Synthesis and Chemical Properties of 3-Phosphono-coumarins and 1,2-Benzoxaphosphorins as Precursors for Bioactive Compounds

Abstract

Coumarins are an important class of natural heterocyclic compounds that have attracted considerable synthetic and pharmacological interest due to their various biological activities. This review emphasizes on the synthetic methods for the preparation of dialkyl 2-oxo-2H-1-benzo- pyran-3-phosphonates and alkyl 1,2-benzoxaphosphorin-3-carboxylates. Their chemical properties as acceptors in conjugate addition reactions, [2+2] and [3+2] cycloaddition reactions are discussed.

Keywords: 1,2-bezoxaphosphorines; 1,2-bezoxaphosphorines-3-phosphonic acid; 1,2-phosphorinines; 2-oxo-2H-1-benzopyrans; 2-oxo-2H-chromenes; [2+2] cycloaddition; [3+2] cycloaddition; conjugate addition; coumarins.

Figure 1

Phosphorus-containing structures 1 and its phosphoroheterocyclic analogue 2.

Figure 2

Biologically active compounds and drugs.

Scheme 1

Knoevenagel condensation reaction of salicylaldehyde (3a) with triethyl phosphono- acetate (4).

Scheme 2

Different synthetic methods for the formation of 3-dialkylphosphonocoumarins 1.

Scheme 3

Knoevenagel condensation reaction with piperidine as catalyst.

Scheme 4

Knoevenagel condensation reaction with organic and inorganic catalysts.

Scheme 5

Different reaction paths explaining the ratio of the products 1 and 2.

Figure 3

Titanium chelate-complex formation.

Scheme 6

Reaction of 2′-bromoacetoxyphenones 8a–e with trimethyl phosphite (9).

Scheme 7

Reaction with compound 10.

Scheme 8

Synthetic method uses vinylphosphonates and phenols.

Scheme 9

Catalytic phosphorylation with Mn(OAc)₃.

Scheme 10

Catalytic phosphorylation with Pd-complexes.

Scheme 11

Proposed mechanism for the synthesis of substituted dialkyl 2-oxo-2H-1-benzopyran-3-phosphonates.

Scheme 12

Ag-catalyzed phosphorylation reaction.

Scheme 13

The proposed radical mechanism of the Ag-catalyzed phosphorylation reaction.

Scheme 14

Phosphorylation reactions by N-heterocyclic carbene palladium complexes.

Scheme 15

Electrochemical phosphorylation of coumarins with diethyl H-phosphonate.

Scheme 16

Electrochemical phosphorylation of coumarins with dialkyl H-phosphonate.

Scheme 17

Synthesis of 3-diethylphosphonocoumarin under coupling reaction.

Scheme 18

Possible mechanism of the reaction involving ortho-quinone methide.

Scheme 19

Transition-metal-catalyzed cross-coupling synthetic protocol for the formation of phosphorus-containing coumarin systems.

Scheme 20

The suggested mechanism of the observed cross-coupling transformation.

Scheme 21

Cascade-radical approach for the formation of 3-functionalized coumarin.

Scheme 22

Rearrangement reaction of intermediate A.

Figure 4

Nucleophilic addition reactions to 3-dialkylphosphonocoumarin.

Figure 5

Structures of phosphorus-containing coumarins that were object of theoretical investigations.

Scheme 23

One-pot tandem hydrogenation/acylation reactions with 3-diethylphosphonocoumarin 1a.

Figure 6

Products isolated from acylation reaction.

Scheme 24

Reaction of 3-diethylphosphonocoumarin 1a with Grignard reagent.

Scheme 25

1,4-conjugate addition reactions with organometallic compounds.

Scheme 26

Reactions with organozinc reagents.

Scheme 27

Radical homodimerization mechanism.

Scheme 28

1,4-conjugate addition reactions to 4-substituted 3-diethylphosphonocoumarins.

Scheme 29

Reaction of 1a with cyclohexanone and N-methylglycine.

Scheme 30

Proposed ylide structure 30 and subsequent interactions.

Scheme 31

Domino reaction with azomethine ylides.

Scheme 32

Synthesis of polycyclic δ-lactams.

Scheme 33

Michael-type addition of nitromethane under different reaction conditions.

Scheme 34

Proposed mechanism for the formation of 45 and 46.

Scheme 35

Michael addition of enolizable ketones to 3-diethylphosphonocoumarin 1 using TBD and Cs₂CO₃.

Figure 7

Proposed synclinal transition state formation.

Scheme 36

Michael addition of enolizable ketones to 3-phosphonocoumarin 1 using TBD.

Scheme 37

Synthesis of dialkyl 1,2-benzoxaphosphorin-3-phosphonates 55 via Knoevenagel reaction.

Scheme 38

Horner-Wadsworth-Emmons reaction catalyzed by DBU.

Figure 8

The structures of obtained 1,2-benzophosphorins of type 2.

Scheme 39

Reactions involving oxaphospholes.

Scheme 40

Multistep procedure for obtaining P-heterocyclic products.

Figure 9

Another example of compounds 61.

Scheme 41

Condensation of a phosphorus-bearing component with substituted phenols.

Scheme 42

Gold-catalyzed hydroarylation of aryl alkynylphosphonates.

Scheme 43

Intramolecular Pd-catalyzed cyclization reaction.

Scheme 44

Proposed mechanism of the intramolecular Pd-catalyzed cyclization reaction.

Scheme 45

Formation of 1,2-benzoxaphosphorines 70.

Scheme 46

Alkylation reaction to products 70 and 71.

Scheme 47

Conditions and results for the coupling reactions.

Scheme 48

Palladium-catalyzed Heck reaction.

Scheme 49

Accomplishing a Diels-Alder reaction with compounds 76.

Figure 10

Cyclized stereoisomers.

Scheme 50

[2+2] Cycloaddition products.

Scheme 51

[3+2] Cycloaddition reaction of 3-diethylphosphonocoumarins 1a and 1c.

Scheme 52

[3+2] Cycloaddition reaction of 1,2-benzoxaphosphorines 2d and 55a,b.