Organometallics in Synthesis€¦ · Organometallics in Synthesis Third Manual . Organometallics in...

Organometallics in Synthesis Third Manual

Organometallics in Synthesis Third Manual

Edited by

Manfred Schlosser Swiss Federal Institute of Technology Lausanne, Switzerland

U

Na

К

Mg

Fe

Pd

Zn

SI

Sn

WILEY

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Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data

Schlosser, M. (Manfred) Organometallics in synthesis : third manual / edited by Manfred Schlosser, Swiss Federal Institute of Technology,

Lausanne, Switzerland, pages cm

Includes bibliographical references and index. ISBN 978-0-470-12217-4 (pbk.)

I. Organic compounds�Synthesis . 2. Organometallic compounds. I. Schlosser, M. (Manfred), editor of compilation. II. Title. QD262.O745 2013 547’.05�dc2 3 2012027800

Printed in the United States of America.

10 9 8 7 6 5 4 3 2 1

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Contents

Preface vii

Contributors ix

Organoalkali Chemistry 1 Manfred Schlosser

Organomagnesium and Organozinc Chemistry 223 Paul Knöchel

Organosilicon and Organotin Chemistry 373 Tamejiro Hiyama

Organoiron Chemistry 545 Hans-Joachim Knölker

Organopalladium Chemistry 777 Stefan Bräse

Index 1001

v

Preface

Experimenting means arts and crafts. The creator of a cultural masterpiece and the designer of novel properties incarnated in a new chemical entity face the same challenge. Expertise, skills, and perseverance are prerequisites. Next they need a blueprint for the execution of the work and, most important for the ultimate triumph, the faculty to adapt the project continuously to the obstacles encountered on the way. To realize a tricky molecular assembly, a researcher has to master both the rational action and the intuition-guided trial-and-error approach. The bases for such conscious or subconscious decision making are Methodology, the critical evaluation of existing methods, and Mechanism, the condensing of single observations into a general and predictive concept. Methods and mechanisms were the central topics of the first Manual and have continued to keep this role with all follow-up volumes.

Other main characteristics of the Manual series remain unaltered here. The attentive reader will nevertheless discover a few innovations. The most arguable one is the revival of w-butyllithium. The old-German «-alkyl is possibly the only unforgivable sin that can be committed against modern cod›ified nomenclature. And correct nomenclature is, as we use to tell our students, not a nonbinding recommendation but a Must. However, as an industrial executive objected, suppliers of chemicals do not sell butyllithium. They only listn-, sec-, and tert-butyllithium in their catalogs. Therefore, he argued, the personnel on night shift needs to know unequivocally what reagent to order and to feed into the reactor.

Before closing, I wish to share with the professional community some really good news. The Manual series is going to be continued soon. Bruce Lipshutz, my friend and partner for many years, is preparing a fourth volume covering copper, gold, rhodium, nickel, titanium, and zirconium. Be assured this will once again become an outstanding collection of chemical arts and crafts.

MANFRED SCHLOSSER December 2012

vii

Contributors

Bräse Stefan Institute of Organic Chemistry, Karlsruhe Institute of Technology, D-76131 Karlsruhe, Germany

Tamejiro Hiyama Research and Development Initiative, Chuo University, Bunkyo-ku, Kyoto 112-8551, Japan

Paul Knöchel Department of Chemistry and Biochemistry, Ludwig-Maximilians-Universitä t München , D-81377 Munich, Germany

Hans-Joachim Knölker Department of Chemistry, Technical University of Dresden, D-01069 Dresden, Germany

Manfred Schlosser Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology, CH-1015 Lausanne, Switzerland

ix

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

2 Chapter 1: Organoalkali Chemistry, by Manfred Schlosser

Contents

1 Introduction 4

2 Coverage 6

3 Reactions 7

3.1 Displacement of Metal by Hydrogen 8 3.1.1 Metalation of Aliphatic or Aromatic Hydrocarbons 9 3.1.2 Neutralization of Organometallic Intermediates 10

3.2 Displacement of the Metal by Another Metal or Metalloid 17 3.2.1 "Uphill" Reactions Generating More Basic Species 17 3.2.2 "Downhill" Reactions Generating More Electrophilic Species 19 3.2.3 Ate Complex Chemistry 24

3.3 Displacement of the Metal by a Heterosubstituent 32 3.3.1 Nitrogen Displaces the Metal 33 3.3.2 Phosphorus Displaces the Metal 35 3.3.3 Oxygen Displaces the Metal 42 3.3.4 Sulfur Displaces the Metal 48 3.3.5 Fluorine Displaces the Metal 53 3.3.6 Chlorine Displaces the Metal 57 3.3.7 Bromine Displaces the Metal 58 3.3.8 Iodine Displaces the Metal 60

3.4 Carbon-Carbon Bond Formation 61 3.4.1 Alkyl and 2-Alkenyl Halides or Sulfonates 62 3.4.2 Ring Opening of Cyclic Amines and Ethers 68 3.4.3 Addition onto Carbon-Carbon Multiple Bonds 73 3.4.4 Addition onto Heteroconjugated Multiple Bonds 82 3.4.5 Nucleophilic Substitution of 1-Alkenyl Halides 85 3.4.6 Nucleophilic Addition onto Arenes and Hetarenes 89 3.4.7 Substitution of Halo-, Alkoxy-, and Metalloarenes or -hetarenes 94 3.4.8 Addition onto Nonaromatic Carbon-Nitrogen Multiple Bonds 99 3.4.9 Addition onto Carbonyl Compounds 104

3.5 Elimination Reactions 115 3.5.1 oc-Elimination (1,1 -Elimination) 116 3.5.2 ß-Elimination s (1,2-Eliminations) 118 3.5.3 5- and ^-Eliminations (1,4- and 1,6-Eliminations) 131 3.5.4 Eliminations Giving Rise to Strained Multiple Bonds 135

Chapter 1: Organoalkali Chemistry, by Manfred Schlosser 3

3.6 Rearrangements 151 3.6.1 Halide-Displacing Carbon [1.2]-Migrations 152 3.6.2 Isomerization by from-Carbon-to-Carbon Migration 157 3.6.3 Isomerization by from-Nitrogen-to-Carbon Migration 162 3.6.4 Isomerization by from-Oxygen-to-Carbon Migration 169 3.6.5 Isomerization by from-Sulfur-to-Carbon Migration 179 3.6.6 Ring Closure of AUylmetals and Ring Opening of Cycloalkylmetals 181 3.6.7 Epilogue 185

4 Acknowledgments 186

5 References 187

4 Organometallics in Synthesis, Third Manual

List of Abbreviations

Ar BNZ

BOC

DEE

El

El-X

eq.

glyme

HEX

LIC-KOR

LIDA

LIDMAE

LIM-KOR

LIT-KOR

LITMP

M-Nu

Nu

NAC-KOR

NMR

PMDTA

PEN

R

spec.

Sv

THF

TOL

TMEDA

argon benzene

fer/-butoxycarbonyl

diethyl ether

electrophilic part of a reagent El-X

electrophilic reagent

(molar) equivalent

ethylene glycol dimethyl ether

hexanes (or petroleum ether of bp -65 °C )

superbasic 1:1 mixture of LiC4H9 and KOC(CH3)3

lithium diisopropylamide

lithium 2-(dimethylamino)ethoxide

superbasic mixture of LiCH(CH3)C2H5 and KOC(CH3);

superbasic mixture of LiC(CH3)3 and KOC(CH3)3

lithium 2,2,6,6-tetramethylpiperid-1 -ide

metal-bearing nucleophile (alkoxide, amide)

nucleophilic group

superbasic 1:1 mixture of LiC4H9 and NaOC(CH3)3

nuclear magnetic resonance

A^7V,7Vf,7V",A ’̂f-pentamethyldiethylenetriamine

pentanes

alkyl or aryl

specifically (on this or that page)

solvent

tetrahydrofuran

toluene

7V,7V,A^^V-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 co-chlorostyrene and subsequent base-mediated dehydrobromination unselectively produces a (Z/E) mixture of l-bromo-2-chloro-l-phenylethenes. Conversely, the metalation of cis- and Jnms-co-chlorostyrene (l-chloro-2-phenylethene) followed by trapping with a source of elemental bromine affords (E)- and (Z)-co-bromo-co-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 nowadays become routine. It is true that lithium has to be removed from industrial waste waters after isolation of the product. This drawback is more than compensated by major advantages. Organoalkali reactions are generally clean and high-yielding. Therefore, they frequently offer the possibility to contract two or more individual stages to a nonstop procedure. The expedient preparation of the analgetic ibuprofene in a six-step-one-flask protocol supports this view convincingly.[8]

Workup can prove to be very costly, and water, due to its high heat of evaporation, is far from being an ideal reaction medium. The solvents employed in organometallic chemistry use to be mixtures of hexanes and an ethereal cosolvent (e.g., tert-butyl methyl ether) or toluene. They can be removed in an energy-efficient manner by distillation. The product left behind is most frequently a salt-like compound such as a metal carboxylate, metal alkoxide, or metal amide. After neutralization with a stoichiometric amount of an anhydrous strong acid, it can be extracted and directly purified.

2 Coverage

The present survey is exclusively devoted to the application of polar organometallic reagents to organic synthesis. This exciting subject was only accessorily treated in the chapter on "Organoalkali Chemistry" that was published as part of the Second Manual[9] of the Organometallics in Synthesis handbook series. A supplement was deemed appropriate if not mandatory.

Under such circumstances, it should prove helpful to start with recalling the contents of the above-mentioned chapter. It is composed of five main sections:

§ 1 Historical Background (9 pages)

§ 2 Structure and Mobility of Polar Organometallics (36 pages)

§ 3 Reactivity and Selectivity of Polar Organometallics (39 pages)

§ 4 Preparation of Organometallic Reagents and Intermediates (200 pages)

§ 5 Handling of Organoalkali Compounds (13 pages)

Before organometallic intermediates can be converted into isolable products, they need to be prepared. Their generation is hence as critical as their ultimate transformation. This explains why more than half of the allotted space, 200 out of 352 pages (references included), has been reserved for this topic. A brief overview of this cornerstone section


(§ 4) will hence be given. There are two times five methods to choose from in order to prepare a reactive organometallic species M-R from an organic precursor Z-R wherein Z represents a halogen X (Cl, Br, I), chalcogen Y (O, S, Se), metalloid Q (Hg, Sn), carbon group (C), or hydrogen (H). If used in its elemental state, the metal (M) may insert reductively into the Z-R bond, or alternatively, if contained in an organometallic reagent M-R’, it can promote a permutational M/Z displacement (Table 1-1). To give an idea of the practical significance of each of these options, the number of pertinent examples and, in parentheses, working procedures selected from the literature and compiled in the Second Manual are listed (Table 1-1).

Table 1-1. Two times five methods for the generation of organometallic intermediates M-R from organic precursors Z-R.

reductive M insertion electrofugal group permutation with

into the Z-R bond Z the M-R' reagent

43 (10) X (halogen) 272 ( 6)

52 ( 5) Y (chalcogen) 26 ( 2)

24 ( 4) Q (metalloid) 87 ( 5)

9 ( 3 ) С (carbon) 13 ( 3)

21 ( 1) H (hydrogen) 663 (56)

Halogen/metal permutation and hydrogen/metal permutation (usually apostrophed as "metalation") dominate the interconversion methods. They employ organoalkali reagents such as phenyllithium, methyllithium, ÿ-butyllithium , seobutyllithium, or the superbasic LIC-KOR mixture. However, even if commercial, these reagents have to be made beforehand. The reaction of a chloro- or bromo-substituted hydrocarbon with lithium, sodium, or magnesium offers a standard entry to them. Thus, ultimately one always has to revert to the metal.

3 Reactions

Depending on the transformation executed, the metal of an organometallic reagent will be replaced by a hydrogen atom, another metal or metalloid, a heterosubstituent, or a carbon entity. Allowing for some further differentiation, we may classify organometallic reactions into eight prototypes (Figure 1-1). They comprise partial or complete neutralization by proton transfer from weak acids (such as hydrocarbons), moderately strong acids (such as amines), or strong acids (in particular, hydroxyl containing ones), but also cover metal/metal(loid) exchange, substitution by a heteroatom or a heterofunctional group, condensation with a carbon electrophile, nucleophilic addition onto multiple bonds, ß-eliminations , and isomerizations or rearrangements.


M-R' H-R

M'-R

X-R

R-C-Ć-Y-M R'-R

Figure 1-1. Classification of organometallic reactions into eight categories: replacement of the metal by hydrogen, another metal (or metalloid), a heterosubstituent, a carbon group, and eliminations or isomerizations.

Operationally simple as they are, such organometallic reactions have conquered a lasting place in modern organic synthesis. What makes them particularly attractive is their complementarity to well-known other methods.

3.1 Displacement of Metal by Hydrogen

An organometallic reagent M-R may react with a hydrocarbon H-Rf under hydrogen/metal permutation to generate a new organometallic intermediate M-R’. Being subject to a variety of factors, the countercurrent metal and proton transfer process can proceed more or less rapidly. To make it occur at all, the substrate H-R’ must be more acidic than the resulting hydrocarbon H-R.

If a metal-carbon (or metal-nitrogen) bond is quenched by a strong proton donor such as methanol or hydrochloric acid, the original reactivity potential is completely lost. The neutralization of the organometallic species is diffusion controlled under such circumstances.[10] The same is the case with an alcohol or an amine such as diisopropyamine. As a rule, OH and NH containing compounds are stronger acids than hydrocarbons. Their deprotonation is quantitative and instantaneous (<1 s) even at dry-ice temperatures (-75 °C). [11]

Although an amide base M-NRf2 is thermodynamically less powerful than alkyl-

or arylmetals, it but may prove kinetically superior. Thus, amines may be used in catalytic amounts to speed up organolithium-driven deprotonations (see example on p. 10).


3.1.1 Metalation of Aliphatic or Aromatic Hydrocarbons

When selecting a metalating agent, one may rely on intuition or undertake extensive screening. In either case, a few guidelines will provide helpful orientation (Figure 1-2). Organomagnesiums cannot deprotonate but the most acidic hydrocarbons. Organolithiums prove to be far more reactive although ÿ-butyllithiu m requires activation by TMEDA or PMDTA to cope even with allylic or benzylic positions. Benzene and olefins lacking allylic sites (e.g., camphene) are already found inert toward such chelates. Although far more reactive, organosodium reagents often lack selectivity. For example, they tend to deprotonate terminal alkenes[12, 13] at allylic and olefinic positions concomitantly and alkylarenes [14-16] at both benzylic and aromatic positions. Organopotassium and the related superbasic mixed-metal reagents exhibit highest basicity along with rather low nucleophilicity. They are powerful enough to metalate various cyclopropanes but no cyclobutanes.[17] Simple alkanes are unreactive, the reported metalations[14,18] of pentane, hexane, and cyclohexane having proved irreproducible.[19]

CH-acid BrMg-C4H9 U-C4H9 Na-C4H9 K-C4H9

CH4 H V / V H

H H

н2с=сн2 н-^-н H H

CH3

Ó kJTXJ

H-C = C-f < ^ H

D' Figure 1-2. Comparitive metalation potency of alkylmagnesium halides,

alkyllithiums, alkylsodiums, and alkylpotassiums (including superbasic mixed-metal reagents): empty boxes mean practically no reaction, gray-screened boxes mean marginal or unselective metalation, and black boxes mean efficient metalation.

Heteroelements in general facilitate metalation reactions. 7V-Methylpiperidine and, by extension, trimethylamine react smoothly with the sec-butyllithium/potassium tert-butoxide (LIS-KOR) mixture at their methyl groups.[20] The same happens when


A^A^N’-tetramethylethylenediamine (TMEDA)[21’ 22] and AW7V’,7V’-tetramethyl-methylenediamine[23] are treated with seobutyllithium or terf-butyllithium. n-Butylpotassium converts dimethyl ether readily to methoxymethylpotassium.[24] Ethyl and methyl vinyl ether require sec- or tert-butyllithium to undergo oc-metalation, whereas n-butyllithium suffices to bring about the or/Ao-lithiation of anisole[25] and the oc-lithiation (at the oxygen-adjacent position) of allyl phenyl ether[26] and benzyl phenyl ether.[27]

Heteroatoms affect both the thermodynamics and the kinetics of acid-base reactions. Although less basic than most organolithiums, organic lithium amides may prove kinetically fitter as Rolf Huisgen and Jürge n Sauer have concluded from one of their landmark studies (Scheme 1-1).[28] The ör/˜o-lithiatio n of fluoro-, chloro-, and bromobenzene proceeds with lithium piperidide some 50 times faster than with phenyllithium but only to a minute extent as the acid/base equilibrium lies far on the haloarene/lithium amide side. The addition of 0.10 molar equivalents of piperidine invigorates the forceful but sluggish phenyllithium reagent. Lithium piperidide efficaceously picks up a proton from the halogen-adjacent position and is continuously replenished, as soon as piperidine is formed, by reaction of the latter with phenyllithium. The 2-bromophenyllithium produced eliminates lithium bromide rapidly at temperatures around or above -100 ° C to set free the short-lived 1,2-didehydrobenzene ("benzynŒ") doomed to be captured by lithium piperidide or any other potent nucleophile.

o*< ,^—-.^. (ai) H-R Li-R j

[R = C6H5lC4H9,CH3] *

(O') Scheme 1-1. Piperidine shuttling lithium from phenyllithium to bromobenzene, thus

generating the labile 2-bromophenyllithium and, next, "benzynŒ" (1,2-dedihydrobenzene) that is instantaneously trapped by lithium piperidide.

3.1.2 Neutralization of Organometallic Intermediates

Why should someone take all the pains to steer a polar metal into a targeted position of an organic backbone just to spoil the intermediate right away by trivial hydrolysis? Such a seemingly nonproductive step may nevertheless become a cornerstone in a carefully planned synthesis edifice. Neutralization can be useful in several respects. First, one hardly finds any cleaner and more economic method for the introduction of


deuterium or tritium into an organic molecule. Next, the selective removal of an extra halogen from a readily accessible over-halogenated intermediate may be a versatile option. Finally, asymmetric (re)protonation represents a particularly attractive approach to secure enantioselectivity.

a) Deuteration

Selectively labeled isotopomers enable the unambiguous identification of deprotonation sites. To this end, benzotrifluoride-4-d was readily prepared by consecutive reaction of 4-bromobenzotrifluoride with w-butyllithium and methanol-O-d (from dimethyl sulfate and heavy water) and benzotrifluoride-2,6-æ/ 2 by three sequential treatments of the substrate with the ÿ-butyllithium/potassiu m ter/-butoxide superbase and deuterium chloride in diethyl ether (from thionyl chloride and heavy water[29]). 3,5-Dibromobenzotrifluoride being unavailable at that time, one had to start from 3-bromobenzotrifluoride and to introduce a second heavy halogen at the 4-position first before sending it by deprotonation-triggered heavy halogen migration to the 5-position. Both heavy halogens were simultaneously replaced by lithium and subsequently by deuterium.[30]

Benzotrifluoride-3,5-аР^

CF3 CF3 CF3 CF3 (iaŁ-7 J \ ( L ) J \ (i.)UC(CH3)3 ' L i - N / ^ / Г |) LiN('C3H7)2 f^\\ (6.0 eg.)

Br (2.)I2 ^ V ^ B r <2-)H2° I/ ^ ^ k

B r ( 2 - ) D 2 0 D > ^

At -100 °C , ÿ-butyllithiu m (25 mmol) is treated consecutively with equimolar amounts of 2,2,6,6-tetramethylpiperidide and 3-brombenzotrifluoride. After 2 h, iodine (25 mmol) is added. 3-Bromo-4-iodobenzotrifluoride (81%; mp 31-33 °C ; bp 80-82 °C / 10 mmHg) is isolated. Treatment with one equivalent of lithium diisopropylamide in THF (50 mL) for 3 h at -75 °C and subsequently with water (50 mL) converts it into the isomeric 3-bromo-5-iodobenzotrifluoride (82%; mp -20 to -15 °C ; bp 64-66 °C/2 mmHg; «D° 1.5584). At -75 °C , the latter compound (15 mmol) and, 10 min later, heavy water (deuterium oxide; 2.0 mL; 2.2 g; 0.11 mol) are added to a solution of excess tert-butyllithium (65 mmol) in pentanes (40 mL) and diethyl ether (60 mL). The labeled product is isolated by distillation (63%; mp -27 to -25 °C ; bp 100-103 °C ; n$ 1.4140).

Heavy water is the cheapest available deuterium source. However, it has one inconvenience. Being inevitably employed in excess, it necessitates extraction or at least drying of the reaction mixture as part of the workup protocol. In contrast, deuterium chloride in diethyl ether can be employed in stoichiometric doses. But also this reagent suffers from a drawback. It reacts, if slowly, with the ethereal solvent. Therefore, the indefinitely storable phenylacetylene-^y-J may often become the deuteration reagent of choice. Due to its high intrinsic acidity and its needle-like slim shape, this terminally deuterated acetylene transfers the isotope label most effectively and in general irreversibly.


Phenylacetylene-(£h(fi l

o- C-H (l.)Li-C4H9

(2.) DCI О- C-D

At 0 °C , a 2.0 M solution of «-butyllithium (0.11 mol) in pentanes (or the same amount of ethereal methyllithium) is added to phenylacetylene (11 mL, 10 g, 0.10 mol) in diethyl ether (10 mL). A 1.5 M ethereal solution of deuterium chloride,[29] freshly prepared and stored in a Schlenk buret at -25 °C , follows immediately afterward. The solvent is removed by slow distillation through a 20 cm long Widmer column. Short-path distillation of the remainder gives a colorless liquid (93%; bp 141-143 °C ; n™ 1.5523). The infrared absorption spectrum of the neat compound reveals a strong and sharp band at 2570 cm-1, whereas the characteristic acetylenie CH-stretching frequency at 3300 cm"1 has disappeared.

b) Selective Removal of One-Halogen-Too-Many

The introduction of bromo substituents can convert the commercial 1,2,3-trifluorobenzene into useful building blocks (Scheme l-2).[32] Consecutive treatment with seobutyllithium and elemental bromine gives l-bromo-2,3,4-trifluorobenzene (1, 95%). l,5-Dibromo-2,3,4-trifluorobenzene (2, 87%) forms when the silane obtained by in situ trapping of 5-bromo-2,3,4-trifluorophenyllithium with chlorotrimethylsilane is heated in the presence of elemental bromine. Upon incubation with lithium diisopropylamide, a basicity gradient-driven heavy halogen migration[6] occurs to provide an intermediate that affords with tetrabromomethane or methanol l,2,3-tribromo-4,5,6-trifluorobenzene (3, 67%) and l,2-dibromo-3,4,5-trifluorobenzene(4, 92%), respectively.

LiN('C3H7)2

^ a + CISi(CH3)3 J ^ ^ ^ ^ B r ( H 3 C ) 3 S i ^ ^ 1

JBr2

иСН(СН3)С2Н5

ЧЛ-F

Br2

Br

LiN('C3H7)2

Br

HOCH3y

Scheme 1-2. Tribromo- (3), dibromo- (2 and 4), and monobromo-(1 and 5) derivatives of 1,2,3-trifluorobenzene.


The latter product can be regioselectively debrominated to 5-bromo-1,2,3-trifluorobenzene (5, 89%) by heavy halogen/lithium permutation and subsequent neutralization.[32] Such a two-steps-forward-and-one-step-back protocol, also apostrophed as the Echternach choreography,[6] may offer an attractive solution in many cases where there is no direct route leading to the required compound.

Starting from l,3-dibromo-2-iodobenzene, the symmetrical 2,2’,6,6’-tetrabromo-biphenyl (6) can be readily prepared by aryl-aryl coupling (see also p. 141).[33] Under carefully controlled conditions, either one or two halogens may be selectively replaced by lithium and subsequently the metal substituted by a variety of electrophiles, phosphinyl groups included (Scheme 1-3). The hydrolysis products 2,2’-dibromobiphenyl and 2,2’,6-tribromobiphenyl {El = H) can also be further elaborated.

Li Br El Br

Br

^ // Br

Br

Br

[ El = electrophile ]

Br Br

Scheme 1-3. Single or double debromination of 2,2’,6,6’-tetrabromobiphenyl (6).

2,2 ',6-Tribromobiphenyl from 2,2 ',6,6 '-tetrabromobiphenyl[33]

Br Br Br Br

(1.) LiC4H9

»• (2.) HOCH3

At -75 °C , w-butyllithium (0.10 mol) in hexanes (52 mL) is added to 2,2’,6,6’-tetrabromobiphenyl (47 g, 0.10 mol; prepared according to § 3.4.7a) in THF (0.50 L). Immediately afterward the mixture is treated with methanol (10 mL) and water (0.20 L). The organic layer is collected and the aqueous phase extracted with diethyl ether (2 x 0.10 L). The combined organic solutions are dried with sodium sulfate before being evaporated. Crystallization from ethanol gives 2,2’,6-tribromobiphenyl (35 g, 91%) as colorless needles; mp 95-97 °C .


In a similar way, the readily accessible gew-dibromoalkenes and gem-dibromocyclopropanes can be subjected to a selective monodebromination by consecutive treatment with an alkyllithium and methanol or water. Moreover, such reactions can be conducted stereoselectively, the sterically more exposed halogen being replaced preferentially. Thus, for example, the treatment of (2,2-dibromovinyl)cyclohexane with a slight excess of Ł-butyllithium at -100 ° C followed by trapping of the intermediates Z-7 and E-l with dry ice affords the (Z)- and (£)-isomeric acids {El = COOH) in a 3:1 ratio.[3436] However, the organometallic intermediate E-l carrying the metal on the same side as the organic groups R is thermodynamically more stable (Scheme 1�4) . Employing a slight excess of the gew-dibromo substrate triggers a continuous halogen/metal permutation that equilibrates the two organolithium species until the (£) isomer 7 is almost exclusively present (Z/E > 99:1) gem-Dibromocyclopropanes behave in the same way as gew-dibromoalkenes (Scheme l-4).[37_39] Equilibration again gives rise to the eftdo-substituted cyclopropyllithium E-H and ultimately to the corresponding derivatives. The remaining bromine atom can be replaced in a separate step or according to a one-pot protocol by another electrophile. In this way, a straightforward sirenin synthesis has been accomplished.[40]

Br

Br

LiC4H9 y

-100 °C '*

у

/

\

Li

R Br

i

^ B r

El-X

El-X

R Br

E-l

[ R = alkyl, aryl; R' = H, alkyl; X = halide, etc.; El = any electrophilic group ]

M JR’ . Br J R' E Br

Br

Br

LiC4H9

-100 °C

M Br EI-X ж: £-8

Scheme 1-4. Stereocontrolled debromination of gew-dibromoalkenes and gew-dibromocyclopropanes

by halogen/metal permutation.

c) Deracemization and Related Stereomutations

If accomplished in the presence of a chiral auxiliary, consecutive deprotonation and reprotonation of a tertiary stereocenter may transform a racemic mixture into an


enriched or even pure enantiomer. Thus, the lithiation of the 1,2,3,4-tetrahydro-l-methyl-N-pivaloylisoquinolines 9 produces configurationally mobile intermediates. They react with the chiral (i?,7?)-di(l-phenylethyl)amine to the (S)-enantiomers in up to 86% å å (Scheme 1-5).[41]

L О , Д Н 0 HN н / " / Н 0 9a : x = H

снз Ll СНз ) НзС

9 b : x = H3co н5с6

Scheme 1-5. Deracemization of 1-methylisoquinolidines (9) by lithiation and subsequent asymmetric reprotonation.

Ylides and enolates lack ordinary carbon-metal bonds and hence are no true organometallics. In the framework of asymmetric reprotonation, they nevertheless play a key role.

The racemic diphenyl(l-phenylethyl)phosphine oxide undergoes clean oc-metalation when treated with Ł-butyllithium in toluene (TOL) at -75 °C . The resulting PO ylide 10, a phospha-enolate, reacts with 3-e«äfo-anilinocampho r to the (S)-9 enantiomer with 82% å å (Scheme l-6).[42]

Scheme 1-6. Deracemization of diphenyl(l-phenylethyl)phosphine oxide by consecutive cx-deprotonation and asymmetric reprotonation

ofthePO ylide 10.

In this context, one may also pay attention to the so-called "betaine-ylides"[43’44]

that act as key intermediates in stereocontrolled Wittig olefination reactions. They are generated from the ordinary adducts obtained by the combination of a phosphine ylide and an aldehyde in the presence of lithium bromide (or another soluble lithium salt). When the P-betaines are a-deprotonated with phenyllithium, the stereocenter at the phosphorus-adjacent carbon atom becomes configurationally mobile. In this way, erythro/threo mixtures can spontaneously convert into virtually pure threo-hetaine ylides (ß-lithioox y ylides, ß-oxid o ylides). Reprotonation and subsequent elimination of triphenylphosphine oxide affords trans olefms,[43] whereas a-substitution by electrophiles other than acids leads to branched alkenes exhibiting a well-defined stereochemistry "("three-dimensional"" Wittig reaction or SCOOPY method).[45]


Fascinating examples of enantioselective enolate reprotonations have been disclosed by Charles Fehr et a/.[46_49] The olfactive profiles of the rose oil fragrances methyl (˜)-a-cyclogeranate(˜-ll ) and (S)-oc-damascone (S-12) are far superior than those of their mirror images. Deprotonation of the racemic methyl ester (11, YR = OCH3) with A7-butyllithium at -100 °C and subsequent reprotonation with (+)-7V-isopropylephedrine gives the methyl ester R-ll having only a moderate å å of 36%.[47] The enantioselectivity increases to 77% and 99% when the phenyl ester (11, YR = OC6H5) and the corresponding thioester (11, YR = SC6H5) are subjected to the same conditions (Scheme 1-7). Upon reprotonation with (-)-TV-isopropylephedrine, the (5)-enantiomeric thiolate (5-11, YR = SC6H5) is obtained of course. Deprotonation of methyl ß -cyclogeranate followed by methoxy displacement by allylmagnesium chloride generates an mixed-metal enolate. Its protonation with (-)-TV-isopropylephedrine and subsequent base-catalyzed double-bond shift afford (*S)-y-damascone (S-l2) in 87% yield and with 75% å å (Scheme l-7).[47’50]

COYR

COOCH3

UC4H9

THF, -100 °C

[ YR

(IOUC4H9

(2.) CIMg-CH2-CH=CH2

1 OLi

= осн3/ ос6н5,

Н5Сб СН3

НО|Л-( [(+)antipode]

SC6H5]

и ОМдСШОСНз

1^ЧЖ^^ ^ г

Н5Сб СИ3

( D M / но н-\ [(-)antipode]

(2.) Al203/DEE

.sCOYR

R-ll

S-12

Scheme 1-7. Deracemization of methyl oc-cyclogeranate (11) and a-damascone (12) by enolate protonation with (+)- and (-)-

N-isopropylephedrine.

In the course of such investigations, an extremely simple way for the transformation of methyl ß-cyclogeranat e into its nonconjugated and hence energetically less favorable y-isomer was found (Scheme l-8).[50] The desired ester (70%) is obtained without any isomeric contamination as a racemate when the LIDA-produced enolate 13a [M = Li] is trapped with chlorotrimethylsilane and the resulting mixed ketene acetal 13b [M = Si(CH3)3] is subsequently hydrolyzed.

AxOOCH3 (1.) LiC4H9

THF-10/+15°C

(2.) CISi(CH3)3

11 UM it ОМ

OCH3 H20 COOCH3

1 3 a : M = Li 1 3 b : M = Si(CH3)3

Scheme 1-8. "Up-hill" isomerization of methyl ß-cyclogeranat e into the y-isomer through the lithium enolate 13a and the (9-silyl enether 13b.


This opens another straightforward access to the much sought after (S)-enantiomer of y-damascone. The racemate resolution of y-cyclogeranic acid is readily accomplished using (-)-(£)-1-phenylethylamine for diastereoisomer formation. Methyl (S^-y-cyclogeranate is simultaneously treated with allylmagnesium chloride and lithium diisopropylamide (LIDA) to convert the emerging ketone quickly into its enolate thus protecting it against addition of a second organomagnesium equivalent. Acid hydrolysis gives a y-damescone isomer (59%). Stirring its solution in DEE with a slurry of alumina suffices to push the terminal double bond into conjugation with the carbonyl group.[50]

3.2 Displacement of the Metal by Another Metal or Metalloid

Each metal or metalloid displays a reactivity pattern of its own. "Metal tuning," the search of the optimal element for a given transformation, is a central issue in metal-mediated organic synthesis.Far from being exhaustive, the survey below highlights just a few typical aspects.

From a practical point of view, the only valid reason for grafting a different metal on a given organic backbone is to modify reactivity and selectivity. There are three different scenarios. The reaction of a polar alkali (or alkali-earth) compound with a mercury(II) halide, a chlorotrialkylsilane, or a chlorotrialkylstannane produces an organometalloid that proves hydrolytically stable at pH 7. Being only residually basic organometalloids, in particular stannanes, usually serve as storage forms from which polar organometallics can be readily regenerated. The metathetical interconversion of an organoalkali with magnesium, zinc, manganese, titanium, zirconium, cerium, boron, or aluminum salts attenuates the basicity without eliminating it completely and, at the same time, increases the electrophilicity, in particular the oxyphilicity, of the new species. This shapes new reactivity patterns. Finally, when a more electropositive metal, for example, sodium or potassium, takes the place of a more electronegative one, for example, lithium, the basicity of the new compound is boosted far beyond its nucleophilicity. This means that organopotassiums and the related superbasic mixed-metal reagents are obviously the best choice for promoting metalation and other deprotonation reactions, whereas lithium, magnesium, zinc, and titanium derivatives excel in addition reactions, in particular, onto carbon-oxygen double bonds.

3.2.1 "Uphill" Reactions Generating More Basic Species

To bring about metal/metal or metalloid/metal displacements, an organometal(loid) is exposed to a more electropositive intruder metal capable of cleaving the original carbon-metal bond reductively. In this way, all kinds of magnesium, lithium, sodium, potassium, and cesium derivatives can be made from organomercurials[9a] as organosodiums, -potassiums and -cesiums from alkyllithiums or aryllithiums (Scheme 1-9).[51’52]


R2Hg ł 2M »► 2 M-R + Hg [amalgamated with M]

R-Li + M ^ M-R + Li [ M = Na, K, Cs ]

Scheme 1-9. Displacement of a carbon-bound mercury or lithium by a

more electropositive metal.

More frequently inorganic ("salt-like") reagents M-X rather than elemental metals are employed for that type of metal exchange. It is always the more electropositive metal that abandons the inevitably weak bond to carbon and combines with the saline counterion X as long as the latter is a halide. Thus, organosodiums and organopotassiums react with lithium bromide to give the corresponding organolithium along with sodium or potassium bromide (Scheme 1-10). There are, however, noteworthy exceptions from such a "downhill" trend as Drahoslav Lim and his group have recognized.[53] Compared with the oxygen-sodium or oxygen-potassium bond, the oxygen-lithium bond is so much stronger that this difference outweighs whatever disparity may exist at the level of carbon-metal bonds. Consequently, alkyl- and aryllithiums react with soluble alkoxides such as sodium and potassium terf-butoxide to produce preferentially, although not purely, the heavier alkali derivatives (Scheme 1-10).

R-M + Li-Br ^ » Li-R + M-Br

R-Li + М-ОС(СН3)з ««- » M-R + Li-OC(CH3)3

[ M = Na, K; R = alkyl, aryl ]

Scheme 1-10. Conversion of organosodiums or organopotassiums into organolithiums using lithium bromide and of organolithiums into organosodiums or organopotassiums

using sodium or potassium ter/-butoxide.

In this respect, a word of warning deems appropriate. Organic derivatives of two different alkali metals tend to form energetically privileged mixed aggregates. Therefore, aliphatic or aromatic sodium or potassium derivatives emanating from an organometal/metal alkoxide permutation are hardly ever pure compounds. Usually the heavier organoalkalis include varying amounts (generally 5-25%) of the corresponding organolithiums or lithium alcoholates. Methylpotassium[54] (and its perdeuterated isotopomer as well[55]) prepared by stirring a slurry of potassium /ert-butoxide in ethereal methyllithium for 5 min at -10 ° C °C still contains some 10-20% of lithium compounds. The precipitate collected after having treated ethereal phenyllithium with sodium tert-butoxide and potassium menthoxide shows sodium/lithium and potassium/lithium ratios of 20:1 and 9:1, respectively.t56] As a matter of fact, even small amounts of lithium contaminants can catalyze or paralyze the reactions of heavier organoalkalis.

The transformation of allylic lithium compounds into their sodium[57] and potassium^8’59] analogs seems to occur with acceptable completeness. Extensive washing

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