Synthesis of Phosphorus(V)-Substituted Six-Membered N-Heterocycles: Recent Progress and Challenges

Abstract

Heterocycles functionalized with pentavalent phosphorus are of great importance since they include a great variety of biologically active compounds and pharmaceuticals, advanced materials, and valuable reactive intermediates for organic synthesis. Significant progress in synthesis of P(O)R₂-substituted six-membered heterocycles has been made in the past decade. This review covers the synthetic strategies towards aromatic monocyclic six-membered N-heterocycles, such as pyridines, pyridazines, pyrimidines, and pyrazines bearing phosphonates and phosphine oxides, which were reported from 2012 to 2022.

Keywords: heterocycles; organophosphorus compounds; pyrazine; pyridazine; pyridine; pyrimidine.

Figure 1

Approaches to synthesis of POR₂-containing pyridines.

Scheme 1

Synthesis of pyridine-2-phosphonates.

Scheme 2

Reaction of diethyl (2-oxobutyl)phosphonate with Mannich bases.

Scheme 3

Rh(II)-catalyzed cyclization of δ-diazo oxime ether.

Scheme 4

Reaction of phosphorylated carbenoid with 2H-azirine.

Scheme 5

Formal [2+2+2]-cycloaddition of 1,6- and 1,7-diynes with diethyl phosphorocyanidate.

Scheme 6

Photocatalytic phosphorylation of halopyridines: (a) Synthesis of 2-phosphine oxide-substituted pyridines; (b) Synthesis of 3-phosphine oxide-substituted pyridines.

Scheme 7

Synthesis of pyridine-3- and pyridine-4-phosphonates from pyridylazo sulfones.

Scheme 8

Photocatalytic reaction of N-ethoxypyridinium salts with phosphine oxides.

Scheme 9

Oxidative coupling of pyridines with dialkyl phosphites in the presence of Ag(I).

Scheme 10

Coupling of pyridines with secondary phosphine oxides in the presence of acetylenes.

Scheme 11

Reaction between N-methoxypyridinium tosylates and secondary phosphines.

Scheme 12

Reaction of pyridine N-oxides with triethyl phosphite.

Scheme 13

Asymmetric synthesis of tertiary pyridine-containing phosphine oxides.

Scheme 14

Synthesis of chiral tertiary pyridine-containing phosphine oxides.

Scheme 15

Cross-coupling of halopyridines with dimethylphosphine oxide.

Scheme 16

Pd(II)-catalyzed cross-coupling of 3-bromopyridines with triethyl phosphite.

Scheme 17

Cross-coupling of pyridine carboxylic acids with dialkyl phosphites.

Scheme 18

Replacement of the OH group of hydroxypyridines mediated by sulfuryl fluoride.

Scheme 19

Replacement of the OH group of hydroxypyridines by the diphenylphosphoryl moiety.

Scheme 20

Cross-coupling of aryl carboxylic acid esters with phosphine oxides.

Scheme 21

Ni(II)-catalyzed replacement of the tosyl group in pyridines.

Figure 2

Approaches to synthesis of POR₂-containing pyridazines.

Scheme 22

Reactions of cyclopropenylium salts with phosphorus-containing diazomethanes.

Scheme 23

Rearrangement of phosphorus-containing bis-azirine.

Scheme 24

Cyclization of γ,δ-unsaturated α-diazo-β-keto phosphonate.

Scheme 25

Synthesis of dimethyl 3,6-diphenylpyridazine-3-phosphonate.

Scheme 26

Phosphorylation of pyridazines: (a) Mrowca et al., 1980 [111]; (b) Kim et al., 2019 [79].

Figure 3

Approaches to synthesis of POR₂-containing pyrimidines.

Scheme 27

Cyclization reactions of guanidine (a) and amidine (b).

Scheme 28

Michaelis–Arbuzov reaction in synthesis of pyrimidine phosphonates: (a) Jansa et al., 2012 [125]; (b) Kunda et al., 2011 [126]; Mohan Naidu et al., 2011 [127]; (c) Golla et al., 2014 [128]; (d) Varalakshmi et al., 2015 [129].

Scheme 29

Photo-Arbuzov reaction in synthesis of pyrimidine-5-phosphonates.

Scheme 30

Photocatalytic phosphorylation of 2-chloropyrimidines.

Scheme 31

Pd₂(dba)₃-catalyzed cross-coupling of halopyrimidines with dimethylphosphine oxide.

Scheme 32

Transition-metal-catalyzed cross-coupling of 2-chloropyrimidines with phosphine oxides.

Scheme 33

NiBr₂-catalyzed electrochemical synthesis of 5-phosphorylpyrimidine.

Figure 4

Approaches to synthesis of POR₂-containing pyrazines.

Scheme 34

Synthesis of phosphorus-containing pyrazines via dimerization of nitrile ylides.

Scheme 35

Dimerization of 4-dimethylamino-3-phosphoryl-2-azadiene.

Scheme 36

Synthesis of 2-POR₂-substituted pyrazines from 1,2-diaza-1,3-butadienes and 1,2-diamines.

Scheme 37

Synthesis of 2-phosphorylpyrazine by the Arbuzov reaction: (a) Golla et al., 2014 [128]; (b) Goddard et al., 2016 [131].

Scheme 38

Synthesis of 2-POR₂-substituted pyrazines by radical phosphorylation: (a) Yuan et al., 2018 [73]; (b) Berger and Montchamp, 2019 [142].

Scheme 39

Synthesis of 2-phosphorylpyrazines under transition metal catalysis.