*2.4. Formal Cycloaddition*

In the context of this review, the so-called "formal cycloadditions" do not belong strictly speaking to the category of metal-catalyzed intramolecular cyclization reactions, however, many of them fit with this definition. The selected examples of formal cycloaddition [n + m] are Pd-catalyzed processes occurring via the formation in a first step of an acyclic palladium-intermediate, followed by an intramolecular carbon-heteroatom bond formation leading to a medium-sized heterocycle with (n + m) atoms.

Zhao and co-workers reported an elegant strategy to access nine-membered *N*,*O*-heterocycles via a formal [5 + 4] cycloaddition [56]. Azadiene **51** derived from benzofuran as the four-atom unit and the substituted vinylethylene carbonate (VEC) **52**, which is the palladium π-allyl alcoholate five-atom unit precursor, react under palladium-catalysis to generate species **53**. The reaction proceeds via the attack of the nitrogen-nucleophile to the terminal carbon of the Pd-π-allyl moiety to deliver product **54** (Scheme 20). The reaction scope proved to be broad with respect to the variation of substituents of both azadiene and VEC, leading to a wide range of benzofuran-fused oxazonines.

**Scheme 20.** Synthesis of 9-membered *N*,*O*-heterocycles by Pd-catalyzed [5 + 4] formal cycloaddition.

The same group developed then a catalytic enantioselective version of the reaction by using Pd catalysts with chiral diphosphine ligands [57]. The benzofuran-fused nine-membered heterocycles were obtained in excellent yield (70–95%) and with high enantioselectivity (86−92% ee).

According to a new strategy that used a 1,3-dipole as a three-atom partner, a formal [5 + 3] cycloaddition was developed by Guo's group [58]. The zwitterionic allylpalladium intermediates were generated either from vinylethylene carbonates **56** or vinyloxiranes **56'** and reacted in situ with azomethine imines **55** to afford eight-membered *N*,*O*-heterocycle **57** in good to excellent yields (Scheme 21). *N*-quinazolinium and *N*-isoquinolinium ylides were successfully employed in the reaction, while other azomethine imines were inert. It should be noted that the regioselectivity of the reaction, namely [5 + 3] vs. [3 + 3] cycloaddition, was not complete; however, the formation of the 8-membered ring products was clearly favored (90:10 to 99:1 ratios). For non-substituted vinylethylene carbonate and vinyloxirane (with R = H), the 6-membered ring cycloadduct was obtained as the major product.

**Scheme 21.** Synthesis of 8-membered *N*,*O*-heterocycles by Pd-catalyzed [5 + 3] formal cycloaddition.

Another strategy that was recently published by Liu and Hu consisted of a Pd-catalyzed [n + 2] formal cycloaddition enabling access to medium-sized heterocycles from eight to eleven-membered rings [59]. Various linker-tethered-bisphenols **58** were used as n-atom (n = 6 to 9) bis-nucleophile partners in reaction with propargylic esters **59** as C2 synthons. Under palladium catalysis conditions, the propargylic benzoate affords a η3-π-propargylpalladium complex, which reacts with the bis-*O*-nucleophile to form the cyclic product **60** (Scheme 22). The reaction shows a broad substrate scope (particularly in 9-membered ring series), excellent regio- and *Z*/*E*-selectivities (>95/5), and high yields.

**Scheme 22.** Synthesis of 8- to 11-membered heterocycles by Pd-catalyzed [n + 2] formal cycloaddition.

#### **3. Methods Using Copper-Catalyzed Reactions**

Copper-mediated and copper-catalyzed coupling reactions were pioneered by Ullmann and Goldberg at the beginning of the 20th century [60]. In its "classical" version, a C–C bond is formed via reductive coupling of haloarenes to give biaryl compounds. This principle was then extended to other nucleophiles, and now various heteroatom-aryl (heteroatom: N, O, S, P) and carbon-aryl bonds are easily accessible via this process. In particular, these reactions have been improved via the use of copper ligands, allowing lower catalyst loading and temperatures and broader substrate scope [46,61–63]. Copper oxidation states can range from Cu(0) to Cu(III). The use of copper catalysts in the synthesis of medium-sized heterocycles, although rare, has many advantages, since copper is abundant, inexpensive, air-stable, and compatible with different functional groups.

## *3.1. Carbon–Carbon Bond Formation*

Schreiber and co-workers explored a branching reaction pathway strategy for a diversity-oriented synthesis (DOS) approach to build biaryl-embedded 9-, 10-, and 11-membered heterocycles via an intramolecular copper-catalyzed C–C bond formation [64]. As an example, the starting chiral aminoether **61** was treated with *t*-BuLi followed by CuCN to give the supposed cyclic organocuprate intermediate **62**, which under oxidizing conditions afforded biaryl atropisomeric 10-membered *N*,*O*-heterocycle **63** at 88% yield (Scheme 23). It has been shown that the nature of the substrate and the reaction conditions (oxidizing agent, solvent, and temperature) influenced the diastereoselectivity. Under optimized conditions, using 1,3-dinitrobenzene (1,3-DNB) as the oxidant and 2-MeTHF as the solvent at −40 ◦C, good yields were obtained in all cases. Thermal isomerization was used to reverse the stereochemistry of the major atropoisomer obtained in kinetic conditions. The diastereomeric ratios were measured for the products obtained under kinetic conditions (kinetic dr), then after heating each product at 150 ◦C for 24–48 h (thermodynamic dr). Considering a future split-pool synthesis, the authors judiciously extended the concept to a solid-phase process.

**Scheme 23.** Stereoselective synthesis of biaryl-containing medium-sized heterocycles via an intramolecular copper-mediated C–C bond formation.

Bode's group developed what they called the Sn amino protocol (SnAP) reagents and employed them in the synthesis of functionalized saturated heterocycles [65]. The transformation occurred under mild reaction conditions and consisted of the condensation of an aldehyde and the SnAP reagent **64**, affording the imine intermediate **65**, which was then engaged in an oxidative radical process catalyzed by copper. Cyclization occurred via C–C bond formation through an *endo* attack to the imine bond by the stabilized radical cation formed in the α-position of heteroatom X. The catalytic cycle ends with the reduction of the cyclic *N*-radical cation by Cu(I) and regeneration of the Cu(II) catalyst. This approach

was compatible with aliphatic, aryl, and heteroaryl aldehydes, allowing access to various 8- and 9-membered saturated *N*,*N*- and *N*,*O*-heterocycle **66** products (Scheme 24).

**Scheme 24.** Synthesis of 8- to 9-membered heterocycles by Cu-catalyzed cyclization involving Sn amino protocol (SnAP) reagents.

Ye and co-workers disclosed the first copper-catalyzed tandem reaction of chiral indolyl homopropargyl amide **67** involving a 5-*endo-*dig hydroamination and a subsequent Friedel–Crafts alkylation [66]. This method afforded bridged aza-[*n*.2.1]-indole-based tropanes in most examples, but was also extended to indole-fused medium-sized heterocycles **68** (Scheme 25). Chirality transfer from the substrates to the desired products allowed excellent enantioselectivitiy and diastereoselectivity.

**Scheme 25.** Synthesis of bridged aza-[*n*.2.1]-indolyl medium-sized heterocycles by copper-catalyzed hydroamination–Friedel–Crafts domino process.

## *3.2. Carbon-Heteroatom Bond Formation*
