycloaddition reaction.

image file: c9qo00243j-s45.tif
Scheme 45 Gold-catalyzed reaction of isoxazol 154 and propiolates 175.

Further, it should be noted that the title heterocycles have a dual nucleophilic character; therefore, they may behave either as O- or N-nucleophiles depending on both their counterpart and reaction conditions. In the presence of gold catalysts, 3,5-disubstituted oxazoles react with propiolate derivatives to afford regioisomeric pyrroles whose formation may be explained considering a nucleophilic O-attack and the subsequent participation of α-oxonium gold carbenes.65

When 3-en-1-ynamides 182 are employed as the starting material, moderate to good yields of azepine derivatives 183 can be obtained by means of a formal [4 + 3] cycloaddition process, as pointed out by Liu et al.66 (Scheme 46; top). The combination of IPrAuCl with silver triflimide proved to be the best catalyst for this transformation, affording cleaner reactions. The nature of the substituents of the enynamides appears to be crucial for the reaction outcome, as 3-aza-bicyclo[4.1.0]hepta-2,4-diene derivatives 184 or 2-amino-4-acylpyrroles 185 were occasionally obtained (Scheme 46; middle). Therefore, while the formation of 2-amino-4-acylpyrroles 185 has been explained before, bicyclic derivatives 184 probably arise from rearrangement on the azepine skeleton under the reaction conditions. As observed, the formation of a seven-membered ring is indeed preferred for small R4 groups as well as for substitution at R3. The chemoselectivity of the reaction seems to depend on the conformational equilibrium between two gold α-imino carbene complex species 186 and 187, which can be considered as gold-stabilized heptatrienyl cations. On the one hand, conformation 187 should be favored for R3 = H, evolving by aza-Nazarov reactions to form pyrroles 185. In addition, bulky R4 groups also favor the formation of conformer 187, thereby yielding pyrrole 185 as the byproducts. On the other hand, all s-cis-configured species 186 should be the preferred geometry for R3 = alkyl and aryl, undergoing 6π electrocyclizations to form azepine products 183.

image file: c9qo00243j-s46.tif
Scheme 46 Formal [5 + 2] cycloaddition of ynamides 182 and isoxazoles 122.

Anthranils 189 are also able to react with ynamide propargyl silyl ethers 188 under gold-catalyzed reaction conditions, leading to the formation of 2-aminoquinolines 190, as pointed out by Hashmi and co-workers.67 This is a formal [3 + 3] cycloaddition reaction, where the evolution of postulated α-imino gold carbene complex intermediate 191 is completely different from what has been described in previous examples; hence, a 1,2-hydrogen shift should take place with deauration, leading to the formation of N-aryl-α,β-unsaturated imine 192. Then, the further evolution involving intramolecular Mukaiyama-type nucleophilic attack from the silyl enol ether to the carbonyl functional group should lead to the formation of 2-aminoquinolines 190 (Scheme 47; top). The umpolung behavior of the carbene carbon, which acts as a nucleophile rather than an electrophile in the proposed mechanism, must be highlighted. The presence of a ynamide moiety is not a prerequisite for the reaction to occur as less-polarized simple propargyl silyl ethers also undergo this type of transformation, although a different catalyst (phosphite gold chloride), more polar solvent combination (trifluoroethanol/dichloroethane), and longer reaction times are necessitated. Quinolines 194 bearing alkyl, alkenyl, or aryl substituents at position 2 have been prepared using this procedure (Scheme 47; bottom).

image file: c9qo00243j-s47.tif
Scheme 47 Gold-catalyzed synthesis of quinolines from anthranils and alkynes. (Substituents omitted in intermediates for simplicity.)

Depending on the surrounding functional groups, the α-imino gold carbene complex intermediate may evolve by different routes, affording complex structures that are difficult to synthesize by other strategies. For instance, the reaction of anthranils 189 with o-ethynylbiaryls 195 in the presence of a phosphite gold catalyst produces diverse N-doped polycyclic aromatic hydrocarbons (PAHs) 196 in moderate to good yields (Scheme 48).68 In this particular case, carbene complex 197 should undergo a regioselective C–H insertion to generate iminophenanthrene intermediate 198; then, a Friedel–Crafts-type cyclization reaction under the reaction conditions should allow the evolution toward the final products. Several points of diversity have been explored in each one of the starting materials to afford a wide variety of N-doped PAHs; some of them have been shown to emit violet-blue fluorescence and display potential applications in materials science.

image file: c9qo00243j-s48.tif
Scheme 48 Synthesis of PAHs. (Substituents omitted in intermediates for simplicity.)

A similar cascade annulation reaction takes place when an aryl group is placed as the substituent at the ynamide nitrogen atom. R.-S. Liu et al. showed that terminal ynamides 199 with anthranils 165 yield 6H-indolo[2,3-b]quinolines 200, employing a JohnPhos gold catalyst, in a fast reaction.69 As stated before, α-imino gold carbene intermediate 201 evolves by a regioselective C–H insertion mechanism to generate indol 202; again, a Friedel–Crafts-type cyclization reaction and further evolution should produce 6H-indolo[2,3-b]quinolines 200 (Scheme 49).

image file: c9qo00243j-s49.tif
Scheme 49 Synthesis of 6H-indolo[2,3-b]quinolines 200. (Substituents omitted in intermediates for simplicity.)

An internal ynamide, tested as a substrate when developing the reaction scope, did not lead to the expected 6H-indolo[2,3-b]quinoline; however, the isolation of one 2-amido-1-azadiene supports the participation of α-imino gold carbene complexes as reaction intermediates in this transformation.69

Besides terminal ynamides, highly polarized dimethylphenoxyacetylene 203 proved to be active against anthranil 147 under smooth reaction conditions, leading to 1,3-dimethylbenzofuro[2,3-b]quinoline 204 in 42% yield (Scheme 50).

image file: c9qo00243j-s50.tif
Scheme 50 Reactivity of anthranil 147 with ynol ether 203.

The gold-catalyzed reaction between anthranils 165 and N-benzyl ynamides 205 follows a similar reaction sequence to generate quinoline-fused polyazaheterocycles 206, as pointed out by Hashmi and co-workers (Scheme 51).70 A gold(III) catalyst (KAuBr4) turned out to be the most efficient for this transformation, which requires further heating at the second step. Proposed α-imino gold carbene complex intermediate 207 should again undergo a regioselective C–H insertion reaction, which, in this case, should be followed by the nucleophilic addition of enamine to the carbonyl group and subsequent elimination to account for the final products 206.

image file: c9qo00243j-s51.tif
Scheme 51 Synthesis of quinoline-fused polyazaheterocycles 206.

2-Aminopyrrols 211 bearing a propenal side chain at the C4 position can be obtained when N-furylmethyl ynamides 209 are employed as the antagonists of anthranils 165. Moreover, for terminal ynamides (R2 = H), pyrrolo[2,3-b]quinolines 210 become the final products if slightly higher temperatures are used (Scheme 52).70 In the proposed mechanism, the evolution of α-imino gold carbene complex intermediate 212 follows a sequence involving (i) an intramolecular nucleophilic attack by the furan moiety to form intermediate 213; (ii) a C–O cleavage with (iii) subsequent aromatization; and (iv) double-bond cis–trans isomerization to produce 2-aminopyrrols 211.

image file: c9qo00243j-s52.tif
Scheme 52 Furan-ring opening in the synthesis of pyrroloquinolines 210.

R.-S. Liu and co-workers have described the synthesis of pyrrolo[2,3-b]quinolines 215 from terminal N-propargyl ynamides 214 and anthranils by a two-step reaction procedure sequentially employing gold(III) and Brønsted acid catalysis71 (Scheme 53). As usual, the mechanistic proposal should involve the formation of α-imino gold carbene complex 216, which is ready to undergo a nucleophilic attack by the tethered internal alkyne to generate alkenyl cation 217. Then, hydration should take place to produce dihydropyrrole 218, which—by in situ oxidation—would lead to isolable 4-aminopyrroles 219. The final treatment with TsOH allows the cyclization of pyrrole adducts 219 into pyrrolo[2,3-b]quinolines 215. Some limitations in the scope of the reaction are as follows: (i) only aryl groups may act as substituents in the triple bond of the alkyne (R2 = aryl) and (ii) substitution is not allowed at position 5 of the anthranil (R5 = H) as, otherwise, the final cyclization reaction would not occur.

image file: c9qo00243j-s53.tif
Scheme 53 Synthesis of pyrrolo[2,3-b]quinolines 215.

Internal N-propargyl ynamides 220 do not undergo cyclization to pyrrolo[2,3-b]quinolines either; on the contrary, after gold catalysis, a further treatment with aqueous HCl produces 4-acylpyrroles 221 in synthetically useful yields (Scheme 54).

image file: c9qo00243j-s54.tif
Scheme 54 Synthesis of pyrroles 221 from internal N-propargyl ynamides 220.

R.-S. Liu and co-workers have also proven that 1,2-benzoisoxazoles (benzo[d]isoxazoles) 222—although being weak nucleophiles—are also reactive to ynamides 76, selectively leading to the formation of benzo[f][1,4]oxazepine derivatives 223 under gold catalysis and mild reaction conditions (Scheme 55; top).72 A 5 mol% loading of a combination of IPrAuCl and AgNTf2 was found to be the best catalyst (Scheme 55; top, conditions 1). Four points of diversity were studied to illustrate the scope of the reaction. Almost simultaneously, the group of Y. Liu reported very similar results, but employing AuBr3 as the catalyst (Scheme 55; top, conditions 2); shorter reaction times and the inclusion of an additional point of diversity were the main contributions of this research.73 Moreover, Me2SAuCl was shown as the catalyst of choice for the preparation of two specific benzo[f][1,4]oxazepines 223 bearing R2 = Ph (Scheme 55; top, conditions 4).

image file: c9qo00243j-s55.tif
Scheme 55 Gold-catalyzed reactivity of 1,2-benzoisoxazoles 222 with ynamides 76. (Substituents omitted in intermediates for simplicity.)

In this reaction, after the usual opening of the benzoisoxazole moiety, α-imino gold carbene complex 224 was proposed as the reaction intermediate. Then, a 6-π-electrocyclization reaction takes place, affording benzooxazepinyl gold species 225, which should evolve to the final products (Scheme 55; top).

Generally, the outcome of the gold-catalyzed reaction of ynamides 76 and 1,2-benzoisoxazoles 222 can be controlled by the catalyst species. Therefore, usually, formal [5 + 1] adducts (benzoxazine derivatives 226) are synthesized instead when JohnPhosAuCl/AgNTf2 or JohnPhosAu(MeCN)SbF6 are employed (Scheme 55; bottom). Nevertheless, some exceptions exist. For instance, a formal [5 + 2] cycloaddition reaction takes place under both the reaction conditions (Scheme 55; top, conditions 1 and 3) in the only example studied for R3 = α-naphthyl. In the same manner, some other combinations of 1,2-benzoisoxazoles 222 and ynamides 76 exclusively lead to the formation of benzoxazine derivatives 226 regardless of the catalyst employed. Its formation is proposed to involve a 1,2-shift of the amide group, but not an α-imino gold carbene complex as an intermediate.

Therefore, although the ligand controls the reaction outcome, some exceptions occur depending on the nature of both the starting materials.

2.6. From dioxazoles and oxadiazoles

Other oxazole derivatives, such as dioxazoles and oxadiazoles, have proven their effectiveness as nitrene transfer reagents for gold-activated alkynes. In this sense, Y. Liu and co-workers described a simple synthesis of oxazoles by the gold-catalyzed reaction of dihydro-1,2,4-dioxazoles 227 and ynamides 76.74 The procedure involves retro [3 + 2] and formal [3 + 2] cycloaddition reactions (Scheme 56). Hence, after the presumable nitrogen attack of dioxazoles 227 to the gold-activated ynamide to form alkenyl gold intermediate 229, retrodonation from the gold atom to produce α-imino gold carbene complex 230 could occur. The formation of intermediate 230 is also triggered by the elimination of a molecule of acetone. Finally, consecutive intramolecular closure and aromatization steps could explain the synthesis of oxazole derivatives 228. The same reactivity pattern could also be proposed for other activated alkynes, such as alkynyl esters or alkynyl ketones.
image file: c9qo00243j-s56.tif
Scheme 56 Gold-catalyzed transformation from dioxazoles 227 to oxazoles 228.

Further, the same authors published a nitrogenous version of this reaction using dihydrooxadiazoles as nitrene transfer reagents75 (Scheme 57). Therefore, the use of oxadiazoles 231 in the gold-catalyzed reaction with ynamides 76 resulted in the formation of imidazoles 232. The reaction seems to proceed via intermediates 233 and 234 in a similar manner as those for their oxygenated analogues.

image file: c9qo00243j-s57.tif
Scheme 57 Oxadiazoles 231 as precursors of α-imino gold carbenes 234.

On the other hand, the use of aromatic oxadiazoles 235 in this field was described by Hashmi and co-workers for the synthesis of N-acylimidazoles 236.76 This reaction occurs with total atom economy as the acyl group remains a part of oxadiazoles 235. As outlined in Scheme 58, the mechanistic proposal for this reaction differs from the one invoked in the two earlier examples since the formation of carbene complex 238 does not require a retro [3 + 2] reaction with the expulsion of a carbonyl moiety (see Schemes 56 and 57). Next, the intramolecular closure of intermediate 238 and aromatization would afford N-acylimidazoles 236.

image file: c9qo00243j-s58.tif
Scheme 58 Gold-catalyzed transformation of oxadiazoles 235 into imidazoles 236.

Finally, the preliminary results described by Davies et al.44 using alkynyl thioethers in their reaction with dioxazoles 227 should also be mentioned. As previously described regarding the use of aminides (Scheme 23), the presence of a sulfur group allows the formation of isoxazole derivatives with novel regioselectivity.

2.7. From indazoles

Indazoles are also suitable substrates for heterocyclic synthesis via α-imino gold carbene complexes. Huang et al. reported a remarkable gold-catalyzed synthesis of 7-pyridinylindoles 240 from indazoles 239 and ynamides 131 derived from oxazolidine carbamates.77 The mechanistic proposal seems to be very similar to the one reported for the use of other heterocycles, such as isoxazoles, dioxazoles, or oxadiazoles, in terms of carbene formation (vide supra). However, from the regiochemistry of the final compound, a special behavior can be inferred as the expected regioisomer was not obtained (Scheme 59). Therefore, the nucleophilic attack could occur, for the first time, over β-carbon instead of α-carbon of ynamides 131. This reactivity could be explained through an initial intramolecular gold-catalyzed reaction of ynamides 131 along with the formation of intermediate 243 (Scheme 59; bottom), which could be isolated and characterized. Compound 243 could undergo a nucleophilic attack from the indazole heterocycle to form intermediate 241, which would initially evolve into α-imino gold carbene complex 242 and finally into indole 240.
image file: c9qo00243j-s59.tif
Scheme 59 Gold-catalyzed reaction of indazoles 239 with ynamides 131.

2.8. From triazapentalenes

Finally, in the last section, the use of 1,2,3-triazapentalenes, or their benzotriazole precursors in gold-catalyzed heterocyclic synthesis has been described. This methodology has been developed by our research group and involves the initial gold-catalyzed intramolecular 5-endo-dig cyclization of 1H-propargyl benzotriazoles 244, giving rise to the formation of dipolar 1,2,3-triazapentalenes 245 (Scheme 60).78
image file: c9qo00243j-s60.tif
Scheme 60 5-Endo-dig cyclization of 1H-propargyl benzotriazoles 244.

Triazapentalenes 245, which can be isolated and handled, are suitable to participate in a new catalytic cycle and attack gold-activated alkynes. In this sense, as outlined in Scheme 61, an atom-economical gold-catalyzed three-component synthesis of ortho-imidazolylpyrazolylbenzenes 246 could be directly achieved from triazapentalenes 245 or their 1H-propargylbenzotriazole precursors 244. Therefore, triazapentalene 245 could enter, after its formation, into a second catalytic cycle to form intermediate 247. Compound 247 could evolve toward carbene intermediate 248, triggered by the breakage of the triazole ring and formation of pyrazole ring. Next, the capture of carbene complex 248 by nitrile 51 and the closure of the ring could explain the formation of imidazolyl pyrazolyl arenes 246.

image file: c9qo00243j-s61.tif
Scheme 61 Synthesis of ortho-imidazolylpyrazolylbenzenes 246.

This reaction, in addition to the examples reported by Hashmi et al.61,67,68 and R.-S. Liu et al.63,64 using anthranils and isoxazoles, respectively, remain—to the best of our knowledge—the sole intermolecular examples of such types of processes that do not require the participation of highly polarized alkynes.

In a very recent work,79 triazapentalenes 245, or their benzotriazole precursors 244, also reacted with ynamides 76 to form indoles 250, upon gold catalysis with IPrAuNTf2 (Scheme 62). The formation of compounds 250 could be explained through the same reactive pattern described for the formation of α-imino gold carbene intermediate 251, followed by intramolecular C–H insertion.

image file: c9qo00243j-s62.tif
Scheme 62 Synthesis of 7-pyrazolylindoles 250.

However, when this reaction was performed using JohnPhosAuNTf2 as the gold catalyst and arylynamides 253 derived from oxazolidinone carbamates, the regioselectivity of the reaction could be controlled or even reversed.79 In this sense, as shown in Scheme 63 for triazapentalene 252, in addition to the gold ligand nature, the electron-donating or electron-withdrawing capability of the aromatic ring of ynamide 253 plays an important role in the regioselectivity of the reaction.

image file: c9qo00243j-s63.tif
Scheme 63 Regiodivergent synthesis of indoles.

As evident from Scheme 63, electron-withdrawing groups favor the formation of indoles 254, emerging from the attack of triazapentalene 252 to the α-carbon of ynamide 253. On the other hand, electron-donating groups direct the reaction mainly through the β-carbon of the gold-activated ynamide. This effect was also observed when using propargyl-1H-benzotriazoles as the starting material. Moreover, both regioisomers could be isolated and characterized. The mechanistic proposal for the formation of regioisomer 255 could be explained in a similar way to the one invoked for the reaction performed with indazoles (see Scheme 59). Therefore, alkenyl gold intermediate 243, obtained from the intramolecular cyclization of ynamides 253, could also be isolated and characterized. Following this methodology, several indoles 257 could be synthesized with high or total regioselectivity (Scheme 64).

image file: c9qo00243j-s64.tif
Scheme 64 Indole synthesis from nucleophilic attack at the β-position of ynamides.

3. Conclusions

In this review, we have shown that several differently functionalized N-heterocycles can be readily prepared by gold-catalyzed electrophilic additions of N-nucleophiles to activated alkynes. Five- to seven-membered heterocyclic rings constitute the current plethora of structural diversities available so far by employing this strategy. A common feature of all these transformations is the participation of α-imino gold carbene complexes as proposed reaction intermediates. For their formation, N-nucleophiles must present a labile bond between the nucleophilic nitrogen atom and a good leaving group. In this approach, a formal nitrene transfer is postulated, with concomitant formation of both metal-stabilized carbene and imino-functional group. Alternatively, α-diazo imino compounds have also been shown to produce α-imino gold carbene complexes under gold-catalyzed conditions; therefore, in this second strategy, a preformed imino group is installed prior to carbene generation. In this comprehensive revision, we have shown that, different from a painter's palette in which all kinds of colors are crammed, the organic chemist's toolbox continues its expansion in terms of new and more diverse and efficient methodologies.

However, there is still plenty of room for growth in this field. For instance, most of the reactions described here involve highly polarized alkynes, such as ynamides, ynol ethers, or ynol thioethers, as starting materials, and the examples with nonpolarized alkynes are still scarce. On the other hand, the option of employing allenes as electrophilic substrates in this type of chemistry remains unexplored. Moreover, most of the chemistry covered in this review yields flat heteroaromatic reaction products and only one example of an enantioselective synthesis process has been reported; therefore, the option of performing enantioselective (or even just stereoselective) transformations, which are always challenging in gold chemistry, has received marginal attention and should be the subject of further research. Finally, there is no direct structural evidence of the existence of such α-imino gold carbene complexes, since they neither have been isolated nor spectroscopically detected or characterized; efforts should be undertaken in this direction.

Therefore, far from being a fully mature topic, the chemistry of α-imino gold carbene complexes is still waiting for courageous and enthusiastic chemists to contribute toward the development of this area.

Conflicts of interest

“There are no conflicts to declare”.


Authors would like to kindly acknowledge financial support from the Spanish MINECO (Grants MINECO-17-CTQ2016-76794-P and MINECO-17-CTQ2016-76840-R) and the Principality of Asturias (FC-GRUPIN-IDI/2018/000231).

Notes and references

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Dedicated to Professor Dr Julius Rebek, Jr. on the occasion of his 75th birthday.

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