5.1.2. Synthesis of Pyrrolyl Pyridines

The one-pot reaction of *N*-substituted acylethynylpyrroles **55** with propargylamine in the presence of CuI selectively afforded 2-(pyrrol-2-yl)-3-acylpyridines **56** (Scheme 31) [78].

**Scheme 31.** The formation of pyrrolyl pyridines **56** from acylethynylpyrroles and propargylamine.

Catalyst-free heating of the reactants led to *N*-propargyl(pyrrolyl)aminoenones **57** which, upon keeping with CuI (equimolar amount) for 2.5 h at the same temperature, underwent the dihydrogenative ring closure to give pyrrolyl pyridines **56** (Scheme 31).

The duration of non-catalytic step strongly depended on the pyrrole structure: the acceptor substituents in the pyrrole ring facilitated the reaction (the reaction time was 6 h), while the donor ones slowed down the process (the reaction time was 16 h). A peculiar feature of this dehydrogenative cyclization is that the intermediate dihydropyridines **58** were aromatized rapidly (they are not usually detectable in the reaction mixture). Only in the case of acylethynyltetrahydroindole dihydropyridine **58** was isolated in 4% yield. Notably, the catalytic ring closure was almost insensitive to the structure of the initial acylethynylpyrroles **55** (the reaction time was about 2.5 h for all the cases).

A less predictable step of the synthesis is the intramolecular nucleophilic addition of the CH-bond adjacent to carbonyl group across the acetylenic moiety (Scheme 32). This CH-bond can be deprotonated under the action of amino group, either intramolecularly (autodeprotonation) to generate intermediate **A** or intermolecularly. Upon the complexing of Cu<sup>+</sup> cation with the triple bond, the latter should be polarized to increase sensitivity towards the nucleophilic attack. This attack is completed by the addition of the carbanionic site to the terminal acetylenic atom to give the intermediate dihydropyridine **58**.

**Scheme 32.** Formation of pyrrolyl pyridines **56** from aminoenones **57**.

The MS spectra of the reaction mixtures showed that the oxidation of intermediate **58** did not take place under the action of DMSO (no Me2S was detected). The air oxygen also did not participate in this process: the same results were obtained both under argon blanket and on air. Therefore, the Cu<sup>+</sup> cation was considered [78] as a likely oxidant.

Latter [79] from the reaction of NH-acylethynylpyrroles **59** with propargylamine in the presence of CuX (X = Cl, Br, I), 3-acyl-2-(pyrrol-2-yl)-5-halopyridines **60** were unexpectedly isolated in 4–14% yields along with 3-acyl-2-(pyrrol-2-yl)pyridines **61** (28–61% yields) (Scheme 33). Evidently, the cause of this difference compared to the previous cyclization [78] was the NH-functionality of the starting acylethynylpyrroles.

**Scheme 33.** Synthesis of pyrrolyl pyridines **60** and **61** from NH-2-acylethynylpyrroles and propargylamine.

Under the above conditions, pyrrolyl pyridines **61** were not halogenated with CuX, thus indicating that construction of the halogenated pyridine ring occurred before its closure. It is supposed (Scheme 34) [79] that hydrogen halides, reversibly generated by the interaction of the NH pyrrole moiety of the intermediate *N*-propargyl(pyrrolyl)aminoenone **57** with CuX, add to the triple bond activated by π-complexing with other CuX molecules to give haloallyl intermediate **B** (Scheme 34). Afterwards, the intramolecular addition of the CH bond to the allyl moiety takes place to form the intermediate 5-halotetrahydropyridyl intermediate **C**. Aromatization of the latter is finalized via the reaction with CuX and further oxidation by Cu<sup>+</sup> cations as previously described for a similar process [78].

**Scheme 34.** Proposed scheme of halopyridines **60** formation.

#### *5.2. Synthesis of Pyrrolizines via Three-Component Cyclization with Benzylamine and Acylacetylenes*

On the platform of acylethynylpyrroles **52**, a new general strategy for the synthesis of functionalized pyrrolizines was developed [80]. It consisted of the two steps: (i) the base-catalyzed addition of a benzylamine to 2-acylethynylpyrroles **52** to give pyrrolylaminoenones **62**; (ii) non-catalyzed addition of *N*-benzyl(pyrrolyl)aminoenones **62** to the triple bond of acylacetylenes **63** followed by the intramolecular cyclization of the intermediate pentadiendiones **64** thus formed to 1-benzylamino-2-acyl-3-methylenoacylpyrrolizines **65** (Scheme 35).

**Scheme 35.** Synthesis of 1-benzylamino-2-acyl-3-methylenoacylpyrrolizines **65**.

The nucleophilic addition of benzylamine to the triple bond of 2-acylethynylpyrroles **52** was realized in the presence K3PO4/DMSO catalytic system to smoothly deliver *N*-benzyl(pyrrolyl)aminoenones **62** in up to 97% yield (Scheme 35). The latter were formed as a mixture of the *E*/*Z* isomers, the *E*-isomer being obviously stabilized by intramolecular H-bonds between the carbonyl group and NH-function of the pyrrole ring. As in the case of the addition of propargylamine to acylethynylpyrrole (see Section 5.1), the structure of the substituents of the pyrrole ring strongly influences the isomer ratio of the adducts: the donor substituents increase the content of the Z-isomers.

Further, the aminoenones **62** chemo- and regioselectively reacted with acylacetylenes **63** to afford the intermediate pentadiendiones **64**, which then cyclized to 1-benzylamino-2-acyl-3 methylenoacylpyrrolyzines **65** in up to 80% yield (Scheme 35).
