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Chapter One
Organoalkali Chemistry
Manfred Schlosser
Institute of Chemical Sciences and Engineering (ISIC-BCh) Swiss Federal Institute of Technology (ETH-EPF) CH-1015 Lausanne, Switzerland
Contents
1 Introduction
2 Coverage
3 Reactions
3.1 Displacement of Metal by Hydrogen
3.1.1 Metalation of Aliphatic or Aromatic Hydrocarbons
3.1.2 Neutralization of Organometallic Intermediates
3.2 Displacement of the Metal by Another Metal or Metalloid
3.2.1 “Uphill” Reactions Generating More Basic Species
3.2.2 “Downhill” Reactions Generating More Electrophilic Species
3.2.3 Ate Complex Chemistry
3.3 Displacement of the Metal by a Heterosubstituent
3.3.1 Nitrogen Displaces the Metal
3.3.2 Phosphorus Displaces the Metal
3.3.3 Oxygen Displaces the Metal
3.3.4 Sulfur Displaces the Metal
3.3.5 Fluorine Displaces the Metal
3.3.6 Chlorine Displaces the Metal
3.3.7 Bromine Displaces the Metal
3.3.8 Iodine Displaces the Metal
3.4 Carbon-Carbon Bond Formation
3.4.1 Alkyl and 2-Alkenyl Halides or Sulfonates
3.4.2 Ring Opening of Cyclic Amines and Ethers
3.4.3 Addition onto Carbon—Carbon Multiple Bonds
3.4.4 Addition onto Heteroconjugated Multiple Bonds
3.4.5 Nucleophilic Substitution of 1-Alkenyl Halides
3.4.6 Nucleophilic Addition onto Arenes and Hetarenes
3.4.7 Substitution of Halo-, Alkoxy-, and Metalloarenes or -hetarenes
3.4.8 Addition onto Nonaromatic Carbon—Nitrogen Multiple Bonds
3.4.9 Addition onto Carbonyl Compounds
3.5 Elimination Reactions
3.5.1 α-Elimination (1,1-Elimination)
3.5.2 β-Eliminations (1,2-Eliminations)
3.5.3 δ- and ζ-Eliminations (1,4- and 1,6-Eliminations)
3.5.4 Eliminations Giving Rise to Strained Multiple Bonds
3.6 Rearrangements
3.6.1 Halide-Displacing Carbon [1.2]-Migrations
3.6.2 Isomerization by from-Carbon-to-Carbon Migration
3.6.3 Isomerization by from-Nitrogen-to-Carbon Migration
3.6.4 Isomerization by from-Oxygen-to-Carbon Migration
3.6.5 Isomerization by from-Sulfur-to-Carbon Migration
3.6.6 Ring Closure of Allylmetals and Ring Opening of Cycloalkylmetals
3.6.7 Epilogue
4 Acknowledgments
5 References
List of Abbreviations
| Ar | argon |
| BNZ | benzene |
| BOC | tert-butoxycarbonyl |
| DEE | diethyl ether |
| El | electrophilic part of a reagent El—X |
| El—X | electrophilic reagent |
| eq. | (molar) equivalent |
| glyme | ethylene glycol dimethyl ether |
| HEX | hexanes (or petroleum ether of bp ~65 °C) |
| LIC-KOR | superbasic 1:1 mixture of LiC4H9 and KOC(CH3)3 |
| LIDA | lithium diisopropylamide |
| LIDMAE | lithium 2-(dimethylamino)ethoxide |
| LIM-KOR | superbasic mixture of LiCH(CH3)C2H5 and KOC(CH3)3 |
| LIT-KOR | superbasic mixture of LiC(CH3)3 and KOC(CH3)3 |
| LITMP | lithium 2,2,6,6-tetramethylpiperid-1-ide |
| M-Nu | metal-bearing nucleophile (alkoxide, amide) |
| Nu | nucleophilic group |
| NAC-KOR | superbasic 1:1 mixture of LiC4H9 and NaOC(CH3)3 |
| NMR | nuclear magnetic resonance |
| PMDTA | N,N,N′,N″,N″-pentamethyldiethylenetriamine |
| PEN | pentanes |
| R | alkyl or aryl |
| spec. | specifically (on this or that page) |
| Sv | solvent |
| THF | tetrahydrofuran |
| TOL | toluene |
| TMEDA | N,N,N′,N′-tetramethylethylenediamine |
1 Introduction
Indispensable tools in modern synthesis, organometallic reagents were perceived as exotic rarities half a century ago. What caused this profound change in attitude? The breakthrough event was without doubt the discovery of the ortho metalation of anisole and other heterosubstituted arenes by the pioneering work of Georg Wittig, Henry Gilman, and Charles Hauser. When in 1979, Heinz Gschwend and H. Rodriguez[1] summarized the progress made in this field, a steadily growing community of disciples in both academia and industry had recognized the potential of the new opportunities and had proliferated the underlying ideas in many directions. However, it needed more to transform episodes into a permanent success story. There are unique features that distinguish the organometallic approach to synthesis from previously existing options and establish it as an alternative or complementary concept.
The most salient particularity is presumably the better polarity balance inherent in reactions of polar organometallics. Saturated aliphatic hydrocarbons are totally inert toward nonradical species, and olefins or arenes are too weakly nucleophilic to combine with anything but the strongest electrophiles. This requires drastic conditions and entails poorly selective processes. In contrast, methyllithium or phenyllithium react smoothly with all kinds of electron-hungry substrates including such “lame ducks” as nitrosyl chloride or mercury acetate. This pronounced nucleophilicity widens the choice of reaction partners almost without any restriction and, as a corollary, ascertains product flexibility. Actually, an alkali metal attached to a carbon skeleton can be viewed like a joker in a card game destined to be traded in against something else.
The regioselective metalation of arenes at a position neighboring a heterosubstituent has been mentioned above. Deviations from the ortho rule do exist but are scarce.[2-5] The metal can nevertheless be systematically directed to meta or para positions if one resorts to the deployment of protective groups or similar stratagems.[6] Organometallics enable regiocontrol also in the alkenyl series. The addition of bromine onto the double bond of ω-chlorostyrene and subsequent base-mediated dehydrobromination unselectively produces a (Z/E) mixture of 1-bromo-2-chloro-1-phenylethenes. Conversely, the metalation of cis- and trans-ω-chlorostyrene (1-chloro-2-phenylethene) followed by trapping with a source of elemental bromine affords (E)- and (Z)-ω-bromo-ω-chlorostyrene, respectively.[7] These examples also shine a spotlight on the typoselectivity (or “chemoselectivity”) issue. Whereas ethylene reacts with bromine under addition, vinyllithium undergoes clean substitution. In other words, the organometallic reaction avoids a two-step sequence of consecutive addition and elimination. Such a shortcut often will be welcome.
A widely overlooked aspect of organometallic reactions is their economy. Actually, they are widely considered to be expensive although the price of the reagent is generally negligible. To work at temperatures of liquid ammonia or dry ice has nowada...
