Efficient Approaches to the Design of Six-Membered Polyazacyclic Compounds-Part 1: Aromatic Frameworks

Abstract

This review summarises the possible applications and basic methodologies for the synthesis of six-membered polyazo heterocycles, namely, diazines, triazines, and tetrazines. The time period covered by the analysed works ranges from the beginning of the 20th century to the present day. This period was chosen because it was during this time that synthetic chemistry, as defined by physicochemical research methods, became capable of solving such complex problems as efficiently as possible. The first part of the review describes the applications of polyazo heterocyclic compounds, whose frameworks are found in the composition of drugs, dyes, and functional molecules for materials chemistry, as well as in a wide variety of natural compounds and their synthetic analogues. The review also systematises the methods for assembling six-membered aromatic polyazo heterocycles, including intramolecular and sequential cyclisation, which determine the possible structural and functional diversity based on the presence and arrangement of nitrogen atoms and the position of the corresponding substituents.

Keywords: azaheterocyclic; diazine; tetrazine; triazine.

Figure 1

Six-membered heterocycles with two nitrogen atoms: (a) pyridazine, (b) pyrimidine, and (c) pyrazine.

Figure 2

Examples of registered medicinal products comprising a pyridazine moiety.

Figure 3

Examples of registered medicinal products comprising a pyrimidine fragment.

Figure 4

Examples of registered medicinal products comprising a pyrazine moiety.

Figure 5

Six-membered heterocycles with three nitrogen atoms: (a) 1,3,5-triazine, (b) 1,2,4-triazine, and (c) 1,2,3-triazine.

Figure 6

Examples of registered medicinal products comprising triazine moieties.

Figure 7

Types of six-membered heterocycles with four nitrogen atoms: (a) 1,2,3,4-tetrazine, (b) 1,2,3,5-tetrazine, and (c) 1,2,4,5-tetrazine.

Figure 8

Examples of registered drugs comprising tetrazine moieties.

Scheme 1

General method for the synthesis of pyridazines [170,171,172,173,174].

Scheme 2

General method for the synthesis of 4 from 3 via the Diels–Alder reaction [176,177,178].

Scheme 3

One-pot [4+2] cyclocondensation of substituted pyridazines [188].

Scheme 4

Pyridazine synthesised under green chemistry conditions using microwave irradiation [189].

Scheme 5

Domino-coupling–isomerisation–condensation reaction [196].

Scheme 6

One-pot synthesis of condensed 2H-pyrimidin-4-amine libraries under microwave irradiation [207].

Scheme 7

Skeletal editing of indoles and pyrroles: (a) recyclarization of indole, and (b) recyclarization of pyrrole [210].

Scheme 8

Electro-oxidative formal [3+3] annulation of 1,3,5-triazinane [211].

Scheme 9

Cyclocondensation pyrroles with tosylmethylisocyanide [212].

Scheme 10

One-pot three-component synthesis of pyrrolo[1,2-a]pyrimidine [213].

Scheme 11

Construction of multisubstituted pyrrolo[1,2-a]pyrimidines [214].

Scheme 12

(a) Cu-catalyzed synthesis and proposed mechanism of unsymmetrical pyrazines, and (b) proposed mechanism [219].

Scheme 13

Co-catalyzed annulation of terminal alkynes and o-phenylenediamines [224].

Scheme 14

Cyclisation reactions of 35 with allylamine and propargylamine [235].

Scheme 15

Synthesis via a Knoevenagel/[4+1] cycloaddition cascade [236].

Scheme 16

Microwave-assisted one-pot tandem reactions for direct conversion of primary aldehydes to triazines [241].

Scheme 17

Condensation of acid chlorides or anhydrides 44 with salt 45 [242].

Scheme 18

Copper-catalysed synthesis of substituted 2,4-diamino-1,3,5-triazines [243].

Scheme 19

Reactivity of 1,2,3,5-tetrazines 50 [157].

Scheme 20

The transformations to construct 1,2,4-triazine derivatives [246].

Scheme 21

Synthesis of triazine derivative [247].

Scheme 22

Multistep synthesis of pyrrolotriazine [248].

Scheme 23

Two-step synthesis of pyrrolotriazine [249].

Scheme 24

The base-mediated cyclisation of (Z)-2,4-diazido-2-alkenoates [250].

Scheme 25

The [5+1] cycloaddition reaction for the directed synthesis of triazine-1-oxides [251].

Scheme 26

Synthesis of 1,2,3,4-tetrazine [254].

Scheme 27

(a,b) Two different methods of synthesis of cyclopenta-annulated 1,2,3,4-tetrazines [255].

Scheme 28

Reaction of 3H-chromeno [2,3-d]pyrimidine with sodium azide [256].

Scheme 29

Cycloadditions of aryl-N-sulphinylamines with substituted triazolium imides [258].

Scheme 30

Synthesis of a monocyclic aromatic 1,2,3,5-tetrazine [259].

Scheme 31

Synthesis of 1,2,3,5-tetrazines [157].

Scheme 32

Pinner’s synthesis mechanism [264].

Scheme 33

One-pot catalysed synthesis of 1,2,4,5-tetrazines directly from nitriles [265].

Scheme 34

Synthesis of s-tetrazines [266].

Scheme 35

Solid-phase synthesis of s-tetrazines [267].

Scheme 36

Two-step synthesis of conjugated s-tetrazine derivatives [268].

Scheme 37

Synthesis of pyrrolo[1,2-b][1,2,4,5]tetrazine [269,270,271].

Scheme 38

Assembly of fused pyrrolopyrazinotetrazine ensembles and reversible fragmentation [272].