Atherton-Todd reaction: mechanism, scope and applications

Abstract

Initially, the Atherton-Todd (AT) reaction was applied for the synthesis of phosphoramidates by reacting dialkyl phosphite with a primary amine in the presence of carbon tetrachloride. These reaction conditions were subsequently modified with the aim to optimize them and the reaction was extended to different nucleophiles. The mechanism of this reaction led to controversial reports over the past years and is adequately discussed. We also present the scope of the AT reaction. Finally, we investigate the AT reaction by means of exemplary applications, which mainly concern three topics. First, we discuss the activation of a phenol group as a phosphate which allows for subsequent transformations such as cross coupling and reduction. Next, we examine the AT reaction applied to produce fire retardant compounds. In the last section, we investigate the use of the AT reaction for the production of compounds employed for biological applications. The selected examples to illustrate the applications of the Atherton-Todd reaction mainly cover the past 15 years.

Keywords: amphiphiles; flame retardant; lipid conjugates; organophosphorus; phosphate; phosphoramidate.

Scheme 1

Pioneer works of Atherton, Openshaw and Todd reporting on the synthesis of phosphoramidate starting from dibenzylphosphite (adapted from [1]).

Scheme 2

Mechanisms 1 (i) and 2 (ii) suggested by Atherton and Todd in 1945; adapted from [1].

Scheme 3

Two reaction pathways (i and ii) to produce chlorophosphate 2. Charge-transfer complex observed when hexahydroazepine was used as a base (iii); adapted from [6] and [9].

Scheme 4

Mechanism of the Atherton–Todd reaction with dimethylphosphite according to Roundhill et al. (adapted from [13] and [17]).

Scheme 5

Synthesis of dialkyl phosphate from dialkyl phosphite (i) and identification of chloro- and bromophosphate as reaction intermediate (ii) (adapted from [18] (i) and [22] (ii)).

Scheme 6

Synthesis of chiral phosphoramidate with trichloromethylphosphonate as the suggested intermediate (i) and directly from a chlorophosphate used as a substrate (ii) (adapted from [–27]).

Scheme 7

Selection of results that address the question of the stereochemistry of the AT reaction (adapted from [–32]).

Scheme 8

Synthesis of phenoxy spirophosphorane by the AT reaction (adapted from [34]).

Scheme 9

Suggested mechanism of the Atherton–Todd reaction, (i) and (ii) formation of chlorophosphate with a hindered or nucleophilic base; (iii) nucleophilic substitution at the phosphorus center with stereoinversion.

Scheme 10

AT reaction in biphasic conditions (adapted from [38]).

Scheme 11

AT reaction with iodoform as halide source (adapted from [37]).

Scheme 12

AT reaction with phenol at low temperature in the presence of DMAP (adapted from [40]).

Scheme 13

Synthesis of a triphosphate by the AT reaction starting with the preparation of chlorophosphate (adapted from [41]).

Scheme 14

AT reaction with sulfonamide (adapted from [42]).

Scheme 15

Synthesis of a styrylphosphoramidate starting from the corresponding aniline (adapted from [43]).

Scheme 16

Use of hydrazine as nucleophile in AT reactions (adapted from [48]).

Scheme 17

AT reaction with phenol as a nucleophilic species; synthesis of dioleyl phosphate-substituted coumarine derivative (i) and synthesis of diethyl aryl phosphate (ii) (adapted from [55] and [56]).

Scheme 18

Synthesis of β-alkynyl-enolphosphate from allenylketone with AT reaction (adapted from [58]).

Scheme 19

Synthesis of pseudohalide phosphate by using AT reaction (adapted from [67]).

Scheme 20

AT reaction with hydrospirophosphorane with insertion of CO₂ in the product (adapted from [69]).

Scheme 21

AT reaction with diaryl phosphite (adapted from [70]).

Scheme 22

AT reaction with O-alkyl phosphonite (adapted from [71]).

Scheme 23

Use of phosphinous acid in AT reactions (adapted from [72]).

Scheme 24

AT reaction with secondary phosphinethiooxide (adapted from [76]).

Scheme 25

Use of H-phosphonothioate in the AT reaction (adapted from [78]).

Scheme 26

AT-like reaction with CuI as catalyst and without halide source (adapted from [80]).

Scheme 27

Reduction of phenols after activation as phosphate derivatives (adapted from [81] i ; [82], ii; and [83], iii).

Scheme 28

Synthesis of medium and large-sized nitrogen-containing heterocycles (adapted from [85]).

Scheme 29

Synthesis of arylstannane from aryl phosphate prepared by an AT reaction (adapted from [86]).

Scheme 30

Synthesis and use of aryl dialkyl phosphate for the synthesis of biaryl derivatives (adapted from [89]).

Scheme 31

Synthesis of aryl dialkyl phosphate by an AT reaction from phenol and subsequent rearrangement yielding arylphosphonate (adapted from [91]).

Scheme 32

Selected chiral phosphoramidates used as organocatalyst; i) chiral phosphoramidate used in the pioneer works of Denmark et al. [101]; ii, iii) synthesis of organocatalysts by using AT reaction (adapted from [107]).

Scheme 33

Determination of ee of H-phosphinate by the application of the AT reaction with a chiral amine (adapted from [108]).

Scheme 34

Chemical structure of selected flame retardants synthesized by AT reactions; (BDE: polybrominated diphenyl ether; DOPO: 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide; DEPA: diethyl phosphoramidate; PAHEDE: phosphoramidic acid-N-(2-hydroxyethyl) diethyl ester; EHP: diethyl 3-hydroxypropylphosphoramidate; MHP: dimethyl 3-hydroxypropylphosphoramidate; PAEDBTEE: phosphoramidic acid-1,2-ethanediylbis-tetraethyl ester; PAPDBTEE: phosphoramidic acid-1,4-piperazinediyl tetraethyl ester; DMAPR: dimethyl allylphosphoramidate; DPAPR: diphenyl allylphosphoramidate; DMAPR: dimethyl diallylphosphoramidate).

Scheme 35

Transformation of DOPO (i) and synthesis of polyphosphonate (ii) by the AT reaction (adapted from [117] and [118]).

Scheme 36

Synthesis of lipophosphite (bisoleyl phosphite) and cationic lipophosphoramidate with an AT reaction (adapted from [119]).

Scheme 37

Use of AT reactions to produce cationic lipids characterized by a trimethylphosphonium, trimethylarsonium, guanidinium and methylimidazolium polar head.

Scheme 38

Cationic lipid synthesized by the AT reaction illustrating the variation of the structure of the lipid domain. The arrows indicate the bond formed by the AT reaction.

Scheme 39

Helper lipids for nucleic acid delivery synthesized with the AT reaction (adapted from [130]).

Scheme 40

AT reaction used to produce red/ox-sensitive cationic lipids (adapted from [135]).

Scheme 41

Alkyne and azide-functionalized phosphoramidate synthesized by AT reactions,(i); illustration of some fluorescent lipids synthesised from these intermediates, (ii) (adapted from [136]).

Scheme 42

Cationic lipids exhibiting bactericidal action – arrows indicate the bond formed by the AT reaction (adapted from [137]).

Scheme 43

β-Cyclodextrin-based lipophosphoramidates (adapted from [138]).

Scheme 44

Polyphosphate functionalized by an AT reaction (adapted from [139]).

Scheme 45

Synthesis of zwitterionic phosphocholine-bound chitosan (adapted from [142]).

Scheme 46

Synthesis of AZT-based prodrug via an AT reaction (adapted from [143]).