Improvements, Variations and Biomedical Applications of the Michaelis-Arbuzov Reaction

Abstract

Compounds bearing the phosphorus-carbon (P-C) bond have important pharmacological, biochemical, and toxicological properties. Historically, the most notable reaction for the formation of the P-C bond is the Michaelis-Arbuzov reaction, first described in 1898. The classical Michaelis-Arbuzov reaction entails a reaction between an alkyl halide and a trialkyl phosphite to yield a dialkylalkylphosphonate. Nonetheless, deviations from the classical mechanisms and new modifications have appeared that allowed the expansion of the library of reactants and consequently the chemical space of the yielded products. These involve the use of Lewis acid catalysts, green methods, ultrasound, microwave, photochemically-assisted reactions, aryne-based reactions, etc. Here, a detailed presentation of the Michaelis-Arbuzov reaction and its developments and applications in the synthesis of biomedically important agents is provided. Certain examples of such applications include the development of alkylphosphonofluoridates as serine hydrolase inhibitors and activity-based probes, and the P-C containing antiviral and anticancer agents.

Keywords: Michaelis–Arbuzov reaction; activity-based probes; pharmaceutical applications; phosphonates; phosphonofluoridates.

Figure 1

Examples of important compounds bearing the P–C bond.

Scheme 1

The Michaelis–Arbuzov (MA) reaction.

Scheme 2

General mechanism of the common MA reaction. R₂ = alkyl, alkoxy, etc.

Scheme 3

Reaction of dichloroacetylene with phosphites.

Scheme 4

MA reaction with a cyclic phosphite.

Scheme 5

Intramolecular MA reaction.

Scheme 6

Production of the stable intermediate methyltriphenoxyphosphonium trifluoromethanesulfonate during the MA reaction. This may be further processed by NaI.

Scheme 7

Mechanism of ZnBr₂-promoted MA reaction.

Scheme 8

Production of racemic mixtures in MA reaction involving S_N1 mechanism.

Scheme 9

Example of an S_N1 mechanism in MA reaction.

Scheme 10

The MA reaction of fluorinated cyclobutenes with phosphites proceeds through a stable phosphorane intermediate.

Scheme 11

Reaction of fluorinated cyclobutenes with X = F.

Figure 2

The unexpected products derived upon decomposition of 1.

Scheme 12

Free-radical mediated MA reaction.

Scheme 13

Insertion MA reaction with [1.1.1]propellane.

Scheme 14

Reaction of [1.1.1]propellane with an optically active organophosphate results in inversion of configuration.

Scheme 15

Insertion MA reaction with 1,3-dihydroadamantane.

Scheme 16

Perkowvs. MA reaction.

Scheme 17

Mechanism of Perkow reaction.

Scheme 18

Pathways for the reaction of 4-substituted α-bromo acetophenones with phosphites.

Scheme 19

Reaction of γ-haloketones with phosphites.

Scheme 20

Rearrangement of phosphites (R′, R″ = O-alkyl), phosphonites (R′ = O-alkyl, R″ = alkyl) or phosphinites (R′, R″ = alkyl) by halomethylsilanes and two examples.

Scheme 21

The catalytic cycle of the reaction (upper) and the mechanisms for the first and second step of the cycle (lower).

Scheme 22

Reaction of alkyl diarylphosphinates with halotrimethylsilanes yields stable phosphonium salts.

Scheme 23

Synthesis of BTSP from hypophosphorous acid.

Scheme 24

The proposed mechanism for the TMSOTf-catalyzed MA reaction.

Scheme 25

Example of LaCl₃-catalyzed MA reaction.

Scheme 26

Conditions for the nanoparticle-assisted MA reaction and chemical formulas of two products produced with 94% yield.

Scheme 27

Formation of phosphonates through nanoparticle-assisted MA reaction under MW irradiation. These derivatives have potent antimicrobial activities in the range of 10–30 μg/mL against the bacteria S. aureus, B. subtilis, E. coli, and P. marginalis, and the fungi A. niger and F. oxysporum [49].

Scheme 28

NiCl₂-catalyzed formation of diarylarylphosphonates from triaryl phosphites and an aromatic or alkyl halide.

Scheme 29

Putative mechanism for the formation of diaryl phosphonates via NiCl₂-catalyzed MA reaction (L = triaryl phosphite, triethyl phosphite, and mixed phosphite; R = Aror Et).

Scheme 30

Aryne-mediated MA reaction.

Scheme 31

One pot conversion of carboxylic acids to phosphonates.

Scheme 32

Electrochemically-mediated MA reaction.

Scheme 33

Continuous flow MA reaction.

Scheme 34

Synthesis of 1,3,5-triazinylphosphonic acids through the MA reaction.

Scheme 35

Photo-MA and representative examples of phosphonylation of bromazepam (upper) and nicergoline (lower).

Scheme 36

Synthesis of benzylphosphonate diesters via intramolecular photochemical MA rearrangement.

Scheme 37

Synthesis of purine phosphonates through the S_NAr mechanism. The investigation of their potential biological activities is underway.

Scheme 38

Regioselectivity for the 6-position in an MA reaction between 2,6-bistriazolylpurines and phosphites.

Scheme 39

Classical MA reaction between 1,2-dibromoethane and phosphite.

Scheme 40

Dehalogenation of vic-dibromides during MA reaction.

Scheme 41

Polymerization of 1,4-bis(trichloromethyl)benzene by phosphite.

Scheme 42

The reaction between iodine derivatives of coumarin and phosphites yields the expected MA products.

Scheme 43

Reaction of chloride derivatives of coumarin with phosphite yields non-regular MA products.

Scheme 44

MA reaction of pyridoyl chlorides with triethyl phosphites.

Scheme 45

Synthesis of phostones from phosphites. The products are derived after prolonged heating.

Scheme 46

General reaction scheme to produce triphenylmethylphosphonates.

Figure 3

Cytotoxicity of triphenylmethylphosphonates against two human malignant melanoma cell lines.

Scheme 47

Synthesis of foscarnet (sodium salt).

Scheme 48

Synthesis of phosphonoformates derivatives of cholines as potential anticancer and antimicrobial agents.

Scheme 49

Synthesis of methylenecyclopropane phosphonate agents. The synthesis of Z-isomer is shown; the E-isomer is prepared in the same manner after chromatographic separation from the Z-precursor.

Scheme 50

Synthesis of phosphonylated N-sulfonamides as new antimicrobials.

Scheme 51

Synthesis of a phosphonate prodrug of AZT.

Scheme 52

Synthesis of phosphonate surfmers. Two molecules have been designed with different spacers, namely C11 and C12.

Scheme 53

Production of mono-ethylphosphonate (A) and bis-ethylphosphonate (B) anchors for the development of phosphonate dendrons.

Scheme 54

Formation of DEP- and MEP-haptens.

Scheme 55

Synthesis of phosphonylated sugar derivatives.

Scheme 56

Synthesis of symmetric phosphonate analogues of triphosphates.

Scheme 57

Synthesis of asymmetric phosphonate analogues of triphosphates.

Scheme 58

Synthesis of potential phosphonate autophagy stimulators.

Scheme 59

Synthesis of lesogaberan.

Scheme 60

MA reaction with para-quinone methides and two relevant examples.

Scheme 61

Synthesis of O-4-nitrophenyl O-ethyl methylphosphonate, a VX surrogate.

Scheme 62

Synthesis of ¹⁴C-radiolabelled sarin.

Figure 4

Chemical formulas of cyclohexyl phosphonofluoridates that act as inhibitors for chymotrypsin-like enzymes.

Scheme 63

Synthesis of FP-biotin.

Figure 5

Chemical structure of B24P. The compound was synthesized with a series of reactions starting from the MA reaction between the 11-undecanoic acid and triethyl phosphite.

Scheme 64

Synthesis of FP-alkyne.

Scheme 65

Labeling of 1-alkyne modified enzyme.

Scheme 66

Synthesis of trans-alkenes from phosphonates and aldehydes.

Figure 6

Stilbene analogue as a potent anticancer agent.

Scheme 67

Synthesis of trans-β-carotene. In the last step, the 11-cis-β-carotene is produced that is isomerized to trans by heating in heptane (as shown).

Scheme 68

Chemical synthesis of nostodione A.

Figure 7

Analogue of nostodione that exhibited the highest antiparasitic activity against Toxoplasmagondii (IC₅₀ = 4.6 μM).