Isomeric and chemical consequences of the direct magnesiation of 1,3-benzoazoles using β-diketiminate-stabilized magnesium bases

Sharon E. Baillie, Victoria L. Blair, Tyne D. Bradley, William Clegg, Jemma Cowan, Ross W. Harrington, Alberto Hernan-Gomez, Alan R. Kennedy, Zoe Livingstone, Eva Hevia

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Abstract

Opening-up new synthetic applications of beta-diketiminate stabilised magnesium complexes, this case study compares the ability of the alkyl [{Ar*NC(Me)CHC(Me)NAr*}Mg(Bu)(THF)] (1) and the amido reagent [{Ar*NC(Me)CHC(Me)NAr*}Mg(TMP)] (2) (Ar* = 2,6-i- Pr-2-C6H3) to promote direct Mg-H exchange towards the series of 1,3-benzoazoles: benzoxazole (boz), benzothiazole (btz) and N-methyl benzimidazole (blm(Me)). Both reagents deprotonate boz at room temperature to yield [{Ar*NC(Me)CHC(Me)NAr*} Mg{O(o-C6H4) NC}(THF)] (3) via the C-O bond cleavage of a putative C2-magnesiated-benzoxazolyl intermediate. Structurally tracking the reactivity of 1 and 2 towards less acidic btz and blm(Me) showed that the behaviour of reagents 1 and 2 diverged dramatically. Kinetically activated TMP-reagent 2 effectively promotes the deprotonative magnesiation of btz and blm(Me) under mild reaction conditions, giving the alpha-metallated intermediates [{Ar* NC(Me) CHC(Me)NAr*}(2)Mg-2{btz*}(2)] (4) and [{Ar*NC(Me)CHC(Me)NAr*}(2)Mg-2{blm(Me)*}(2)] (7) (btz* = 2-benzothiazolyl; blm(Me)* = 2-N-methylbenzimidazolyl). Analysis of crystallographic and NMR data revealed that in 4 and 7 the metallated carbon atoms display a markedly carbenic character and that in solution these species exist at room temperature solely as the ring-closed products, without any observable equilibration to the acyclic isomers. Contrastingly, alkyl reagent 1 decreases the magnesiation rate of btz facilitating an intriguing new cascade activation process of two molecules of substrate involving a sequence of deprotonation/coordination/C-C coupling and ring-opening reactions to yield [{Ar*NC(Me)CHC(Me)NAr*}Mg{(btz*)C(H)]=N(o-C6H4) S}] (5). Hydrolysis of 5 followed by addition of the radical oxidant TEMPO ultimately produces the homocoupled product bis(benzothiazole) 6 in a 72% isolated yield. Thus, this establishes a novel transition-metal-free method to prepare homocoupled thiazoles. More straightforwardly, the coordination product [{Ar*NC(Me)CHC(Me)NAr*}Mg(Bu)(blm(Me))] (8) was obtained when equimolar amounts of blm(Me) and 1 were reacted, illustrating the kinetic stubbornness of the Mg-C bond in butyl derivative 1. Complex 8 can be envisaged as a valuable guide to the constitution of a premetallation complex (in relation to the complex-induced proximity effect, CIPE).

LanguageEnglish
Pages1895-1905
Number of pages11
JournalChemical Science
Volume4
Issue number4
Early online date14 Feb 2013
DOIs
Publication statusPublished - 2013

Fingerprint

Magnesium
Benzoxazoles
Thymidine Monophosphate
Thiazoles
Deprotonation
benzothiazole
Oxidants
Isomers
Transition metals
Hydrolysis
Carbon
Chemical activation
Nuclear magnetic resonance
Derivatives
Atoms
Temperature
Molecules
Kinetics
Substrates

Keywords

  • magnesium complexes
  • magnesiation
  • magnesiation rate

Cite this

Baillie, Sharon E. ; Blair, Victoria L. ; Bradley, Tyne D. ; Clegg, William ; Cowan, Jemma ; Harrington, Ross W. ; Hernan-Gomez, Alberto ; Kennedy, Alan R. ; Livingstone, Zoe ; Hevia, Eva. / Isomeric and chemical consequences of the direct magnesiation of 1,3-benzoazoles using β-diketiminate-stabilized magnesium bases. In: Chemical Science. 2013 ; Vol. 4, No. 4. pp. 1895-1905.
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abstract = "Opening-up new synthetic applications of beta-diketiminate stabilised magnesium complexes, this case study compares the ability of the alkyl [{Ar*NC(Me)CHC(Me)NAr*}Mg(Bu)(THF)] (1) and the amido reagent [{Ar*NC(Me)CHC(Me)NAr*}Mg(TMP)] (2) (Ar* = 2,6-i- Pr-2-C6H3) to promote direct Mg-H exchange towards the series of 1,3-benzoazoles: benzoxazole (boz), benzothiazole (btz) and N-methyl benzimidazole (blm(Me)). Both reagents deprotonate boz at room temperature to yield [{Ar*NC(Me)CHC(Me)NAr*} Mg{O(o-C6H4) NC}(THF)] (3) via the C-O bond cleavage of a putative C2-magnesiated-benzoxazolyl intermediate. Structurally tracking the reactivity of 1 and 2 towards less acidic btz and blm(Me) showed that the behaviour of reagents 1 and 2 diverged dramatically. Kinetically activated TMP-reagent 2 effectively promotes the deprotonative magnesiation of btz and blm(Me) under mild reaction conditions, giving the alpha-metallated intermediates [{Ar* NC(Me) CHC(Me)NAr*}(2)Mg-2{btz*}(2)] (4) and [{Ar*NC(Me)CHC(Me)NAr*}(2)Mg-2{blm(Me)*}(2)] (7) (btz* = 2-benzothiazolyl; blm(Me)* = 2-N-methylbenzimidazolyl). Analysis of crystallographic and NMR data revealed that in 4 and 7 the metallated carbon atoms display a markedly carbenic character and that in solution these species exist at room temperature solely as the ring-closed products, without any observable equilibration to the acyclic isomers. Contrastingly, alkyl reagent 1 decreases the magnesiation rate of btz facilitating an intriguing new cascade activation process of two molecules of substrate involving a sequence of deprotonation/coordination/C-C coupling and ring-opening reactions to yield [{Ar*NC(Me)CHC(Me)NAr*}Mg{(btz*)C(H)]=N(o-C6H4) S}] (5). Hydrolysis of 5 followed by addition of the radical oxidant TEMPO ultimately produces the homocoupled product bis(benzothiazole) 6 in a 72{\%} isolated yield. Thus, this establishes a novel transition-metal-free method to prepare homocoupled thiazoles. More straightforwardly, the coordination product [{Ar*NC(Me)CHC(Me)NAr*}Mg(Bu)(blm(Me))] (8) was obtained when equimolar amounts of blm(Me) and 1 were reacted, illustrating the kinetic stubbornness of the Mg-C bond in butyl derivative 1. Complex 8 can be envisaged as a valuable guide to the constitution of a premetallation complex (in relation to the complex-induced proximity effect, CIPE).",
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Baillie, SE, Blair, VL, Bradley, TD, Clegg, W, Cowan, J, Harrington, RW, Hernan-Gomez, A, Kennedy, AR, Livingstone, Z & Hevia, E 2013, 'Isomeric and chemical consequences of the direct magnesiation of 1,3-benzoazoles using β-diketiminate-stabilized magnesium bases' Chemical Science, vol. 4, no. 4, pp. 1895-1905. https://doi.org/10.1039/c3sc22326d

Isomeric and chemical consequences of the direct magnesiation of 1,3-benzoazoles using β-diketiminate-stabilized magnesium bases. / Baillie, Sharon E.; Blair, Victoria L.; Bradley, Tyne D.; Clegg, William; Cowan, Jemma; Harrington, Ross W.; Hernan-Gomez, Alberto; Kennedy, Alan R.; Livingstone, Zoe; Hevia, Eva.

In: Chemical Science, Vol. 4, No. 4, 2013, p. 1895-1905.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Isomeric and chemical consequences of the direct magnesiation of 1,3-benzoazoles using β-diketiminate-stabilized magnesium bases

AU - Baillie, Sharon E.

AU - Blair, Victoria L.

AU - Bradley, Tyne D.

AU - Clegg, William

AU - Cowan, Jemma

AU - Harrington, Ross W.

AU - Hernan-Gomez, Alberto

AU - Kennedy, Alan R.

AU - Livingstone, Zoe

AU - Hevia, Eva

PY - 2013

Y1 - 2013

N2 - Opening-up new synthetic applications of beta-diketiminate stabilised magnesium complexes, this case study compares the ability of the alkyl [{Ar*NC(Me)CHC(Me)NAr*}Mg(Bu)(THF)] (1) and the amido reagent [{Ar*NC(Me)CHC(Me)NAr*}Mg(TMP)] (2) (Ar* = 2,6-i- Pr-2-C6H3) to promote direct Mg-H exchange towards the series of 1,3-benzoazoles: benzoxazole (boz), benzothiazole (btz) and N-methyl benzimidazole (blm(Me)). Both reagents deprotonate boz at room temperature to yield [{Ar*NC(Me)CHC(Me)NAr*} Mg{O(o-C6H4) NC}(THF)] (3) via the C-O bond cleavage of a putative C2-magnesiated-benzoxazolyl intermediate. Structurally tracking the reactivity of 1 and 2 towards less acidic btz and blm(Me) showed that the behaviour of reagents 1 and 2 diverged dramatically. Kinetically activated TMP-reagent 2 effectively promotes the deprotonative magnesiation of btz and blm(Me) under mild reaction conditions, giving the alpha-metallated intermediates [{Ar* NC(Me) CHC(Me)NAr*}(2)Mg-2{btz*}(2)] (4) and [{Ar*NC(Me)CHC(Me)NAr*}(2)Mg-2{blm(Me)*}(2)] (7) (btz* = 2-benzothiazolyl; blm(Me)* = 2-N-methylbenzimidazolyl). Analysis of crystallographic and NMR data revealed that in 4 and 7 the metallated carbon atoms display a markedly carbenic character and that in solution these species exist at room temperature solely as the ring-closed products, without any observable equilibration to the acyclic isomers. Contrastingly, alkyl reagent 1 decreases the magnesiation rate of btz facilitating an intriguing new cascade activation process of two molecules of substrate involving a sequence of deprotonation/coordination/C-C coupling and ring-opening reactions to yield [{Ar*NC(Me)CHC(Me)NAr*}Mg{(btz*)C(H)]=N(o-C6H4) S}] (5). Hydrolysis of 5 followed by addition of the radical oxidant TEMPO ultimately produces the homocoupled product bis(benzothiazole) 6 in a 72% isolated yield. Thus, this establishes a novel transition-metal-free method to prepare homocoupled thiazoles. More straightforwardly, the coordination product [{Ar*NC(Me)CHC(Me)NAr*}Mg(Bu)(blm(Me))] (8) was obtained when equimolar amounts of blm(Me) and 1 were reacted, illustrating the kinetic stubbornness of the Mg-C bond in butyl derivative 1. Complex 8 can be envisaged as a valuable guide to the constitution of a premetallation complex (in relation to the complex-induced proximity effect, CIPE).

AB - Opening-up new synthetic applications of beta-diketiminate stabilised magnesium complexes, this case study compares the ability of the alkyl [{Ar*NC(Me)CHC(Me)NAr*}Mg(Bu)(THF)] (1) and the amido reagent [{Ar*NC(Me)CHC(Me)NAr*}Mg(TMP)] (2) (Ar* = 2,6-i- Pr-2-C6H3) to promote direct Mg-H exchange towards the series of 1,3-benzoazoles: benzoxazole (boz), benzothiazole (btz) and N-methyl benzimidazole (blm(Me)). Both reagents deprotonate boz at room temperature to yield [{Ar*NC(Me)CHC(Me)NAr*} Mg{O(o-C6H4) NC}(THF)] (3) via the C-O bond cleavage of a putative C2-magnesiated-benzoxazolyl intermediate. Structurally tracking the reactivity of 1 and 2 towards less acidic btz and blm(Me) showed that the behaviour of reagents 1 and 2 diverged dramatically. Kinetically activated TMP-reagent 2 effectively promotes the deprotonative magnesiation of btz and blm(Me) under mild reaction conditions, giving the alpha-metallated intermediates [{Ar* NC(Me) CHC(Me)NAr*}(2)Mg-2{btz*}(2)] (4) and [{Ar*NC(Me)CHC(Me)NAr*}(2)Mg-2{blm(Me)*}(2)] (7) (btz* = 2-benzothiazolyl; blm(Me)* = 2-N-methylbenzimidazolyl). Analysis of crystallographic and NMR data revealed that in 4 and 7 the metallated carbon atoms display a markedly carbenic character and that in solution these species exist at room temperature solely as the ring-closed products, without any observable equilibration to the acyclic isomers. Contrastingly, alkyl reagent 1 decreases the magnesiation rate of btz facilitating an intriguing new cascade activation process of two molecules of substrate involving a sequence of deprotonation/coordination/C-C coupling and ring-opening reactions to yield [{Ar*NC(Me)CHC(Me)NAr*}Mg{(btz*)C(H)]=N(o-C6H4) S}] (5). Hydrolysis of 5 followed by addition of the radical oxidant TEMPO ultimately produces the homocoupled product bis(benzothiazole) 6 in a 72% isolated yield. Thus, this establishes a novel transition-metal-free method to prepare homocoupled thiazoles. More straightforwardly, the coordination product [{Ar*NC(Me)CHC(Me)NAr*}Mg(Bu)(blm(Me))] (8) was obtained when equimolar amounts of blm(Me) and 1 were reacted, illustrating the kinetic stubbornness of the Mg-C bond in butyl derivative 1. Complex 8 can be envisaged as a valuable guide to the constitution of a premetallation complex (in relation to the complex-induced proximity effect, CIPE).

KW - magnesium complexes

KW - magnesiation

KW - magnesiation rate

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