Structurally engineered deprotonation/alumination of THF and THTP with retention of their cycloanionic structures

Elaine Crosbie, Pablo Garcia-Alvarez, Alan R. Kennedy, Jan Klett, Robert E. Mulvey, Stuart D. Robertson

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Metalation has served well for over 80 years as a vehicle for transforming inert C[BOND]H bonds in organic compounds to reactive C[BOND]metal bonds.1 Progress in metalation was accelerated greatly by the development of DoM (directed ortho-metalation),2 pioneered by Snieckus, Beak, and others, a special type of lithiation (aromatic C[BOND]H to Cδ−[BOND]Liδ+) reliant on the high polarity of carbon–lithium bonds in organolithium reagents. Many other metals could not engage in metalation due to the lower polarity/lower reactivity of their corresponding carbon–metal bonds. However, this obstacle has now been cleared by the recognition that when part of a mixed-metal system or other multicomponent mixture, these metals (for example, magnesium, zinc, aluminum or manganese) can exhibit greatly enhanced metalating properties often superior in terms of functional-group compatibility or reaction conditions to that of lithium. Interest in these new “low polarity” metalating agents is widespread with coverage in fundamental chemistry journals,3 process chemistry journals,4 interdisciplinary science journals,5 and in news items in scientific media.6 Knochel’s turbo-Grignard reagents (e.g., (iPr)MgCl⋅LiCl) 7 are examples that have been commercialized. A spectacular demonstration of the special reactivity of bimetallic bases came with the α-zincation of tetrahydrofuran (THF) by the sodium dialkyl(amido)zincate [(TMEDA)Na(μ-TMP)(μ-CH2SiMe3)Zn(CH2SiMe3)] (TMEDA=N,N,N′,N′-tetramethylethylenediamine; TMP=2,2,6,6-tetramethylpiperidine) to produce [(TMEDA)Na(μ-TMP)(μ-OC4H7)Zn(CH2SiMe3)].5 Conventional metalation of THF invariably initiates decomposition by ring opening,8 but in this low-polarity zincation the 5-atom ring of the sensitive α-deprotonated THF anion remains intact. However, this reaction is extremely slow (best yield was 52.7 % after 2 weeks) and requires a massive stoichiometric excess of the cyclic ether (i.e., carried out in neat THF solvent). Here we report a vastly superior methodology to the cyclic THF α-anion, mediated by a lithium aluminate base with a higher amido content than the alkyl-rich zincate reagent. An analogous reaction with the sulfur analogue, tetrahydrothiophene (THTP), is also reported.
LanguageEnglish
Pages9388-9391
Number of pages4
JournalAngewandte Chemie International Edition
Volume49
Issue number49
Early online date26 Oct 2010
DOIs
Publication statusPublished - 2010

Fingerprint

Deprotonation
Thymidine Monophosphate
Metals
Lithium
Anions
Carbon
Cyclic Ethers
Beak
Manganese
Aluminum
Organic compounds
Sulfur
Magnesium
Functional groups
Zinc
Demonstrations
Sodium
tetrahydrothiophene
tetrahydrofuran
Decomposition

Keywords

  • deprotonation
  • ether cleavage
  • lithium
  • organoaluminates
  • thiophenes
  • directed ortho-metalation
  • polysubstituted aromatics
  • reactivity
  • anions
  • amide

Cite this

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title = "Structurally engineered deprotonation/alumination of THF and THTP with retention of their cycloanionic structures",
abstract = "Metalation has served well for over 80 years as a vehicle for transforming inert C[BOND]H bonds in organic compounds to reactive C[BOND]metal bonds.1 Progress in metalation was accelerated greatly by the development of DoM (directed ortho-metalation),2 pioneered by Snieckus, Beak, and others, a special type of lithiation (aromatic C[BOND]H to Cδ−[BOND]Liδ+) reliant on the high polarity of carbon–lithium bonds in organolithium reagents. Many other metals could not engage in metalation due to the lower polarity/lower reactivity of their corresponding carbon–metal bonds. However, this obstacle has now been cleared by the recognition that when part of a mixed-metal system or other multicomponent mixture, these metals (for example, magnesium, zinc, aluminum or manganese) can exhibit greatly enhanced metalating properties often superior in terms of functional-group compatibility or reaction conditions to that of lithium. Interest in these new “low polarity” metalating agents is widespread with coverage in fundamental chemistry journals,3 process chemistry journals,4 interdisciplinary science journals,5 and in news items in scientific media.6 Knochel’s turbo-Grignard reagents (e.g., (iPr)MgCl⋅LiCl) 7 are examples that have been commercialized. A spectacular demonstration of the special reactivity of bimetallic bases came with the α-zincation of tetrahydrofuran (THF) by the sodium dialkyl(amido)zincate [(TMEDA)Na(μ-TMP)(μ-CH2SiMe3)Zn(CH2SiMe3)] (TMEDA=N,N,N′,N′-tetramethylethylenediamine; TMP=2,2,6,6-tetramethylpiperidine) to produce [(TMEDA)Na(μ-TMP)(μ-OC4H7)Zn(CH2SiMe3)].5 Conventional metalation of THF invariably initiates decomposition by ring opening,8 but in this low-polarity zincation the 5-atom ring of the sensitive α-deprotonated THF anion remains intact. However, this reaction is extremely slow (best yield was 52.7 {\%} after 2 weeks) and requires a massive stoichiometric excess of the cyclic ether (i.e., carried out in neat THF solvent). Here we report a vastly superior methodology to the cyclic THF α-anion, mediated by a lithium aluminate base with a higher amido content than the alkyl-rich zincate reagent. An analogous reaction with the sulfur analogue, tetrahydrothiophene (THTP), is also reported.",
keywords = "deprotonation, ether cleavage, lithium, organoaluminates, thiophenes, directed ortho-metalation, polysubstituted aromatics, reactivity, anions, amide",
author = "Elaine Crosbie and Pablo Garcia-Alvarez and Kennedy, {Alan R.} and Jan Klett and Mulvey, {Robert E.} and Robertson, {Stuart D.}",
year = "2010",
doi = "10.1002/anie.201005119",
language = "English",
volume = "49",
pages = "9388--9391",
journal = "Angewandte Chemie International Edition",
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Structurally engineered deprotonation/alumination of THF and THTP with retention of their cycloanionic structures. / Crosbie, Elaine; Garcia-Alvarez, Pablo; Kennedy, Alan R.; Klett, Jan; Mulvey, Robert E.; Robertson, Stuart D.

In: Angewandte Chemie International Edition , Vol. 49, No. 49, 2010, p. 9388-9391.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structurally engineered deprotonation/alumination of THF and THTP with retention of their cycloanionic structures

AU - Crosbie, Elaine

AU - Garcia-Alvarez, Pablo

AU - Kennedy, Alan R.

AU - Klett, Jan

AU - Mulvey, Robert E.

AU - Robertson, Stuart D.

PY - 2010

Y1 - 2010

N2 - Metalation has served well for over 80 years as a vehicle for transforming inert C[BOND]H bonds in organic compounds to reactive C[BOND]metal bonds.1 Progress in metalation was accelerated greatly by the development of DoM (directed ortho-metalation),2 pioneered by Snieckus, Beak, and others, a special type of lithiation (aromatic C[BOND]H to Cδ−[BOND]Liδ+) reliant on the high polarity of carbon–lithium bonds in organolithium reagents. Many other metals could not engage in metalation due to the lower polarity/lower reactivity of their corresponding carbon–metal bonds. However, this obstacle has now been cleared by the recognition that when part of a mixed-metal system or other multicomponent mixture, these metals (for example, magnesium, zinc, aluminum or manganese) can exhibit greatly enhanced metalating properties often superior in terms of functional-group compatibility or reaction conditions to that of lithium. Interest in these new “low polarity” metalating agents is widespread with coverage in fundamental chemistry journals,3 process chemistry journals,4 interdisciplinary science journals,5 and in news items in scientific media.6 Knochel’s turbo-Grignard reagents (e.g., (iPr)MgCl⋅LiCl) 7 are examples that have been commercialized. A spectacular demonstration of the special reactivity of bimetallic bases came with the α-zincation of tetrahydrofuran (THF) by the sodium dialkyl(amido)zincate [(TMEDA)Na(μ-TMP)(μ-CH2SiMe3)Zn(CH2SiMe3)] (TMEDA=N,N,N′,N′-tetramethylethylenediamine; TMP=2,2,6,6-tetramethylpiperidine) to produce [(TMEDA)Na(μ-TMP)(μ-OC4H7)Zn(CH2SiMe3)].5 Conventional metalation of THF invariably initiates decomposition by ring opening,8 but in this low-polarity zincation the 5-atom ring of the sensitive α-deprotonated THF anion remains intact. However, this reaction is extremely slow (best yield was 52.7 % after 2 weeks) and requires a massive stoichiometric excess of the cyclic ether (i.e., carried out in neat THF solvent). Here we report a vastly superior methodology to the cyclic THF α-anion, mediated by a lithium aluminate base with a higher amido content than the alkyl-rich zincate reagent. An analogous reaction with the sulfur analogue, tetrahydrothiophene (THTP), is also reported.

AB - Metalation has served well for over 80 years as a vehicle for transforming inert C[BOND]H bonds in organic compounds to reactive C[BOND]metal bonds.1 Progress in metalation was accelerated greatly by the development of DoM (directed ortho-metalation),2 pioneered by Snieckus, Beak, and others, a special type of lithiation (aromatic C[BOND]H to Cδ−[BOND]Liδ+) reliant on the high polarity of carbon–lithium bonds in organolithium reagents. Many other metals could not engage in metalation due to the lower polarity/lower reactivity of their corresponding carbon–metal bonds. However, this obstacle has now been cleared by the recognition that when part of a mixed-metal system or other multicomponent mixture, these metals (for example, magnesium, zinc, aluminum or manganese) can exhibit greatly enhanced metalating properties often superior in terms of functional-group compatibility or reaction conditions to that of lithium. Interest in these new “low polarity” metalating agents is widespread with coverage in fundamental chemistry journals,3 process chemistry journals,4 interdisciplinary science journals,5 and in news items in scientific media.6 Knochel’s turbo-Grignard reagents (e.g., (iPr)MgCl⋅LiCl) 7 are examples that have been commercialized. A spectacular demonstration of the special reactivity of bimetallic bases came with the α-zincation of tetrahydrofuran (THF) by the sodium dialkyl(amido)zincate [(TMEDA)Na(μ-TMP)(μ-CH2SiMe3)Zn(CH2SiMe3)] (TMEDA=N,N,N′,N′-tetramethylethylenediamine; TMP=2,2,6,6-tetramethylpiperidine) to produce [(TMEDA)Na(μ-TMP)(μ-OC4H7)Zn(CH2SiMe3)].5 Conventional metalation of THF invariably initiates decomposition by ring opening,8 but in this low-polarity zincation the 5-atom ring of the sensitive α-deprotonated THF anion remains intact. However, this reaction is extremely slow (best yield was 52.7 % after 2 weeks) and requires a massive stoichiometric excess of the cyclic ether (i.e., carried out in neat THF solvent). Here we report a vastly superior methodology to the cyclic THF α-anion, mediated by a lithium aluminate base with a higher amido content than the alkyl-rich zincate reagent. An analogous reaction with the sulfur analogue, tetrahydrothiophene (THTP), is also reported.

KW - deprotonation

KW - ether cleavage

KW - lithium

KW - organoaluminates

KW - thiophenes

KW - directed ortho-metalation

KW - polysubstituted aromatics

KW - reactivity

KW - anions

KW - amide

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U2 - 10.1002/anie.201005119

DO - 10.1002/anie.201005119

M3 - Article

VL - 49

SP - 9388

EP - 9391

JO - Angewandte Chemie International Edition

T2 - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

SN - 1433-7851

IS - 49

ER -