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The Preparation of Organolithium Reagents and Intermediates

Organolithium Compounds (2004)

  1. Frédéric Leroux1,
  2. Manfred Schlosser2,
  3. Elinor Zohar3,
  4. Ilan Marek3

Published Online: 15 DEC 2009

DOI: 10.1002/9780470682531.pat0305

Patai's Chemistry of Functional Groups

Patai's Chemistry of Functional Groups

How to Cite

Leroux, F., Schlosser, M., Zohar, E. and Marek, I. 2009. The Preparation of Organolithium Reagents and Intermediates. Patai's Chemistry of Functional Groups. .

Author Information

  1. 1

    Université Louis Pasteur (ECPM), Laboratoire de stéréochimie, Strasbourg, France

  2. 2

    Swiss Federal Institute of Technology, Institute of Molecular and Biological Chemistry, Lausanne, Switzerland

  3. 3

    Technion—Israel Institute of Technology, Department of Chemistry and Institute of Catalysis, Science and Technology, Haifa, Israel

Publication History

  1. Published Online: 15 DEC 2009

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Abstract

  1. Top of page
  2. Introduction
  3. Reductive Metal Insertion into Carbon–Halogen Bonds
  4. Permutational Halogen/Metal Interconversions
  5. Permutational Hydrogen/Metal Interconversions (‘Metalations’)
  6. The Brook Isomerization
  7. The Shapiro Reaction
  8. The Sulfoxide/Lithium Displacement
  9. Acknowledgments
  10. References
  • 1
    Introduction
  • 2
    Reductive Metal Insertion into Carbon–Halogen Bonds
  • 3
    Permutational Halogen/Metal Interconversions
  • 4
    Permutational Hydrogen/Metal Interconversions (‘Metalations’)
  • 5
    The Brook Isomerization
  • 6
    The Shapiro Reaction
  • 7
    The Sulfoxide/Lithium Displacement
  • 8
    Acknowledgments

1 Introduction

  1. Top of page
  2. Introduction
  3. Reductive Metal Insertion into Carbon–Halogen Bonds
  4. Permutational Halogen/Metal Interconversions
  5. Permutational Hydrogen/Metal Interconversions (‘Metalations’)
  6. The Brook Isomerization
  7. The Shapiro Reaction
  8. The Sulfoxide/Lithium Displacement
  9. Acknowledgments
  10. References

To attach a metal to an organic entity, one has to displace an already present substituent Z (Table 1)1a. Five classes of leaving groups may be considered: halogens (X = Cl, Br, I), chalcogens (Y = O, S, Se, Te), metalloids (Q = Hg, Sn), carbon (in particular triarylmethyl units) and hydrogen. The source of the metal can be either the element (M) itself or a metal derivative (M[BOND]R), in general a commercial organometallic reagent or a metal salt. In the first case, the metal undergoes a reductive insertion into the C[BOND]Z (C[BOND]X, X[BOND]Y, C[BOND]Q, C[BOND]C or C[BOND]H) bond and the displaced substituent Z is expelled as a nucleofugal group. Alternatively, a permutational interconversion may be performed whereby the displaced substituent Z is transferred as an electrofugal group to the organic part (R) of the reagent.

original image
Table 1. A Survey of the Standard Methods Applied to the Preparation of Organometallic Compounds: Three Crosses Mean ‘Generally Applicable’, Two ‘Restricted, Though Important Scope of Applicability’ and One ‘Narrow Scope’
Reductive insertionZ (leaving group)Permutational interconversion
inline image inline image inline imageX (halogen) inline image inline image inline image
inline image inline imageY (chalcogen) inline image
inline image inline imageQ (metalloid) inline image inline image
inline imageC (carbon) inline image
inline imageH (hydrogen) inline image inline image inline image

What makes the permutation approach so attractive is the ease of execution and the mild reaction conditions. A possible drawback is its moderate exothermicity which may prevent the interconversion to go to completion but rather to stop as soon as an equilibrium composition is attained. Moreover, to rely on an organometallic exchange reagent merely defers the problem. Ultimately, the genesis of any organometallic compound can be traced back to the elemental metal.

For reasons of space only the most important methods for the generation of organometallic reagents and intermediates can be covered in this Chapter. This holds for the reductive insertion of lithium into organic halides (Section 2), the permutational interconversion of organic halides with organolithiums (Section 3) and the permutational interconversion of hydrocarbons with organolithiums (‘metalation’, Section 4). In addition, three special methods will be featured, the Brook isomerization (Section 5), the Shapiro reaction (Section 6) and the sulfoxide/alkyllithium interconversion (Section 7). These topics have been neglected for a long while, but begin to find now the attention they deserve because of their unexploited potential. Readers who seek information about other prominent methods such as the reductive ether cleavage1b or the selenium/lithium1c and tin/lithium1d permutations are referred to a recently edited Handbook1.

2 Reductive Metal Insertion into Carbon–Halogen Bonds

  1. Top of page
  2. Introduction
  3. Reductive Metal Insertion into Carbon–Halogen Bonds
  4. Permutational Halogen/Metal Interconversions
  5. Permutational Hydrogen/Metal Interconversions (‘Metalations’)
  6. The Brook Isomerization
  7. The Shapiro Reaction
  8. The Sulfoxide/Lithium Displacement
  9. Acknowledgments
  10. References

Standard reagents such as methyllithium, ethyllithium, butyllithium, hexyllithium, isopropyllithium, sec-butyllithium, tert-butyllithium and phenyllithium are nowadays commercially available, even in various solvents and concentrations2. However, in general it is less expensive to make such reagents themselves rather than to purchase them. References to the preparation of primary alkyllithiums (Table 2), secondary or tertiary alkyllithiums (Table 3), 1-alkenyllithiums (Table 4) and aryllithiums without or with hetero-substituents (Tables 5 and 6) have been compiled below.

Table 2. Primary Alkyllithiums Li[BOND]R (Including Neopentylic Ones) by Metal Insertion into Halides R[BOND]X: Yields as Determined by Titration1e or after Trapping with an Electrophile El[BOND]X′
Li[BOND]RXSνaProductEl[BOND]X′Reference
  1. a

    Solvent Sν: PET = petroleum ether (pentanes, hexanes, heptanes), DEE = diethyl ether, THF = tetrahydrofuran.

  2. b

    Various electrophiles.

Li[BOND]CH3Cl, Br, IDEEca 80%titration 3, 4
Li[BOND]C2H5Cl, BrPET50%titration 5-9
Li[BOND]C3H7ClPETca 80%titration 5, 10
Li[BOND]C4H9Cl, BrPETca 95% b 11, 12
Li[BOND]C6H13ClDEE≥90%titration 13
Li[BOND]C8H17ClTHF94%H2O 14
Li[BOND]C12H25ClDEE77%titration 15, 16
Li[BOND]CH2C(CH3)3ClPET; DEE71%[(H3C)2CH]2CO 17, 18
Li[BOND]CH2Si(CH3)3ClPET; DEE90%isol. by sublim. 19
Table 3. Secondary and Tertiary Alkyllithiums Li[BOND]R: Yields of Trapping Products as a Function of the Precursor Halide X and the Electrophile El[BOND]X′ Used
Li[BOND]RXSνaProductEl[BOND]X′Reference
  1. a

    Solvent Sν : PET = petroleum ether (pentanes, hexanes, heptanes), DEE = diethyl ether.

  2. b

    inline image

  3. c

    inline image

  4. d

    inline image

  5. e

    inline image

Li[BOND]CH(CH3)2BrPET45%titration 5
Li[BOND]CH(CH3)C2H5ClPET50%titration 20
Li[BOND]C(CH3)3ClPET62%CO2 21
   89%titration 22-24
Li[BOND]CH(CH2)2bBrDEE88%SnCl4 25
Li[BOND]CH(CH2)5cClDEE70%GeCl4 26
Li[BOND]C7H11dClPET51%CO2 27
Li[BOND]C10H15eClPET82%D2O 28
Table 4. 1-Alkenyllithiums Li[BOND]R: Yields of Trapping Products as a Function of the Precursor Halide X and the Electrophile El[BOND]X′ (Common Temperature Range: +25 °C to +50 °C)
Li[BOND]RXSνaProductEl[BOND]X′Reference
  1. a

    Solvent Sν: DEE = diethyl ether, THF = tetrahydrofuran.

  2. b

    Various electrophiles El[BOND]X′.

Li[BOND]CH[DOUBLE BOND]CH2ClTHF70–80% b 23, 29, 30
Li[BOND]CH[DOUBLE BOND]C(CH3)2BrDEE30%H5C6CHO 31, 32
inline imageBrDEE75%H3CCOOC2H5 33
inline imageClDEE40%H5C6CHO 31, 32
Table 5. Aryllithiums Li[BOND]R Lacking Hetero-Substituents by Metal Insertion into Haloarenes, the Reactions Being Generally Conducted in Diethyl Ether and in the Temperature Range of 0 °C to +40 °C (Refluxing Ether)
Li[BOND]RXaProductEl[BOND]X′bReference
  1. a

    X = Halogen in the starting material, being displaced by metal.

  2. b

    The concentration of the organometallic solution prepared was determined either by the titration1e of an aliquot or by isolation of the product formed upon the trapping of an aliquot using an electrophilic reagent El[BOND]X′.

  3. c

    In diethyl ether or tetrahydrofuran.

inline imageCl, Brcca 85%CO2 34-38
inline imageBr93%Titration 39
inline imageBr86%Titration 39
inline imageBr95%Titration 34-37, 39
inline imageI50% inline image 40
inline imageBr, Ica 75%CO2 41, 42
inline imageBr72%Titration 41
inline imageBr87%Titration 41, 43
inline imageBr75%Titration 44
inline imageBr85%CO2 45, 46
Br44%Titration 
inline imageBr80%Titration 39
inline imageBr81%SiCl4 39, 47
Table 6. Aryllithiums Li[BOND]R Carrying Amino and Alkoxy Substituents Prepared in Diethyl Ether by Metal Insertion into the Corresponding Bromoarene
Li[BOND]RProductEl[BOND]X′aReference
  1. a

    El[BOND]X′ = electrophilic trapping reagent.

  2. b

    inline image; then oxidation with CrO3.

inline image0%(H5C6)3PbCl 48
inline image58%(H5C6)3SiCl 49, 50
inline image65%CO2 22, 51
inline image22%R′COOC2H5b 52
inline image85%titration 53
inline image66%titration 53

Whenever possible, alkyllithiums should be prepared from chloroalkanes in paraffinic media for reasons of economy. As a 1930 landmark study has revealed, both bromoalkanes and iodoalkanes react rapidly with butyllithium in benzene and extremely rapidly in diethyl ether (Table 7) producing butane, 1-butene, 2-butene, octane and possibly also methylcyclopropane.

Table 7. Butyllithium in the Presence of Butyl Chloride, Bromide and Iodide (0.50 M Initial Concentrations): Half-Lives τ1/2 (in Hours) as a Function of the Solvent Benzene (BNZ) or Diethyl Ether (DEE) at Ambient Temperature54
H9C4[BOND]X + LiC4H9inline image (in hours)inline image (in hours)
X = I3<0.1
X = Br40 0.5
X = Cl>10040

When the halogen in the precursor is exceptionally mobile as an anion, even chloro compounds may give poor yields due to extensive self-destruction. For example, chloromethyl methyl ether can be expediently converted into methoxymethyllithium only if sodium/lithium alloy is used and a carefully elaborated protocol is meticulously followed55. In the case of 7-chloronorbornadiene, the lithium/4,4′-di-tert-butylbiphenyl ‘radical anion’ has to be employed56, 57 to further reduce the contact time between 7-norbornadienyllithium and its labile precursor. Many reductive metal insertions into carbon–halogen bonds require the presence of electron carriers such as 4,4′-di-tert-butylbiphenyl, naphthalene or anthracene. The in situ generation of ‘radical anions’ from sub-stoichiometric amounts of suitable arenes is highlighted in Chapter Arene-Catalyzed Lithiation.

3 Permutational Halogen/Metal Interconversions

  1. Top of page
  2. Introduction
  3. Reductive Metal Insertion into Carbon–Halogen Bonds
  4. Permutational Halogen/Metal Interconversions
  5. Permutational Hydrogen/Metal Interconversions (‘Metalations’)
  6. The Brook Isomerization
  7. The Shapiro Reaction
  8. The Sulfoxide/Lithium Displacement
  9. Acknowledgments
  10. References

When treated with butyllithium in diethyl ether at −50 °C, bromobenzene undergoes the permutational exchange of the halogen against the metal only slowly, but rapidly at 0 °C. The transformation is complete after a few seconds if conducted in tetrahydrofuran at −75 °C. Iodobenzene reacts instantaneously in any case.

In contrast to the bromo and iodo analogs, organic chloro compounds are relatively inert toward organolithium reagents. There are only a few classes of chlorinated substrates, notably gem-dichlorocyclopropanes58, 1,1-dichloro-1-alkenes59, 60 and doubly vicinal oligochlorobenzenes (1,2,3-trichlorobenzene61, 62, 1,2,3,4-tetrachlorobenzene61, 62, hexachlorobenzene63 etc.) that are capable of sustaining the halogen/lithium permutation mode.

How well an organolithium reagent fares as an exchange component depends on its basicity. Thus, tert-butyllithium outperforms sec-butyllithium, which in turn is superior to butyllithium. Methyllithium is the least reactive alkyllithium but still surpasses phenyllithium, at least at low concentrations, i.e. the order is:

mathml alt image

To make neopentyllithium or any other alkyllithium from the corresponding iodoalkane, tert-butyllithium is the best, if not the only choice (Tables 8 and 9). Besides its reactivity, it offers another distinct advantage. It reacts with its own exchange products, 2-bromo-2-methylpropane (tert-butyl bromide) or 2-iodo-2-methylpropane (tert-butyl iodide) rapidly, even at −75 °C, with elimination of lithium halide. In this way, any equilibrium can be rigorously and irreversibly shifted to one side. This explains why tert-butyllithium can be used to generate 1-adamantyllithium 2, equally a tertiary alkyllithium, from 1-iodoadamantane 1 (equation 1)76.

original image(1)
Table 8. Primary Aliphatic Organolithiums Li[BOND]R by Halogen/Metal Permutation between Haloalkanes X[BOND]R and tert-Butyllithium in Diethyl Ether at −75 °C
Li[BOND]RXaProductEl[BOND]X′bReference
  1. a

    X = halogen displaced by the metal.

  2. b

    El[BOND]X′ = electrophilic trapping reagent.

  3. c

    Using butyllithium rather than tert-butyllithium.

  4. d

    C10H15 = 2-adamantyl.

  5. e

    At −45 °C rather than −75 °C.

Li[BOND]CH3cBr64%titration 64-66
Li[BOND]C4H9I91%H9C4CH[DOUBLE BOND]O 67
Li[BOND]C8H17I93%H3CCOCH3 67
Li[BOND]C10H15d, eI66%CO2 68
inline imageI91%CO2 67
Li[BOND](CH2)2C6H5I91%CO2 67-69
Li[BOND]CH2C(CH3)3I89%H7C3CH[DOUBLE BOND]O 67
Li[BOND](CH2)2CH[DOUBLE BOND]CH2I88%ClSn(CH3)3 69
Li[BOND](CH2)3CH[DOUBLE BOND]CH2I87%CO2 70
Li[BOND](CH2)2C[TRIPLE BOND]C[BOND]C4H9I80%ClSn(CH3)3 69
Li[BOND](CH2)4C[TRIPLE BOND]C[BOND]C6H5I87%D2O 71
Table 9. Cyclopropyl- and Other Cycloalkyllithiums Li[BOND]R by Halogen/Metal Permutation between Haloalkanes X[BOND]R and Reagents Li[BOND]R′ in Diethyl Ether (DEE)
Li[BOND]RLi[BOND]R′XaTbProductEl[BOND]X′cReference
  1. a

    X = halogen which is displaced by the metal.

  2. b

    Exchange and trapping temperature.

  3. c

    El[BOND]X′ = electrophilic trapping reagent.

  4. d

    In tetrahydrofuran (THF) rather than DEE.

inline image dLiCH(CH3)3Br−75 °C91%(H5C6)2CO 72, 73
inline imageLiCH(CH3)2Br

0 °C

15%CO2 74
inline imageLiC(CH3)3I−60 °C60–90%H5C6CHO 75
inline imageLiC(CH3)3I−70 °C60–90%H5C6CHO 75
inline imageLiC(CH3)3I−70 °Cca 70%H5C6CHO 76
inline imageLiC4H9Br+25 °C41%CO2 77, 78

Alkoxy groups or halogen atoms at the α- or β-position of open-chain or cyclic alkyllithiums diminish the basicity of such species and hence facilitate the halogen/metal permutation. Other than tert-butyllithium, also sec-butyllithium or butyllithium, even methyllithium, or phenyllithium, can now be employed (Tables 10 and 11).

Table 10. α-Fluoro-, α-Chloro-, α-Bromo- and α-Iodoalkyllithiums Li[BOND]R by Halogen/Metal Permutation Using Organometallic Reagents Li[BOND]R′
Li[BOND]RLi[BOND]R′XaTProductEl[BOND]X′bReference
  1. a

    X = halogen being displaced.

  2. b

    El[BOND]X′ = electrophilic trapping reagent.

  3. c

    Halogen/metal exchange performed in the presence (in situ) of the electrophile.

  4. d

    The isolated product emanated from a subsequent reaction.

  5. e

    Detected by NMR.

  6. f

    Diethyl ether (DEE) rather than THF as the solvent.

  7. g

    Or butyllithium.

Li[BOND]CH2CLiC4H9I−75 °C88%H5C6CHOc 79-82
Li[BOND]CH2ILiC4H9I−75 °C89% inline image d 83
Li[BOND]CH(CH3)ClLiCH(CH3)C2H5Br−115 °C63%H5C6CHO 84
Li[BOND]CH(CH3)BrLiCH(CH3)C2H5Br−115 °C59%H5C6CHO 84
Li[BOND]C(CH3)2BrLiCH(CH3)C2H5Br−115 °C41%H5C6CHO 84
Li[BOND]C(C6H5)2ClLiC4H9Cl−100 °C75%CO2 85
Li[BOND]CBr2CH3LiC4H9Br−100 °C e 60
Li[BOND]C2F5LiCH3c, fI−75 °C88%H5C2CHO 86
Li[BOND]C3F7LiCH3c, fI−40 °C54%(H5C6)2CO 87, 88
Li[BOND]C7F15LiC4H9cI−90 °C38%CO2 89
Li[BOND]CF(CF3)2LiCH3c, fI−75 °C53%H5C6CHO 90
Li[BOND]CCI3LiC4H9Cl−100 °C76%CO2 85, 91
Li[BOND]CBr3LiC6H5gBr−110 °C91%CO2 60, 92
Table 11. α- or β-Alkoxy- and α-Halocyclopropyllithiums Li[BOND]R by Halogen/Metal Permutation between Bromocyclopropanes and Organolithium Reagents Li[BOND]R′ Followed by Trapping with Electrophiles El[BOND]X′
Li[BOND]RLi[BOND]R′SνaTProductEl[BOND]X′bReference
  1. a

    Solvent (Sν): DEE = diethyl ether, THF = tetrahydrofuran.

  2. b

    El[BOND]X′ = electrophilic trapping reagent.

  3. c

    Product isolated after subsequent transformation.

  4. d

    7,7-Diiodonorcarane as the starting material.

  5. e

    Detected by NMR.

  6. f

    Bn = CH2C6H5.

inline imageLiC(CH3)3DEE−75 °C92% inline image 93
inline imageLiC(CH3)3DEE−75 °C85%H13C6CHO 93
inline imageLiC(CH3)3DEE−75 °C81% inline image c 94
inline imageLiC4H9THF−135 °C9%H2O 95
inline imageLiC4H9THF−110 °C64%Br2 58, 95
inline imageLiC4H9THF−100 °C39% inline image 96-99
inline image dLiC4H9THF−80 °C e 92
inline imageLiC4H9THF−100 °C70%(H3C)2CO 100
inline imageLiC4H9THF−100 °C60%(H3C)2CO 100, 101
inline imageLiC4H9THF−100 °C80%H9C4CHO 100
inline image fLiC4H9DEE−95 °C83%HOC2H5 102-104
inline imageLiCH3DEE−80 °C88%CO2 105
inline imageLiCH3DEE−80 °C65%CO2 105

Being less basic than the saturated analogs, vinyllithium as all other acyclic or cyclic 1-alkenyllithiums can be prepared from iodo or bromo and sometimes even chloro precursors using butyllithium or tert-butyllithium (Tables 12 and 13). Hetero-substituents such as dialkylamino, alkoxy and silyloxy groups or halogen atoms again accelerate the exchange process considerably (Table 14). This holds for O-lithiated hydroxy or carboxy functions as well (Table 15).

Table 12. 1-Alkenyllithiums Li[BOND]R by Halogen/Metal Permutation
Li[BOND]RXaLi[BOND]R′SνbTProductEl[BOND]X′cReference
  1. a

    X = halogen displaced by the metal.

  2. b

    Solvent (Sν): PET = petroleum ether (pentanes, hexanes, heptanes), DEE = diethyl ether, THF = tetrahydrofuran.

  3. c

    El[BOND]X′ = electrophilic trapping reagent.

  4. d

    Or LiC(CH3)3.

  5. e

    Or LiC2H5.

inline imageBrLiC(CH3)3THF−115 °C74%(SC6H5)2 106, 107
inline imageILiC(CH3)3PET+25 °C71%H5C6CHO 106, 107
inline imageILiC4H9dPET+25 °C71%H5C6CHO 106, 108
inline imageILiC4H9eDEE−50 °C91%H3CCHO 109
inline imageILiC(CH3)3PET+25 °C74%H5C6CHO 110
inline imageILiC(CH3)3PET+25 °C77%H5C6CHO 110
inline imageBrLiC(CH3)3DEE−80 °C24%c-(H2C)5CO 111
inline imageILiC4H9eDEE−50 °C91%(H5C2)2CO 109
Table 13. 1-Cycloalkenyllithium Compounds Li[BOND]R by Halogen/Metal Permutation
Li[BOND]RXaLi[BOND]R′SνbTProductEl[BOND]X′cReference
  1. a

    X = halogen displaced by the metal.

  2. b

    Solvent (Sν): DEE = diethyl ether, THF = tetrahydrofuran.

  3. c

    El[BOND]X′ = electrophilic trapping reagent.

  4. d

    Prepared in situ from trihalocyclopropanes.

  5. e

    Bis(trimethylsilyl)peroxide.

  6. f

    59% with CO2.

 CldLiCH3DEE+25 °C72%CO2 112
inline imageBrdLiCH3DEE+25 °C78%CO2 113
inline imageBrLiC(CH3)3THF−75 °C73%I2 106
inline imageBrLiC(CH3)3THF−75 °C52% e 106
inline imageBrLiC(CH3)3THF−75 °C93%ClSi(CH3)3 106
inline imageBrLiC(CH3)3THF−75 °C83%(SCH3)2 114
inline imageBrLiC4H9THF−60 °C7%fFClO3 115, 116
Table 14. Hetero (β-Amino, β- or γ-Alkoxy, β- or γ-Silyloxy, α- or β-Halo) Substituted 1-Alkenyllithiums Li[BOND]R by Halogen/Metal Permutation
Li[BOND]RXaLi[BOND]R′bSνcTProductEl[BOND]X′dReference
  1. a

    X = halogen in the precursor.

  2. b

    Exchange reagent Li[BOND]R′: LIT = LiC(CH3)3, LIC = LiC4H9, LIM = LiCH3.

  3. c

    Solvent (Sν): PET = petroleum ether; DEE = diethyl ether, THF = tetrahydrofuran.

  4. d

    El[BOND]X′ = electrophilic trapping reagent.

  5. e

    NQ2 = 2, 2, 5, 5-tetramethyl-1-aza-2,5-disilolanyl.

  6. f

    SiR″2R″′ = Si(CH3)2C(CH3)3.

  7. g

    Not specified.

  8. h

    R″′ = cis-CH2[BOND]CH = CH[BOND](CH2)3[BOND]COOCH3.

  9. i

    (H2C)5CO = Cyclohexanone; product isolated after acid hydrolysis as an α,β-unsaturated carbonyl compound.

inline image eBrLITDEE−80 °C82%H5C6NCO 117
inline imageBrLITTHF−70 °C100%(H3C)2NCHO 118, 119
inline imageBrLICTHF−75 °C75%H5C6CHO 120-122
inline imageBrLICTHF−75 °C75%(H5C6)2CO 121
inline imageBrLICTHF−75 °C67%(H3C)3SiCl 121, 123
inline imageILICPET−70 °C90%D2O 124
inline imageBrLITTHF−120 °C93%H5C6CHO 125
inline imageBrLITDEE−70 °C97%β-ionone 126
inline imageILITDEE−75 °C70%CO2 127
inline image fILITPET g g inline image h 128, 129
inline imageBrLICDEE−75 °C25%(H2C)5CO 130
inline imageClLICDEE−110 °C90%H2O 131
 ClLICTHF−135 °C82%(H2C)5COi 132
inline imageClLITDEE−60 °C90%(H2C)5COi 133, 134
 BrLIMDEE−75 °C66%(H2C)5COi 135
inline imageBrLICDEE−85 °C51%H5C6COCH3 136
inline imageBrLICTHF−110 °C92%CO2 137
Table 15. 1-Alkenyllithiums Li[BOND]R Carrying Lithiooxy or Lithiooxycarbonyl Groups (at the γ or β Position, Respectively): Generation by Halogen/Metal Permutation Using Exchange Reagents Li[BOND]R′ in Diethyl Ether or, with Respect to the First and Last Two Entries, in Tetrahydrofuran
Li[BOND]RXaLi[BOND]R′TbProductEl[BOND]X′cReference
  1. a

    X = halogen displaced by the metal.

  2. b

    If the temperature at T which the organometallic intermediate was generated varied, only the highest one is given.

  3. c

    El[BOND]X′ = electrophile used to trap the organometallic intermediate.

  4. d

    First the lithium β-bromoenolate was generated from the corresponding α-bromoketone using 2.0 equiv. of LiCH3.

  5. e

    Similar results were obtained with O-tert-butyldimethylsilyl protected 1-alkenyl bromides as the precursors.

  6. f

    Or sec-butyllithium.

  7. g

    Isolated as the lactone.

inline imageBrdLiC(CH3)30 °C88% inline image 138
inline imageBrdLiC(CH3)30 °C64% inline image 138
inline image eBr, ILiC(CH3)3f−75 °C55%H5C6CHO 139
inline image eBr, ILiC(CH3)3−75 °C57%H5C6CHO 139
inline image eBr, ILiC(CH3)3f−75 °C28%H5C6CHO 139, 140
inline image eBr, ILiC(CH3)3−75 °C65%(H3C)3CCHO 139
inline imageBrLiC4H9−100 °C38%H5C6CHOg 141
inline imageBrLiC4H9−100 °C61%H5C6CHOg 141
inline imageBrLiC4H9−100 °C47%H5C6CHOg 138

Bromo- and iodoarenes are the oldest and most typical substrates for permutational halogen/metal interconversions. Butyllithium is routinely used for this purpose (Table 16). Hetero-substituents such as dialkylamino or bis(trialkylsilyl)amino, cyano or nitro (Table 17), alkoxy and 2-tetrahydropyranyloxy (Table 18), lithiooxy or lithiooxycarbonyl (Table 19) and fluoro or trifluoromethyl (Table 20) and chloro, bromo or iodo (Table 21) are well tolerated.

Table 16. Heteroatom-Free Aryllithiums Li[BOND]R by Halogen/Metal Permutation between Bromo- or Iodoarenes and Butyllithium
Li[BOND]RXaSνbTProductEl[BOND]X′cReference
  1. a

    X = halogen displaced by the metal.

  2. b

    Solvent (Sν): PET = petroleum ether, DEE = diethyl ether.

  3. c

    El[BOND]X′ = electrophilic trapping reagent.

  4. d

    Or in benzene or in diethyl ether.

  5. e

    In DEE in the range of −75 °C to +40 °C (reflux), in pure hydrocarbon media at +25 °C.

  6. f

    In the presence of N,N,N′,N′-tetramethylethylenediamine (TMEDA).

inline imageBr, IPETd e65%CO2 142-145
inline imageBrDEE+50 °C84%CO2 142, 143
inline imageBrDEE+50 °C65%CO2 142, 143
inline imageBrPET+25 °C86%CO2 142, 143
inline imageIDEE−70 °C76%CO2 146
inline imageBrDEE+25 °C62%CO2 142-145, 147
inline imageBrDEE−75 °C60%Cl3SiBr 148, 149
inline imageBrDEE+25 °C87%crystallized 150
inline imageBrDEE+25 °C97%CO2 151, 153
inline imageBrDEE+25 °C77%CO2 151
inline image fBrDEE+40 °C51%CO2 154
inline imageBrPET+25 °C72%CO2 155
Table 17. Amino-, Cyano- and Nitro-Substituted Aryllithiums Li[BOND]R by Halogen/Metal Permutation Using Butyllithium or Phenyllithium
Li[BOND]RLi[BOND]R′aSνbTProductEl[BOND]X′cReference
  1. a

    Li[BOND]R′ = organometallic exchange reagent.

  2. b

    Solvent (Sν): DEE = diethyl ether, THF = tetrahydrofuran.

  3. c

    El[BOND]X′ = electrophilic trapping reagent.

inline imageLiC4H9THF−75 °C83%(H5C6)2CO 156
inline imageLiC4H9DEE+49 °C32%CO2 157
inline imageLiC4H9DEE+40 °C56%CO2 157, 158
inline imageLiC4H9DEE0 °C80%(H5C6)2CO 159
inline imageLiC4H9THF−80 °C75%H5C6CHO 160
inline imageLiC4H9DEE+40 °C71%CO2 161
inline imageLiC4H9THF−100 °C72% inline image 162
inline imageLiC4H9DEE−70 °C17%CO2 163
inline imageLiC4H9THF−100 °C97%CO2 164
inline imageLiC6H5THF−100 °C61%CO2 164
inline imageLiC6H5THF−100 °C41%CO2 164
inline imageLiC6H5THF−100 °C82%CO2 164
Table 18. Alkoxy- and Acetal-Substituted Aryllithiums Li[BOND]R by Halogen/Metal Permutation between Bromo- or Iodoarenes and Butyllithium
Li[BOND]RXaSνbTProductEl[BOND]X′cReference
  1. a

    X = halogen displaced by the metal.

  2. b

    Solvent (Sν): PET = petroleum ether; DEE = diethyl ether, THF = tetrahydrofuran, BNZ = benzene.

  3. c

    El[BOND]X′ = electrophilic trapping reagent.

  4. d

    Or using phenyllithium in DEE at +25 °C.

  5. e

    Not specified.

  6. f

    OTHP = (2-tetrahydropyranyl)oxy.

  7. g

    1-p-Anisyl-3-phenyl-2-butanone.

  8. h

    N-Benzyl-6-aza-2-bicyclo[2.2.2]octanone.

inline image dBr, IDEE+25 °C90%(H5C6)2CO 165-167
inline imageBrTHFd−75 °C52%CO2 168, 169
inline imageBr, IBNZ+25 °C82%CO2 142-144
inline imageBrPET+25 °C eD2O 170
inline imageBrTHF−75° eD2O 170
inline image fBrTHF−75 °C80% g 171
inline imageBr, IDEE−75 °C42% h 172
inline imageBrTHF−75 °C52% inline image 173, 174
inline imageBrTHF−75 °C38% inline image 175
inline imageBrTHF−75 °C75% inline image 176
Table 19. Lithiooxy-Substituted Aryllithiums Li[BOND]R by Halogen/Metal Permutation between Butyllithium and O-Lithiated Bromophenols, Bromobenzyl Alcohols, Bromo-2-Phenethyl Alcohols and Bromobenzoic Acids
Li[BOND]RaSνbTProductEl[BOND]X′cReference
  1. a

    OLi by deprotonation of OH prior to the halogen/metal permutation.

  2. b

    Solvent (Sν): DEE = diethyl ether, THF = tetrahydrofuran.

  3. c

    El[BOND]X′ = electrophilic trapping reagent.

  4. d

    Using tert-butyllithium rather than butyllithium.

  5. e

    (1) SO2, (2) HO3SONH2.

inline imageDEE+25 °C67%CO2 177-181
inline image dTHF0 °C61% e 182
inline imageDEE,THF+25 °C75%CO2 177-181
inline image dTHF0 °C61%H5C6CN 183
inline imageDEE+25 °C32%CO2 162
inline imageDEE+25 °C18%CO2 162
inline imageDEE+25 °C45%CO2 162
inline imageDEE+25 °C52%CO2 162
inline imageDEE−75 °C35%CO2 161, 177-181
inline imageDEE−75 °C62%CO2 166, 177-181, 184
Table 20. Fluoro- and Trifluoromethyl-Substituted Arylithium Li[BOND]R by Halogen/Metal Permutation between Bromoarenes and Butyllithium
Li[BOND]RSνaTProductEl[BOND]X′bReference
  1. a

    Solvent (Sν): DEE = diethyl ether, BNZ = benzene.

  2. b

    El[BOND]X′ = trapping electrophile.

  3. c

    R′2 = 4,4-Dimethyl-2,2′-biphenyldiyl.

inline imageDEE−70 °C84%(H5C6)2CO 185
inline imageDEE−40 °C65%CO2 186
inline imageBNZ+25 °C50%CO2 144
inline imageDEE−75 °C83%CO2 187, 188
inline imageDEE−75 °C77%CO2 189
inline imageDEE−75 °C51%H2O 190, 191
inline imageDEE+25 °C61%CO2 192
inline imageDEE−50 °C64%CO2 193
inline imageDEE0 °C48%Cl2C = CF2 194
inline imageDEE−75 °C94%CO2 195
inline imageDEE−70 °C78%R′4As+Ic 196
Table 21. Chloro-, Bromo- and Iodo-Substituted Aryllithiums Li[BOND]R by Halogen/Metal Permutation between Bromoarenes and Butyllithium in Diethyl Ether
Li[BOND]RTProductEl[BOND]X′aReference
  1. a

    El[BOND]X′ = electrophilic trapping reagent.

  2. b

    Also from the corresponding iodoarenes and also in benzene rather than diethyl ether.

  3. c

    From hexachlorobenzene.

  4. d

    Nucleophilic addition of 3-bromophenyllithium to the 4-position of pyrimidine followed by the elimination of lithium hydride.

  5. e

    R′2 = 4,4′-dimethyl-2,2′-biphenyldiyl.

  6. f

    From 1,4-diiodobenzene.

inline image−90 °C93%CO2 197
inline image b+25 °C42%CO2 142, 143, 184
inline image b+25 °C90%CO2 142-144
inline image c−10 °C71%(H5C6)2CO 198, 199
inline image−100 °C38%CO2 142, 143, 200
inline image+35 °C44% inline image d 201, 202
inline image+25 °C90%CO2 144, 203, 204
inline image−75 °C93%F7C3COOC2H5 205
inline image−15 °C16%CO2 122
inline image+25 °C67%H2O 142, 143
inline image−70 °C30%R′4P+Ie 196
inline image f+25 °C80%(H5C2)3GeBr 206

Bromopyridines and bromoquinolines smoothly undergo a halogen/metal interconversion when treated at low temperatures with butyllithium in diethyl ether or tetrahydrofuran (Table 22). Additional hetero-substituents such as dialkylamino and alkoxy groups or halogen atoms may be present in the substrate. 2,5-Dibromopyridine gives rise to a solvent-controlled optional site selectivity. When the exchange is accomplished in tetrahydrofuran, the nitrogen-remote halogen at the 5-position is displaced221 whereas the reaction occurs in toluene at the site adjacent to the nitrogen atom220. Not only pentabromopyridine227 but also pentachloropyridine224-226 are subject to a butyllithium-promoted rapid interconversion at the 4-position.

Table 22. Pyridyl- and Quinolyllithiums Li[BOND]R by Halogen/Metal Permutation Using Butyllithium as the Exchange Reagent
Li[BOND]RXaSνbTProductEl[BOND]X′cReference
  1. a

    X = halogen displaced by the metal.

  2. b

    Solvent (Sν): DEE = diethyl ether, THF = tetrahydrofuran, TOL = toluene.

  3. c

    El[BOND]X′ = electrophilic trapping reagent.

inline imageBrDEE−15 °C69%H5C6CHO 207-209
inline imageBrDEE−35 °C62%CO2 207-212
inline imageBrDEE−75 °C55%(H5C6)2CO 211-213
inline imageBrTHF−60 °C80%H3CI 214
inline imageBrDEE−40 °C82%H3CCON(CH3)2 215-219
inline imageBrTOL−75 °C79%(H3C)2CO 220
inline imageBrTHF−100 °C85%D2SO4 221
inline imageClDEE−35 °C84%H2O 222
inline imageIDEE−35 °C65%CO2 223
inline imageClDEE−75 °C29%CO2 224-226
inline imageBrDEE−75 °C16%CO2 227
inline imageBr, IDEE−50 °C50%(H5C6)2CO 228, 229
inline imageBrDEE−45 °C48%CO2 184, 207-213

Numerous examples of halogen/metal permutations involving five-membered nitrogen heterocycles such as pyrroles, indoles, pyrazoles and imidazoles (Table 23) or five-membered chalcogen heterocycles such as furans, thiophenes, benzothiophenes and selenoles (Table 24) are known. If two or more competing halogens are available in a given substrate, they can be sequentially replaced, first by lithium and subsequently

Table 23. Pyrryl-, Indolyl-, Pyrazolyl- and Imidazolyllithiums Li[BOND]R by Halogen/Metal Permutation between a Five-Membered Bromoheterocycle and Butyllithium in an Ethereal Solvent
Li[BOND]RSνaTProductEl[BOND]X′bReference
  1. a

    Solvent (Sν): DEE = diethyl ether, THF = tetrahydrofuran; in case of mixtures (containing, e.g., petroleum ether) only the most polar component is indicated.

  2. b

    El[BOND]X′ = trapping electrophile.

  3. c

    SiR′2R″ = Si(CH3)2C(CH3)3.

  4. d

    tert-Butyllithium instead of butyllithium.

  5. e

    4-Iodo-1-triphenylmethylimidazole as the starting material.

  6. f

    Plus 7% 2-isomer.

  7. g

    Plus 14% 5-isomer.

inline imageTHF−75 °C83%(H3C)3SiCl 230
inline imageTHF−75 °C88%CO2 231, 232
inline image c, dTHF−75 °C94%(H3C)3SnCl 233-235
inline image dDEE−100 °C77%CO2 236
inline imageDEE−30 °C74%(H5C6)2CO 237
inline imageDEE−30 °C81%CO2 237
inline imageDEE+25 °C97% inline image 238
inline imageDEE−30 °C80%CO2 237
inline image eTHF−75 °C51%f(H3C)2NCHO 239
inline imageTHF−100 °C42%CO2 240
inline imageDEE−75 °C54%g(H3CS)2 241-243
Table 24. Furyl-, Thienyl-, Benzothienyl- and Selenophenyllithiums Li[BOND]R by Halogen/Metal Permutation between Haloheterocycles and Butyllithium in Diethyl Ether
Li[BOND]RXaTProductEl[BOND]X′bReference
  1. a

    X = halogen in the precursor.

  2. b

    El[BOND]X′ = electrophilic trapping reagent.

  3. c

    Using sec-butyllithium instead of butyllithium.

  4. d

    Using phenyllithium instead of butyllithium.

  5. e

    Using ethyllithium instead of butyllithium.

inline imageBr−70 °C63%(H9C4O)3B/H2O 244-248
inline imageBrc−70 °C78%H5C6N(CH3)CHO 249
inline imageBr−45 °C49%H3CCON(CH3)2 246-248
inline imageBr−80 °C65%H2O 249
inline imageBr−45 °C61%(H9C4O)3B/H2O 246-248, 250
inline imageI+25 °C58%CO2 251
inline imageI−70 °C78%CO2 252, 253
inline imageBr−75 °C51%(H3C)2NCHO 254
inline imageBr−70 °C90%CO2 253
inline imageCl0 °C69%CO2 255, 256
inline imageBrd+40 °C65%CO2 257
inline imageIe−100 °C51%CO2 258

by a suitable electrophile El, starting at the intrinsically most acidic position and ending with the least acidic one. Thus, 5,7-dibromo-2,3-dihydro-1-benzofuran 3 reacts first at the 7-position259 and 1-(benzyloxy)methyl-2,4,5-triiodoimidazole 4260 or its tribromo analog261 exchanges with butyllithium first the halogen at the 2-position and next the halogen at the 5-position (equation 2).

original image(2)

Regioselectivity in the exchange of formally equal halogens can be found also outside the heterocyclic series. Inductive effects appear to be the controlling factor. For example, 3,3′,5-tribromodibenzyl ether (1,3-dibromo-5-[(3-bromophenylmethoxy)methyl]benzene; 5) is exclusively converted into 3-bromo-5-[(3-bromophenylmethoxy)methyl]benzoic acid (equation 3) when treated consecutively with butyllithium in tetrahydrofuran262 at −75 °C and dry ice.

original image(3)

Stereoselectivity is encountered when 1,1-dibromoalkenes 696, 102-104, 263-265 or gem-dibromocyclopropanes 7102-104, 266, 267 are submitted to a halogen/metal permutation (equation 4). In the initial stages of the reaction the sterically less hindered exo-oriented halogen is replaced preferentially. However, due to the reversibility of the permutational process, an equilibration sets in showing the endo-Li-isomers to be the thermodynamically strongly favored species (equation 4).

original image(4)

4 Permutational Hydrogen/Metal Interconversions (‘Metalations’)

  1. Top of page
  2. Introduction
  3. Reductive Metal Insertion into Carbon–Halogen Bonds
  4. Permutational Halogen/Metal Interconversions
  5. Permutational Hydrogen/Metal Interconversions (‘Metalations’)
  6. The Brook Isomerization
  7. The Shapiro Reaction
  8. The Sulfoxide/Lithium Displacement
  9. Acknowledgments
  10. References

Acid/base reactions in aqueous medium, even if just isoenergetic rather than exoenergetic (for example, the proton transfer from a hydronium ion to a water molecule), are generally diffusion-controlled processes. The analogous reaction between a paraffinic hydrocarbon, say methane, and the conjugate base, methanide (methyl anion), could only be accomplished in the gas phase. If the experiments were attempted in a condensed phase, only alkanes or cycloalkanes would be sufficiently inert toward the alkylmetal which would replace the inaccessible alkanide ion. Due to the extremely low polarity of the medium, alkylmetals would not only persist as contact species or, in other words, prove unable to dissociate into ions but, worse, they would even form oligomeric or polymeric clusters, so-called aggregates. Thus, they can attain a reactive, deprotonation-triggering state only after having undergone an energy-expensive structural reorganization. The claimed hydrogen/metal permutation between butylpotassium and pentane, hexane and cyclohexane268 has never been experimentally verified, not to speak of having been applied to practical preparative work.

Standard organolithium reagents such as butyllithium, sec-butyllithium or tert-butyllithium deprotonate rapidly, if not instantaneously, the relatively acidic hydrocarbons of the 1,4-diene, diarylmethane, triarylmethane, fluorene, indene and cyclopentadiene families and all terminal acetylenes (1-alkynes) as well. Butyllithium alone is ineffective toward toluene but its coordination complex with N,N,N′,N′-tetramethylethylenediamine does produce benzyllithium in high yield when heated to 80 °C269. To introduce metal into less reactive hydrocarbons one has either to rely on neighboring group-assistance or to employ so-called superbases.

4.1 The Superbase Approach

The ‘LIC-KOR’ reagent consisting of stoichiometrically equal amounts of butyllithium (‘LIC’) and potassium tert-butoxide (‘KOR’) was conceived in Heidelberg and optimized in a trial-and-error effort270, 271. The fundamental idea was simple. To activate butyllithium optimally by deaggregation and carbon–metal bond polarization, a ligand was required that would surpass as an electron donor any crown ether but not suffer from the drawback of the latter, i.e. its proneness to β-elimination. Whereas pinacolates and other vic-diolates272 proved too labile to be generally useful, potassium tert-butoxide or any other bulky, hence relatively soluble, potassium or cesium alkoxide was found to serve the purpose273.

Later, in Lausanne, further mixed metal reagents were tested. LIC-KOR confirmed its role as a faithful ‘workhorse’271 in numerous situations, e.g. the metalation of 2- or 4-fluoroanisole274 and 2- or 4-fluoro-1-(methoxymethoxy)benzene275. The mixture of methyllithium and potassium tert-butoxide (‘LIM-KOR’) gives optimum results if congested positions are targeted276, whereas the mixture of tert-butyllithium and potassium tert-butoxide (‘LIT-KOR’) shows a perfect discrimination between sterically hindered and freely accessible positions277. The mixture of butyllithium and sodium tert-butoxide (‘LIC-NAOR’) outperformed all other reagents in the metalation of norbornene, norbornadiene and cycloheptatriene278. The yields of the metalation by the different reagents of these substrates are shown below.

original image

Even before the term ‘superbase’ was coined273, 279, there existed already a tacit understanding about where to place the bar of qualification for this label. The crucial benchmark chosen was to metalate benzene rapidly in high yield and at ambient temperature. The above-mentioned mixed metal reagents and the pentylsodium/potassium tert-butoxide (‘NAC-KOR’) mixture as well (metalation of norcarane280, nortricyclane281, 282, camphene282, 283, bicyclo[2.2.2]octene280 and 6-bicyclo[3.2.0]heptene278, 284 in 30, 60, 71 and 66% yield of trapping products) pass this test without problems. Other combinations fail to attack benzene to any significant extent. This is, for example, the case with TMEDA-activated butyllithium (‘LIC-TMEDA’), the butyllithium/lithium 2-(dimethylamino)ethoxide blend (‘LIC-LIDMAE’, ‘Caubère's base’285) or with the complexes lithium diisopropylamide/potassium tert-butoxide (‘LIDA-KOR’, ‘Margot–Mordini mix’)286-288 and lithium 2,2,6,6-tetramethylpiperidide/potassium tert-butoxide/N,N,N′,N′,N′-pentamethyldiethylenetriamine (‘LITMP-KOR-PMDTA’, ‘Faigl mix’)289.

Ailing reactivity as a base must not necessarily be a handicap. The LIC-KOR mixture is of course immensely more powerful than butyllithium alone. This offers the possibility to functionalize whole families of otherwise inert hydrocarbons290, 291. What should not be overlooked, however, is the fact that the chemical potential of the so-called superbase is attenuated when compared to butylpotassium. The latter reagent is instantaneously destroyed when brought in contact with tetrahydrofuran even at temperatures below −100 °C. In contrast, the LIC-KOR mixture survives in the same solvent almost indefinitely at −75 °C and can be exposed to −50 °C at least for a while292. Thus, a manifold of aromatic, benzylic and allylic organometallic intermediates can be generated in an ethereal medium under particularly mild and hence optimally selective conditions. The symbiotic action of two different metals obviously suppresses erratic side reactions without diminishing too much the deprotonation power of the superbasic reagent. Although its detailed structure remains unknown, there can be no doubt about a progressive change in its composition regardless of whether or not a substrate is present or, in other words, a chemical transformation occurs simultaneously. Potassium tert-butoxide exists in tetrahydrofuran mainly as a tetramer and in hexanes as a virtually insoluble polymer. However, at the end of a LIC-KOR promoted metalation of a hydrocarbon, the oxygen atoms are mostly, yet by far not exclusively, associated with lithium (the exceptional strength of the O[BOND]Li bond being the obvious driving force) whereas the heavier alkali metal is mainly found attached to the carbon backbone. The enhanced metal mobility in allylic or benzylic structures makes it even possible to isolate pure potassium species after the specific removal of lithium tert-butoxide by extraction with hot benzene or toluene293.

4.2 Neighboring Group Assistance to Metalations

As pointed out above, neither methane nor its higher homologs (ethane, propane, hexane) can be effectively metalated. The introduction of a hetero-substituent changes this outset profoundly. Second-row and third-row elements (such as silicon, phosphorus and sulfur) will not be considered in this context as they are known to acidify hydrocarbons strongly due to d-orbital resonance (or polarization) effects. But also the first-row elements nitrogen, oxygen and fluorine can distinctly facilitate the deprotonation of paraffinic hydrocarbons.

The metalation of trimethylamine294 with butyllithium, N-methylpiperidine295 with sec-butyllithium in the presence of potassium tert-butoxide and N,N,N′,N′-tetramethylethylenediamine296, 297 (TMEDA), all exclusively at methyl groups, have been reported. The yields were moderate but increased substantially with N,N,N′,N″,N″-pentamethylethylenetriamine297 (PMDTA, 8) as the substrate which underwent a deprotonation both at the terminal and inner methyl groups in varying, stoichiometry-dependent ratios. Ring strain combined with dipole-activation enabled the smooth lithiation of an α-methylene group in N-(tert-butoxycarbonyl)pyrrolidine 9298 providing again excellent yields of trapping products (equation 5).

original image(5)

No reproducible metalation of a saturated, open-chain or cyclic ether with butyllithium, sec-butyllithium or tert-butyllithium has been described so far292. The intermediates generated by the treatment of dimethyl ether or tert-butyl methyl ether with potassium tert-butoxide activated butyllithium or sec-butyllithium gave trapping products in only poor yields (3–30%), far below the yields (75–95%) achieved with butylpotassium292. Due to ring strain acidification, oxiranes undergo the hydrogen/metal permutation quite readily when treated, for example, with sec-butyllithium and a diamine ligand such as N,N-dibutyl-3,7-diazabicyclo[3.3.1]nonane or sparteine at −90 °C. However, the resulting C-lithiated intermediates isomerize through ring-opening if not being trapped in situ299 or stabilized by an α-trialkylsilyl- or α-triarylsilyl substituent (as in 10, equation 6)300-302.

original image(6)

Fluoromethane would presumably tend to react by an SN2 process rather than by deprotonation, whatever the base used. On the other hand, potassium tert-butoxide303 and fluoride304 suffice already to set free the trifluoromethyl anion from trifluoromethane (fluoroform). Being extremely fragile, the trifluoromethanide must be trapped in situ, for example by addition to N,N-dimethylformamide.

The three-membered carbocycle being activated by ring strain, cyclopropane and congeners are metalated, if sluggishly, by alkylsodiums when activated or not by potassium tert-butoxide1f (see also Section 4.1). Hetero-substituted cyclopropanes react much more readily. Thus, sec-butyllithium in the presence of TMEDA metalates cleanly the cyclopropyl 2,4,6-tris(isopropyl)benzoate305. N-tert-Butoxycarbonyl-2-methylaziridine 11 and congeners can be selectively substituted at the 3-position by treating them consecutively with sec-butyllithium and the appropriate electrophile306. The tert-butyl-N-ethyl-N-cyclopropylcarbamate 12 is lithiated in the three-membered ring, again at a nitrogen-adjacent position306. In contrast, the N-BOC protected 4-azaspiro[2.5]octane 13 is attacked exclusively at the three-membered ring, in other words at a β-position with respect to the nitrogen atom rather than at the α-methylene group of the six-membered ring307 (equation 7).

original image(7)

An olefinic double bond can be conceived as a two-membered ring308. The specific geometry at the unsaturated centers makes the latter prone to deprotonation. Nevertheless, superbasic reagents are required for the metalation of heteroatom-free alkenes (see Section 4.2), the only exception being the remarkably acidic cyclopropenes which do react with alkyllithiums alone309, 310.

The attachment of nitrogen, oxygen or fluorine substituents at the double bond activates the olefinic positions sufficiently to make them undergo rapid hydrogen/metal permutation when treated with alkyllithiums. Thus, 1-vinylbenzotriazole 14a and both 1-propenylbenzotriazoles 14b,14c are readily deprotonated by butyllithium at the olefinic α-position311. The two 2-propenylbenzotriazoles act in the same way311. Unexpectedly, tert-butyllithium promotes the proton abstraction from the β-position of chelating enamines, regardless whether the α-position is vacant, as in N-1-heptenyl-N,N′,N′-trimethyl-1,2-ethanediamine 15, or occupied, as in N-1-cyclohexenyl-N,N′,N′-trimethyl-1,2-ethanediamine 16312. N-Lithioamido groups can mediate the metalation of terminal olefinic sites even if the functionality is placed at a remote γ-position. This is illustrated by N-(tert-butyl)allylamine 17313 and N-(trimethylsilyl)allylamine 18314 as typical substrates (equation 8).

original image(8)

Ethyl vinyl ether 19a315-317 and methyl vinyl ether318 19b are metalated by tert-butyllithium at the oxygen-adjacent methine site. β-Alkyl groups retard the reaction substantially. Thus, 1-methoxy-2-methyl-2-propene was found to be inert toward all alkyllithiums, activated or not. However, 1-methoxymethoxy-2-methyl-2-propene 20, just as the corresponding tetrahydropyranyloxy derivative too, reacts smoothly with sec-butyllithium at the olefinic α-position319. If no α-position is accessible as is the case with 1-methoxymethoxy-1-phenylethylene 21320, the β-position may be attacked. 1-Ethoxy-2-bicyclo[2.2.1]oct-2-enyllithium, which owes its chemical stability to the Bredt rule, can be easily generated by treatment of the bridgehead ether 22 with tert-butyllithium321. The neighboring group assistance provided by the alkoxy substituent located in a β′-position with respect to the double bond becomes evident when one compares this substrate with 2-bicyclo[2.2.2]octene itself, which is completely inert toward ordinary alkyllithium and reacts only with superbases280. Finally, metal can be introduced in the terminal olefinic position of linalool 23 or other 1,1-dialkylated allyl alcohols using butyllithium in hexanes and in the presence of TMEDA322, 323. This is another one of the rare examples where a γ-positioned hetero-substituent exerts control over the outcome of a metalation reaction (equation 9).

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The metalation of fluoroethylene (vinyl fluoride) has not yet been reported although trifluoroethylene 24324, 325, (E)-α,β-difluorostyrene 25326 and both (Z)- and (E)-isomers of 1,2-difluoro-1-alkenes (26, cis isomer shown)326, 327 undergo smooth metalation at the α-position. Proton abstraction from β-positions occurs with gem-difluoroethylene324, 325, 328 and 1,1,3,3,3-pentafluoropropene329 (equation 10).

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When moving from methane or other simple (cyclo)alkanes through cyclopropanes to alkenes, a progressive increase in acidity and reactivity was recognized. Both cyclopropanes and alkenes are deprotonated by alkylsodiums or superbases. The possibility of π-cloud polarization330 makes benzene (and derivatives thereof) even more reactive. If employed in excess, it is metalated by the LIC-KOR mixture in the course of minutes if not seconds. No hydrogen/metal permutation can be accomplished with pyridine, as the nucleophilic addition of the organometallic reagent to the imine entity is the predominant process331. However, hetero-substituted pyridines or quinolines can be smoothly metalated. Furans, thiophenes, pyrroles and other five-membered heterocycles contain the electronegative element already incorporated in a slightly strained ring. This ensures particularly fast and complete deprotonation of the α-positions. The proton mobility again increases in the direction of the arrows shown in the scheme below.

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The neighboring group-assisted metalation of arenes and heterocycles is an area too vast to be included into this Chapter. Major aspects have been summarized in Chapter Directed Metallation of Aromatic Compounds of this book and a comprehensive, though still not exhaustive treatment of this theme can be found in a recent monograph1g.

5 The Brook Isomerization

  1. Top of page
  2. Introduction
  3. Reductive Metal Insertion into Carbon–Halogen Bonds
  4. Permutational Halogen/Metal Interconversions
  5. Permutational Hydrogen/Metal Interconversions (‘Metalations’)
  6. The Brook Isomerization
  7. The Shapiro Reaction
  8. The Sulfoxide/Lithium Displacement
  9. Acknowledgments
  10. References

The Brook isomerization is the migration of a silyl group from a carbon atom to an oxygen anion as illustrated in its simplest [1,2] form (e.g. 27 to 28 in equation 11)332.

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The isomerization is driven forward by the increased thermodynamic stability of the silyl ether product relative to the alcohol starting material due to the formation of a Si[BOND]O bond in place of a Si[BOND]C bond333. Investigations revealed that all types of silyl carbinols rearrange, often fairly readily, when treated with small amounts of active metals, organometallic reagents or bases332. This isomerization has been extensively studied mechanistically by Brook and shown to proceed intramolecularly via a mechanism involving a hypervalent pentacoordinate silicon species with retention of configuration at silicon and inversion of configuration at carbon334. In accord with that mechanistic hypothesis, substrates having substituents on carbon that help delocalize negative charge, e.g. aryl or vinyl, accelerate the rate of the isomerization. The counterpart of this isomerization, the retro-Brook (or silyl Wittig or West) isomerization, namely the transfer of silicon from oxygen to carbon (28 into 27), has also been observed and synthetically used335.

In this section, we will concentrate on the chemistry of the Brook isomerization mediated by organolithium compounds and on their unusual routes to potentially useful carbanions.

5.1 Anionic [1,2] Brook Isomerization

A general approach is to generate silyl alkoxides by addition of suitable organometallic reagents (RLi) to silyl ketones such as acyl silanes. If either one of the alkyl groups (from the acylsilane 29 or from the alkyllithium 30) contains a α-leaving group, the carbanion 32, coming from the [1,2] Brook isomerization of 31, can undergo a β-elimination to form a silyl enol ether 33 (equation 12)336.

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The importance of this approach to 33 lies in the fact that enolization of 1-phenyl-2-butanone does not give pure 33 under kinetic or thermodynamic conditions. Moreover, if the acylsilane possesses a stereogenic center in the α-position, the addition occurs according to the Felkin–Anh mode337.

If the addition involves an alkynyllithium such as 34, the first-formed alkoxide intermediate 35 isomerizes into the propargylic-allenic lithium reagent. Reactions with electrophiles lead to either 36a or the allenol silyl ethers 36b (equation 13)338.

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By using this strategy, intramolecular alkylations to unusual enol ethers 37 are easily accessible (equation 14)338.

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Allenyl silyl ethers 40 have also been prepared by the reaction of 2-lithiofurans 38 with acylsilanes 39 via the Brook isomerization (equation 15)339.

Even the starting acylsilane 39 can be easily prepared via a Brook isomerization by the reaction of silylmethyllithium 41 with carbon monoxide340. Initially, the reaction gives the corresponding unstable acyllithium 42 which underwent the Brook isomerization affording the stable lithium enolate (equation 16).

If the alkenyllithium 43 is used as organolithium compound with 39, siloxyallyllithium reagents 44 are formed341. As example, the isomerization of the silyl(allyl)alkoxides 44 gives the corresponding lithio-(Z)-silyl enol ethers 45 which react with various electrophiles to give 46 (equation 17)342.

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This strategy was very recently used for the total synthesis of δ-Araneosene343. In the first step of the synthesis, methyl tert-butyldimethylsilyl ketone 47 was treated with 2-propenyllithium 48 in ether and then with 2-isopropylallyl bromide 49 in THF to give the (Z)-enol silyl ether 50 in 82% yield. The sequence of reactions that leads to 50 includes (1) carbonyl addition of 48, (2) Brook isomerization and (3) allylation of the resulting allylic lithium reagent (equation 18)344.

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Ketone enolate 51 could also serve as a two-carbon component in [3 + 2] annulation when reacted with β-heteroatom-substituted α,β-unsaturated acylsilane 52345. For instance, the enolate of 3-methyl-2-butanone 51 (R = i-Pr) reacts with [β-(trimethylsilyl)acryloyl]trialkylsilane (52, X = SiMe3) at low temperature to give the corresponding cyclopentanol 53 as single isomer (equation 19). Reactions of benzoylsilanes and crotylsilanes with lithium enolates afford the cyclopropane diol derivatives346.

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Similarly, the [3 + 4] annulation of the E- and Z-isomers of β-hetero-substituted acryloylsilanes 52 with lithium enolates of α, β-unsaturated methyl ketones 54 gave stereospecifically the cis-6,7-cyclopentyl-5-trimethylsilyl-3-cycloheptenone 55 (equation 20)347. The stereospecificity in the annulation was explained by an anionic oxy-Cope isomerization of the 1,2-divinylcyclopropanediol intermediate 56, which was generated through the Brook isomerization of the initial 1,2-adduct (equation 20).

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Metalloaldimines 57 bearing a silicon linked to a carbon can be alkylated with a range of carbon electrophiles. When 57 is treated with an aldehyde, the resulting adduct 58 undergoes the Brook isomerization providing a new lithioaldimine intermediate 59. Reaction of this lithioaldimine with electrophiles such as chlorotrimethylsilane provides a new imidoylsilane 60 in 62% yield (equation 21)348.

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In contrast to 1,2-migrations between C and O, there are few reports on the Brook isomerization of α-silylamine (aza-Brook isomerization). The reaction of (α-silylallyl)amine 61 with n-C4H9Li in THF at low temperature followed by the addition of HMPA and CH3I gives the methylated product 62 in quantitative yield. These results indicate that an aza-Brook isomerization occurs, i.e. the silyl group of 61 migrates from carbon to nitrogen and the lithium salt of an allyl anion 63 is produced (equation 22)349.

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5.2 Anionic [1,3] Brook Isomerization

1,3-Isomerization of silicon from carbon to alkoxide is rare since olefin formation via 1,2-elimination of β-silyloxy is rapid (known as the Peterson olefination, equation 23)350.

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Thus, only few reports were disclosed for the [1,3] Brook isomerization; Utimoto, Oshima and coworkers have reported that the treatment of tert-butyldimethyl(dibromomethyl)silane 64 with LDA followed by the addition of an excess of benzaldehyde lead to the 1,3-diol monosilyl ether 66 via the intermediacy of lithium carbenoid 65 (equation 24)351. The rate of isomerization was dependent on the solvent used and HMPA was found to be the best solvent352.

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5.3 Anionic [1,4] Brook Isomerization

When a solution of lithium enolate 68, prepared by the addition of N,N-dimethyl-2-trimethylsilylacetamide 67 to a THF solution of LDA, is treated with an equivalent amount of propylene oxide 69, a single product 71 is obtained in 75% yield (equation 25)353. This result is rationalized by assuming an initial addition of 68 at the less substituted side of the epoxide, followed by the first observed 1,4-migration of silicon from carbon to oxygen (70 to 71).

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This isomerization was used in the heteroconjugate addition to the acyclic system. Therefore, the substituted olefin 72, in which the double bond is conjugated with both sulfone and silicon atoms, undergoes a diastereoselective addition of CH3Li354. The resulting lithium alcoholate is quantitatively converted into the silyl ether dianion 73 and the addition of deuterium oxide afforded the functionalized product 74 in excellent yield (equation 26)355.

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Enantiopure 77 was easily prepared by treatment of 2-trimethylsilyl-1,3-dithiane 75 and chiral epoxides 76 in a sequential addition in the presence of a crown ether. In this sequence, a monosilylated 1,5-diol 77 is obtained, allowing a discrimination of the two hydroxy groups formed (equation 27)356.

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However, this process requires a reaction time of 2 days and is inapplicable to unsymmetrical couplings (two different epoxides). As the study described in equation 24 revealed a dramatic solvent effect on similar Brook isomerizations in the adduct of lithio dihalo(trialkylsilyl)methanes with epoxides (isomerization did not occur following metalation and initial alkylation in THF but proceeded readily upon addition of HMPA), the effect of HMPA for promoting the Brook isomerization was studied once the first alkylation was complete (equation 28)357.

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Thus, metalation of 78 and alkylation with epoxide E1 in Et2O or THF likewise furnished the unrearranged carbinols exclusively. Then, addition of HMPA or DMPU induced the 1,4-Brook isomerization (equation 28) and addition of a second epoxide leads to 79 in 60% yield. Then, the introduction of two different electrophiles is now successful and scalemic epoxides are particularly well suited to this process, because the configurations of the resulting carbinols stereocenters are predetermined, circumventing the formation and separation of unwanted diastereomers.

Assembling a five-component coupling product in a single operation further extended this methodology. Following alkylation of dithiane 78 with epoxide (−)79 (2.6 equivalent each) to generate the unrearranged alkoxy dithiane 80, sequential addition of HMPA and (−)-epichlorohydrin 81 (1 equivalent) furnished the bis(silyloxy dithiane) carbinols (+)82 in 66% yield (equation 29)357.

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Finally, addition of the carbanions derived from 83 to non-enolizable aldehydes is a facile process. Aryl and tertiary alkyl aldehydes gave trimethylsilyl allyl ethers 85 by a [1,4]-Brook isomerization (equation 30)358. The stereochemistry of the intermediate alkoxides 84 dramatically influences the reaction conditions required359.

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6 The Shapiro Reaction

  1. Top of page
  2. Introduction
  3. Reductive Metal Insertion into Carbon–Halogen Bonds
  4. Permutational Halogen/Metal Interconversions
  5. Permutational Hydrogen/Metal Interconversions (‘Metalations’)
  6. The Brook Isomerization
  7. The Shapiro Reaction
  8. The Sulfoxide/Lithium Displacement
  9. Acknowledgments
  10. References

The Shapiro reaction occurs when a tosylhydrazone 86, easily prepared from a ketone and tosylhydrazine, is treated with 2 equivalents of an ethereal solution of n-butyllithium 87, resulting first in the removal of the N[BOND]H proton to give the anion 88 and then of a one proton from the less-substituted α position to give the dianion 89. Elimination of lithium p-toluenesulfinate in the rate-limiting step gives the lithium alkenyldiazenide 90, which suffers loss of nitrogen to afford the alkenyllithium 91 (equation 31)360, 361.

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Unfortunately, the vinyl anion undergoes protonation under these reaction conditions and leads to the simple alkene 92 as the major product. It has been suggested that the proton source is actually the tosylhydrazone monoanion 88362, and that the basicity of 91 is strong enough to abstract an α proton from the unreacted tosylhydrazone monoanion 88 or even from 89 by ortho-metalation of the tosyl ring. Thus, in order to avoid this protonation in the reaction, an excess of base (>3 equivalents) was required to obtain good conversion into alkenyl derivatives.

Moreover, a deuterium quenching study has shown that quantitative formation of the dianion 89 occurs at −78 °C, but if the reaction mixture is allowed to warm to 0 °C, the excess of n-butyllithium quantitatively ortho-metalates the ring to give a trianion before the vinyl anion is formed in a significant amount363. The trianion then decomposes to the vinyl anion, which is stable under these conditions and can be trapped by electrophiles. The use of only 2 equivalents of alkyllithium leaves the ring unmetalated and vulnerable to further reactions. Thus, the requirement for an excess of base stems from the need to premetalate the tosyl ring, as in the formation of 93, thus removing the acidic ortho-hydrogen before it can protonate the alkyllithium product (equation 32).

In order to use only a stoichiometric amount of alkyllithiums, a modified sulfonylhydrazone leaving group containing no acidic ortho protons was required, such as 2,4,6-triisopropylbenzenesulfonyl (Trisyl 94) (equation 33).

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As a result, trisylhydrazones 95 allow the use of just 2 equivalents of alkyllithium, and thus only a single equivalent of electrophile (E) is needed to trap the resultant vinyllithium 97 to form the functionalized alkene 98. Moreover, trisylhydrazone dianions 96 undergo the elimination reaction much faster than do those derived from tosylhydrazones. This rate enhancement allows the use of even more acidic solvents, such as tetrahydrofuran.

6.1 Regioselectivity

Arenesulfonylhydrazones exist as mixtures of E- and Z-isomers. The ratio is dependent upon the size of the groups attached to the azomethine carbon, but the E isomer is the major isomer364 (i.e. 99 and 100, equation 34). Then, for these unsymmetrically substituted species, deprotonation of the monoanion occurs at the less-substituted α position (RCH3 > R2CH2 > R3CH) to give the corresponding less-substituted vinyllithium products 101 and 102 (in a ratio usually >50:1) (equation 34)362.

On the other hand, differential substitution adjacent to equivalently substituted α positions does not afford a good regiochemical control (compare 103 and 104, equation 35)365, 366.

It is also possible to generate the more highly substituted vinyllithium regioisomer in some cases by using an in situ alkylation step (see Section 6.3 for further functionalization).

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6.2 Stereoselectivity

The issue of stereoselectivity of the vinyllithium formed from acyclic arylhydrazones has also been addressed. For symmetrical linear-chain ketone derivatives such as 105, the E-vinyllithium 106 is the exclusive product (equation 36)362, 367-372.

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These results are consistent with a syn deprotonation of the hydrazone monoanion conformer, in which the α-alkyl group R is anti to the hydrazone moiety (a lower steric interaction in 107 than in 108) during the formation of the dianion (equation 37)373.

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When medium and large ring ketones are also treated with ArSO2NH[BOND]NH2 and then with n-C4H9Li, the E isomer is also the predominant form (equation 38)374.

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6.3 Further Functionalization

The syn-directed deprotonation of arylhydrazones can be used to reverse the normal preference of the less-substituted vinyllithium. By employing a one-flask dianion alkylation procedure, the formation of an almost exclusive stereoisomer of acyclic vinyllithiums

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could be achieved that would be impossible to prepare selectively by the direct reaction. Less than 2% of the less-substituted regioisomer is produced. As example, acetone trisylhydrazone 109 can be converted into the corresponding dianion 110, followed by alkylation into 111 at low temperature with a primary alkyl iodide. This functionalized monoanion is regiochemically stable at that temperature and, upon the addition of one more equivalent of alkyllithium base such as s-C4H9Li, it undergoes an exclusive syn deprotonation at the more highly-substituted α-position to give a dianion 112, which now can rearrange into 113 by simply warming the reaction mixture (equation 39)373.

This sequence reverses completely the regioselectivity observed for the direct reaction of 2-octanone trisylhydrazone 114 (equation 40). Indeed, only the isomer 115 is obtained.

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6.4 The Catalytic Shapiro Reaction

As described previously, the Shapiro reaction requires stoichiometric amounts of base to generate the alkyllithium reagents. An efficient catalytic method of the Shapiro reaction, which showed excellent regio- and stereo-selectivity, has also been reported. Indeed, the combination of ketone phenyl aziridinylhydrazones 116 and a catalytic amount of lithium amides leads to the corresponding alkene 117 in good overall yield (equation 41)375.

A regioselective deprotonation with amide base by preferential abstraction of the α-methylene hydrogen syn to the phenylaziridyl moiety in 116 and subsequent decomposition of the resulting monoanion furnishes, with extrusion of styrene and nitrogen, the alkyllithium 118. After abstraction of the amine proton, the cis-alkene 117 is formed with regeneration of the lithium amide base for further use in the catalytic cycle.

6.5 Application of the Shapiro Reaction

The Shapiro reaction provides a convenient, easy and straightforward method to convert ketones into a plethora of olefinic substances in high yields. Many of these vinyllithium derivatives are useful for further synthetic manipulations. No attempt is made in this chapter to cover all the applications of the Shapiro reaction and only few representative examples will be described. A variety of polyolefins such as 119, used for cation olefin cyclization, can be stereospecifically formed in a concise and modular approach in a single step from the components shown in equation 42 via the Shapiro reaction376.

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The sequence of steps involved in the present route to trisubstituted olefins is described in equation 43. Double deprotonation of acetone 2,4,6-triisopropylbenzenesulfonylhydrazone 109, first at nitrogen and then at the α-methyl that is syn to the N-trisyl group, followed by coupling with an alkyl halide at −65 °C produces the unsymmetrical hydrazone intermediate 120. At low temperature 120 is configurationally stable and the N-trisyl group remains syn to the alkylated carbon. Subsequent deprotonation with TMEDA and n-C4H9Li occurs at the α-carbon syn to the N-trisyl group to give 121.

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Warming of the resulting dianion 121 to 0 °C for several minutes effects extrusion of N2 and formation of Z-vinyllithium reagent 122Li. Conversion of the vinyllithium reagent 122Li to the mixed cuprate 122Cu with lithium 2-thienylcyanocuprate and coupling at 0 °C with a second electrophile produces the trisubstituted olefin 119 in a single-pot operation.

The use of the trisylhydrazone 124 of 2-butanone 123 in the coupling process provides access to products containing an ethyl-substituted olefin 126. The starting unsymmetrical hydrazone 124 undergoes deprotonation and alkylation at the terminal α-carbon leading to a single metallated olefinic product 125Li (equation 44). The electrophilic component 2,3-dibromopropene leads to 126, which can be further elaborated via subsequent reactions.

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An elegant application of the catalytic Shapiro reaction has been found in the synthesis of the natural product 129 (equation 45), a component of the sex pheromone of the summer fruit tortrix moth (Adoxophyes orana)377.

The selective lithiation of 2-hexanone phenylaziridinyl-(E)-hydrazone 127 with LDA and subsequent alkylation with 8-(tert-butyldimethylsilyloxy)octyl bromide gave (Z)-hydrazone 128 in 65% yield. Its LDA-catalyzed selective decomposition followed by hydrolysis of the silyl ether yielded (Z)-9-tetradecen-1-ol, which was acetylated to afford the target compound 129 in 80% yield with a complete regioselectivity and a cis/trans ratio of 99.6/0.4.

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7 The Sulfoxide/Lithium Displacement

  1. Top of page
  2. Introduction
  3. Reductive Metal Insertion into Carbon–Halogen Bonds
  4. Permutational Halogen/Metal Interconversions
  5. Permutational Hydrogen/Metal Interconversions (‘Metalations’)
  6. The Brook Isomerization
  7. The Shapiro Reaction
  8. The Sulfoxide/Lithium Displacement
  9. Acknowledgments
  10. References

The reaction of sulfinyloxirane 130 with n-C4H9Li takes place at the sulfinyl group to afford the desulfinated epoxide 133 in good yield378. This reaction proceeds at −100 °C with concomitant formation of phenyl n-butyl sulfoxide 132. Thus, oxiranyllithium 131 picks up the acidic proton of the in situ formed 132 to generate the reduce epoxide 133 (equation 46)379.

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The reaction is stereospecific and the configuration of the carbon bearing the sulfinyl group is retained. Therefore, isomeric sulfinyloxiranes 134 and 135 gives epoxides 136 and 137 respectively on treatment with n-C4H9Li at −100 °C (equation 47)380. However, the reaction temperature as well as the amounts of butyllithium are critical for the success of this reaction381.

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This procedure was extended to a method for asymmetric synthesis of optically active epoxides starting from optically active sulfoxides382. As the oxiranyllithium 131 reacts with the acidic hydrogen of the n-butyl aryl sulfoxide, the introduction of electrophiles to the reaction mixture was problematic. Therefore, the reaction was performed by addition of 1 equivalent of t-C4H9Li at −100 °C to 130 and the sulfoxide–lithium exchange reaction was found to be extremely rapid (within a few seconds at this temperature). Moreover, as t-butyl aryl sulfoxide 138 has now no more acidic hydrogen, the addition of several electrophiles leads to functionalized epoxides 139 (equation 48)383.

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Several alkylmetals384 including alkyllithium derivatives react also with sulfinylaziridine 140 to give the aziridinyllithium 141 via a stereospecific desulfinylation at low temperature385. The corresponding aziridinyllithium 141 generated is stable at low temperature, such as −30 °C, and can react with a large variety of electrophiles such as aldehydes, ketones and chloroformates, to give functionalized aziridines (equation 49)386.

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The sulfoxide–lithium exchange reaction of alkenyl sulfoxides 142 possessing leaving groups in a β-position was also developed387 and it has been found that the reaction gives good yields of the corresponding allenes 143 (equation 50)388.

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α-Sulfinyl ketones having two alkyl groups on the α-carbon (such as 145) can be easily prepared from the isopropyl p-tolyl sulfoxide 144 (or cyclohexyl p-tolyl sulfoxide 146). Then, the resulting enol triflate 147 was prepared by reaction of 145 with LDA followed by the addition of PhNTf2 in the presence of HMPA as a cosolvent. Once all the starting material was consumed, excess n-C4H9Li was added to promote the sulfoxide–lithium exchange, which gives after β-elimination the corresponding trisubstituted allene 148 (or 149) in moderate yield (equation 51)387.

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The same methodology was successfully applied for the preparation of alkynes 152 and alkenes389 153 from α-sulfinyl ketones 150 and β-mesyloxy sulfoxides 151, respectively (equation 52).

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Finally, the addition of the carbanion of 1-chloroalkyl p-tolyl sulfoxides 154 to carbonyl compounds gave the adducts 155, which were treated with alkyllithium such as t-C4H9Li to afford the one-carbon homologated carbonyls compounds 158, from their lithium enolate forms 157, having an alkyl group at the α-position, via the carbenoid β-alkoxides 156 (equation 53)390.

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8 Acknowledgments

  1. Top of page
  2. Introduction
  3. Reductive Metal Insertion into Carbon–Halogen Bonds
  4. Permutational Halogen/Metal Interconversions
  5. Permutational Hydrogen/Metal Interconversions (‘Metalations’)
  6. The Brook Isomerization
  7. The Shapiro Reaction
  8. The Sulfoxide/Lithium Displacement
  9. Acknowledgments
  10. References

The Lausanne authors are indebted to the Swiss National Science Foundation, Bern (grant 20-63′584-00). The Israeli authors thank the Israel Science Foundation administered by the Israel Academy of Sciences and Humanities (79/01-1) and the Fund for the Promotion of Research at the Technion.

References

  1. Top of page
  2. Introduction
  3. Reductive Metal Insertion into Carbon–Halogen Bonds
  4. Permutational Halogen/Metal Interconversions
  5. Permutational Hydrogen/Metal Interconversions (‘Metalations’)
  6. The Brook Isomerization
  7. The Shapiro Reaction
  8. The Sulfoxide/Lithium Displacement
  9. Acknowledgments
  10. References