3.2.2. C–O Bond Formation

Based on previous work dealing with the synthesis of 7-, 8-, and 9-membered *N*-linked biaryl ring systems, Spring and co-workers [72] developed an *O*-linked version consisting of a copper-catalyzed intramolecular *O*-arylation to access biarylether-based oxazocines and oxazonines [73]. The acyclic **85** substrates are constituted from two aryl groups bearing an OH and a Br as an *ortho*-substituent, respectively, and tethered by an *N*-alkyl function (Scheme 31). Under the optimized reaction conditions involving the CuI/2,6-tetramethylheptanedione (TMHD) catalytic system, the *O*-arylation showed a broad substrate scope, accessing various biaryl-fused 8- and 9-membered *N*,*O*-heterocycle **86** products. Good to excellent yields were obtained for oxazocines excepting for those bearing ortho-substituents and for oxazonines. Complementary experiments demonstrated the crucial role of the substituted nitrogen atom present in the substrate structure. Indeed, the copper chelation by the nitrogen atom leads to a pre-organized species of type **A** that facilitates cyclization via the catalytic species **B**. A more flexible tertiary amine ligand placed as the *N*-substituent (R = CO2CH2CH2NMe2) was also efficient.

**Scheme 31.** Copper-catalyzed intramolecular *O*-arylation to access dibenzoxazocines and oxazonines.

#### **4. Methods Using Gold- or Silver-Catalyzed Reactions**

Gold (I or III) complexes are the most effective catalysts for electrophilic activation of alkynes, with a wide field of synthetic applications; few other less-acidic late transition metals, such as Pt (II) or Ag(I), can be used as an alternative. The large tolerance of gold catalysis toward heteroatoms make gold catalysis a powerful and useful tool for the synthesis of functionalized molecular scaffolds, including heterocyclic cores [74].

#### *4.1. Carbon–Carbon Bond Formation*

Echavarren and co-workers described gold-catalyzed hydroarylation of alkynylindole **87** (Scheme 32) [75,76]. As is often the case, a competition between *exo*- and *endo*-cyclization was observed. The regioselectivity was controlled by the oxidation state of the gold catalyst. Indeed, indoloazocine **88** products were obtained as major products with the gold(III) catalyst, while indoloazepine **89** products were obtained mostly with the gold(I) catalyst. The same authors applied the methodology for the preparation of **90**,a1*H*-azocino[5, 4-*b*]indole skeleton of lundurines A-D [77].

**Scheme 32.** Gold-catalyzed cyclization of alkynylindole.

On their side, Eycken and co-workers obtained indoloazocine derivatives **92** via a cationic gold(I)-catalyzed alkyne hydroarylation of propargyl amide derivatives **91** (Scheme 33) [78]. A substrate scope expansion was achieved via the application of the method on some previously unreactive substrates and substrates bearing additional substituents on the indole core.

**Scheme 33.** Gold-catalyzed alkyne hydroarylation of propargyl amide derivatives.

Ohno and co-workers reported gold(I)-catalyzed cascade reactions of anilines **93** to form eight-membered ring-fused indoles **94** or propellane-type indoline 95 (Scheme 34) [79]. Depending on the reaction conditions, with IPr ligands and protic solvents such as ethanol, the formation of eight-membered ring-fused indoles **94** is favored. The reaction proceeded through an activation of alkyne by cationic gold, which promoted a 5-*endo*-dig hydroamination followed by 8-*endo*-dig hydroarylation.

**Scheme 34.** Gold-catalyzed cascade reactions of aniline derivatives.

Shi and co-workers developed gold-catalyzed cascade reactions for the construction of eight-membered ring-fused indolizines **97** from indoles or pyrroles **96** (Scheme 35) [80]. The cascade reaction proceeded through two-fold hydroarylations (6-*endo*-dig and 8-*endo*-dig) in the presence of the gold(I)- catalyst.

**Scheme 35.** Gold-catalyzed cascade reactions of indole derivatives.

The challenging synthesis of medium-sized heterocycles possessing a *trans* double bond was described by Tang, Shi, and co-workers (Scheme 36) [81]. They described a gold(I)-catalyzed 1,2-acyloxy migration–intramolecular cyclopropanation–ring enlargement cascade reaction. The reaction provided access to ten- and eleven-membered *O*- or *N*-heterocycle **99** products and was highly chemo-selective at the C5 position of furan **98**.

**Scheme 36.** Gold-catalyzed cascade reactions for the construction of ten- and eleven-membered rings.

The same authors described a gold(I)-catalyzed cycloisomerization of vinylidenecyclopropane-ene **100** for the construction of *O*-heterocycles **101**–**103** through controllable carbene or non-carbene processes (Scheme 37) [82]. Depending on the substituents adjacent to the oxygen atom (R<sup>1</sup> = H, F), a gold carbene is generated via rearrangement of vinylidenecyclopropane, giving access to eight-membered ring compounds **101**. The non-carbene processes allow the formation of fiveor six-membered rings **102** and **103** through allyl migration.

**Scheme 37.** Gold(I)-catalyzed cycloisomerization of vinylidenecyclopropane-enes.

Kumar, Waldmann, and co-workers developed a rare 8-*endo*-dig cyclization reaction of *O*-propargyloxy styrene **104** products catalyzed by gold(I) complexes (Scheme 38) [83]. The transformation provides access to eight-membered ring **105**.

**Scheme 38.** Synthesis of benzoxocines by gold(I)-catalyzed 8-*endo*-dig cyclization.

She and co-workers reported the formation of eight- or nine-membered ring ethers and amines of **107** (Scheme 39) [84]. The strategy is based on a gold(I)-catalyzed cascade reaction involving enynyl ester **106** isomerization and intramolecular [3+2] cyclization. The geometry of the olefinic bond has an influence on this transformation, as only *Z* olefins underwent this reaction, while *E* olefins resulted in decomposition of the starting material.

**Scheme 39.** Synthesis of 8- and 9-membered ring ethers and amines by gold(I)-catalyzed cascade reaction.

#### *4.2. Carbon–Heteroatom Bond Formation*

## C–O Bond Formation

The hydroalkoxylation of alkynes is the most convenient method for the synthesis of *O*-heterocycles. The high alkynophilicity of gold complexes allows these reactions, providing either the *exo*-dig or *endo*-dig product. However, few examples of 8-membered *O*-heterocycles are described and they are often in competition with 7-membered *O*-heterocycles.

During their study on the synthesis of alkylidene lactone with silver(I) or gold(I) catalysts, Porcel and co-workers observed the formation 8-membered *O*-heterocycle **110** and *N*,*O*-heterocycle **112** (Scheme 40) [85]. Indeed, while terminal alkynoic acids were regioselectively transformed into 7-membered *O*- or *N*,*O*-heterocycles, the hydroalkoxylation of non-terminal alkynoic acids **108** and **109** was not regioselective, and the 8-membered *O*- or *N*,*O*-heterocycles were observed as minor products.

**Scheme 40.** Ag(I)- and Au(I)-catalyzed hydroalkoxylation of alkynoic acids.

Schreiber and co-workers described the development of a gold(I)-catalyzed 8-*endo*-dig hydroalkoxylation of alkynamide **114** products with good regioselectivities in favor of the 8-membered ring (up to 20:1) in order to form oxazocenone **115** (Scheme 41) [86]. This method was applied to a substrate with higher structural complexity to obtain **117**, an analog of a previously described bioactive benzoxazocenone [87,88].

**Scheme 41.** Au(I)-catalyzed hydroalkoxylation for oxazocenone synthesis.

A recent publication referred to silver-catalyzed hydroalkoxylation of C2-alkynyl quinazolinone 118 for the synthesis of quinazolinone-fused, eight-membered *N*,*O*-heterocycle **119** (Scheme 42) [89]. The authors made mechanistic studies revealing that the silver catalyst might be involved in bidentate coordination of the imine group and alkyne to favor 8-*endo*-dig cyclization. It is interesting to note that they also synthesized one benzodiazocine **120** product at 27% yield.

**Scheme 42.** Ag(I)-catalyzed 8-*endo*-dig cyclization for quinazolinone-fused 8-membered heterocycle synthesis.

On their side, Ohno and co-workers developed a gold(I)-catalyzed cascade reaction of 2-alkynyl-*N*propargylaniline **121** by rearrangement of the propargyl group, providing access to fused indoline **122** (Scheme 43) [90]. During their study, the relatively low nucleophilicity of the indole bearing a bromo-substituent induced a side reaction and the production of the 8-membered *O*-heterocycle **123** in 20% yield.

**Scheme 43.** Au(I)-catalyzed cyclization of 2-alkynyl-*N*-propargylanilines.

#### **5. Conclusions**

This review has shown that the synthesis of medium-sized heterocycles by transition-metal -catalyzed intramolecular carbon–carbon or carbon–heteroatom bond formation represents an active area of research. Due to the interest aroused by these compounds in the field of drug discovery, other innovative methods will no doubt emerge to access these structures.

**Author Contributions:** All the authors participated in drafting the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** The authors thank the Ministère de l'Enseignement Supérieur, de la Recherche et de l'Innovation (MESRI doctoral grant for M.C.), the University of Strasbourg (IDEX postdoctoral grant for A.B.L.), and the Centre National de la Recherche Scientifique (CNRS).

**Conflicts of Interest:** The authors declare that there are no conflicts of interest.

#### **References**


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