3.2.1. C–N Bond Formation

#### N-arylation

Using a reagent-based diversity-oriented-synthesis strategy named "click, click, cyclize", Hanson's team built a library of sultam (cyclic sulfonamide) compounds [67]. They were able to produce a variety of 5- to 8-membered *S*-, *N,S*-, and *N*-heterocycles by exploring cyclization via alkylation, carbonylation, ring-closing metathesis, and copper-catalyzed *N*-arylation. A sulfonamide linchpin **69** substrate was prepared in two steps from 2-bromobenzylamine, then submitted to an intramolecular *N-*arylation by treatment with 1,10-phenanthroline and CuI under microwave irradiation to afford the 8-membered sultam **70** at 56% yield (Scheme 26).

**Scheme 26.** Synthesis of a sultam skeleton via Cu-catalyzed intramolecular *N*-Arylation.

Zhao and co-workers designed phosphoramidate and carbamate **71** derivatives that were efficiently transformed into medium (8 to 10 atoms) and large-sized *N*-heterocycles (12 and 16 atoms) upon submission to a copper-catalyzed intramolecular *N*-arylation [68]. The cyclization reaction conditions involved copper iodide and proline in toluene, giving access to *N*-heterocycle **72** (Scheme 27). The products were deprotected under acidic conditions. Intramolecular cyclization did not take place from the free amino group at the *N*-termini. Based on this result, the authors suggested that the presence of *N*-phosphoryl and *N*-Boc restrains substrate conformation and favors intramolecular *N*-arylation.

**Scheme 27.** Synthesis of medium *N*-heterocycles via Cu-catalyzed intramolecular *N*-arylation.

Al-Tel and co-workers developed a one-pot procedure comprising two sequential steps, SN2 and *N*-arylation reactions, to access benzene-fused 8- and 9-membered *N*-heterocycles, most of which were tricyclic systems [69]. Structural diversity was provided by the selective SN2 step between a variety of **73** or **74** dinucleophiles and bromobenzene derivatives **75** or **76**. Among the selected ambident nucleophiles were pyrrolidine- and piperidine-2-carboxamide, 2-aminobenzamides, 2-aminothiophenol, and (1*H*-indol-2-yl)methanamine. The resulting substrates were directly involved in copper iodide- or L-proline-catalyzed cyclization via *N*-arylation under microwave irradiation, affording benzo-embedded medium-sized *N*-heterocycles **77** and **78** in moderate to good yields (Scheme 28).

## N-Vinylation

Li and co-workers reported a copper-catalyzed intramolecular C–N bond formation between alkenyl halides and sulfonamides providing 5-, 6-, 7-, and 8-membered heterocyclic enamines [70]. The best catalytic system consisted of CuI/N,N'-dimethylethylene-diamine (DMEDA), with Cs2CO3 as the base and DMF as the solvent. The endocyclic alkenyl halide **79** generated benzoxazocine **80** as an endocyclic medium-sized enamide (Scheme 29).

**Scheme 28.** One-pot synthesis of medium-sized *N*-heterocycles via SN2 reaction followed by Cu-catalyzed intramolecular *N*-arylation.

**Scheme 29.** Synthesis of a benzoxazocine by Cu-catalyzed *N*-vinylation.

#### Hydroamination

Buchwald and co-workers dedicated efforts to developing many strategies for copper-catalyzed hydroamination of olefins. An asymmetric intramolecular variant was proposed and applied to the synthesis of medium-sized *N*,*O*-heterocycles [71]. In this process, the chiral alkylcuprate formed by hydrocupration of the double bond reacted with an electrophilic nitrogen. The catalytic chiral copper species (CuH/L\*) was formed from Cu(OAc)2 and dimethoxy(methyl)silane (DMMS) in the presence of an enantiopure bidentate phosphine ligand. The *N*-benzyl-*O*-pivaloylhydroxylamine moiety was used as the electrophilic nitrogen function, as this improved the yields and enantioselectivities of the reactions. This protocol was used for the enantioselective intramolecular hydroamination of the styryl double bond of substrates **81** and **82** to access benzoxazocine **83** and benzoxazonine **84**, respectively, with high yields and excellent enantiomeric excess (Scheme 30).

**Scheme 30.** Asymmetric synthesis of medium-sized *N*,*O*-heterocycles via copper-catalyzed intramolecular hydroamination.
