comprehensive organic synthesis ii || 6.18 eliminations to form alkenes, allenes, and alkynes and...

6.18 Eliminations to Form Alkenes, Allenes, and Alkynes and RelatedReactionsRA Biggs, University of Oklahoma, Norman, OK, USAWW Ogilvie, University of Ottawa, Ottawa, ON, Canada

r 2014 Elsevier Ltd. All rights reserved.

This article is a revision of the previous edition article by Adolf Krebs, Juergen Swienty-Busch, Vol. 6, pp 949–973, © 1991, Elsevier Ltd.

6.18.1 Introduction 802
6.18.2 b-Eliminations 803 6.18.2.1 Mechanistic Drift 805 6.18.2.2 Elimination Versus Substitution 806 6.18.2.3 Regiochemical Control 807 6.18.2.4 Stereoselectivity 810 6.18.3 a-Eliminations 812 6.18.4 Stereoselective Methods 812 6.18.4.1 Eliminations to Form E-Alkenes 812 6.18.4.1.1 Doubly substituted alkenes from alkyl halides 812 6.18.4.1.2 Doubly substituted alkenes from alcohols 813 6.18.4.1.3 Doubly substituted alkenes from vicinal dihalides 815 6.18.4.1.4 Doubly substituted alkenes using other leaving groups 815 6.18.4.2 Eliminations to Form Z-Alkenes 817 6.18.4.2.1 Disubstituted Z-alkenes 818 6.18.4.3 Trisubstituted Alkenes 819 6.18.4.4 Tetrasubstituted Alkenes 823 6.18.5 Stereospecific Methods 824 6.18.5.1 Alkenes from Vicinal Dihalides 824 6.18.5.2 Vicinal Diols or Dialkoxy Derivatives 825 6.18.5.3 Halohydrin Derivatives 825 6.18.5.4 b-Hydroxy Selenides 826 6.18.5.5 Epoxides 826 6.18.5.6 Episulfides 828 6.18.5.7 Aziridines 828 6.18.5.8 Epi-Phosphonium 828 6.18.5.9 Phenylsulfides 829 6.18.6 Eliminations to Form Terminal Alkenes 829 6.18.6.1 Preparation from Alkyl Halides 830 6.18.6.2 Preparation from Alcohols 830 6.18.6.3 Preparation from Epoxides 830 6.18.6.4 Terminal Olefins from Selenium and Sulfur-Based Leaving Groups 831 6.18.7 Eliminations to Form Allenes 832 6.18.7.1 Stereocontrolled Methods 832 6.18.7.2 Other Methods 833 6.18.7.3 From Alkene Precursors 834 6.18.7.4 From Alkyne Precursors 836 6.18.8 Eliminations to Form Alkynes 836 References 838
6.18.1 Introduction

Elimination reactions are oxidative processes that generate π bonds through the removal (elimination) of two atoms, one of whichis usually a hydrogen. These reactions differ from other methods of introducing unsaturation in that the reaction ‘adds’ double ortriple bonds to an existing carbon framework. The term elimination is normally reserved for those processes that generate π bondsbetween carbon atoms.1,2,3 When the newly formed π bond involves a heteroatom such as nitrogen or oxygen, the process isnormally called an oxidation (Figure 1).

Comprehensive Organic Synthesis II, Volume 6 doi:10.1016/B978-0-08-097742-3.00627-3802

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X

H+ HX

B

A

+ AB

X+ HX

H

(1)

(2)

(3)

Figure 1 Types of elimination reactions.

Eliminations to Form Alkenes, Allenes, and Alkynes and Related Reactions 803

The most common eliminations in organic synthesis are those that involve vicinal atoms, and these processes are normally calledβ-eliminations (equation 1). The elimination may result from the removal of two vicinal heteroatoms, but the majority ofβ-eliminations involve at least one hydrogen atom that is removed by an external base or solvent. In α-elimination processes, atoms areoften removed through reactions that involve carbenes. The carbene intermediates then rearrange to produce carbon–carbon π bonds(equation 2). These reactions are often encountered when A and B are halogens and frequently involve metal halide exchanges. Suchmethods find utility in alkyne synthesis. Cascading processes that form conjugated systems are also possible (equation 3) but aresomewhat less common. These reactions tend to be encountered during the preparation of complex ring systems.

6.18.2 b-Eliminations

These processes typically proceed through the loss of a leaving group and removal of a vicinal hydrogen, although in some casesboth of the eliminated atoms may be heteroatoms. There are three general mechanisms for elimination reactions, which differ inthe sequence of bond-breaking events.

The first pathway invokes a concerted process of bond formation and cleavage. The hydrogen and leaving group are removed ina single step, forming the double bond, through a process called an E2 (bimolecular) elimination (Figure 2).4,5

H

X

Base

Figure 2 E2 Mechanism.

This mechanism proceeds through a single transition state that implicates the substrate and the base. Depending on thereaction conditions chosen, the bond-forming and -breaking events may not be completely synchronous. From a synthetic point ofview, this should be kept in mind, as selectivity and yields can often be influenced by small changes in reagents or conditions. Ifthe transition state is asynchronous, either the carbon–hydrogen bond or the carbon-leaving group bond may be elongated relativeto the other. This produces a situation in which the elimination begins to adopt character of other β-elimination pathways (E1 orE1cb). This may have synthetic consequences (regiochemical and stereochemical), and the practitioner should always consider thepossibility that a change in selectivity or yield could be due to a drift in mechanism.

E2 reactions may require the use of strong bases and/or elevated temperatures,6 conditions that may pose difficulties forcomplex total synthesis. Regiochemistry and stereochemistry are under kinetic control in these processes and can be reliablypredicted in many cases.

If the hydrogen is removed before the leaving group, an intermediate carbanion is formed and the mechanism is designated asan E1cb (unimolecular conjugate base) process. Typically, these reactions are favored when the carbanion is stabilized by thepresence of electron-withdrawing groups adjacent to the carbanion site.7,8 This class of elimination is extremely common insynthesis because conditions are mild and the reactions generally afford good regio- and stereocontrol (Figure 3).

EWG

H

X

Base

EWG

X

EWG

Figure 3 E1cb Mechanism.

MAC_ALT_TEXT Figure 1



804 Eliminations to Form Alkenes, Allenes, and Alkynes and Related Reactions

E1cb reactions are followed when acidic hydrogens are found on the substrate, when the conjugate base is stabilized by anelectron-withdrawing group or resonance. Any group capable of anion stabilization with an appropriately located leaving groupcan potentially produce an E1cb reaction. These processes are commonly encountered in Knoevenagel and other aldol-basedprocesses.9,10,11

Considerable variation is possible in the E1cb process, depending on the acidity of the hydrogen, strength and concentration ofthe base, and nature of the leaving group.12 If a large amount of base is used relative to the substrate, and the hydrogen is acidicenough, then the starting substrate will be completely converted into its conjugate base. This collapses the rate expression and thereaction will appear to follow first order kinetics (Figure 4).

EWG

H

X

Base

EWG

X

EWG

k2k1

k−1

Figure 4 E1cb(anion).

These types of eliminations are very sensitive to the nature of the leaving group and electron-withdrawing function and areoften associated with very strong electron-withdrawing groups adjacent to the carbanion. Such a reaction is called an E1cb(anion).

If reprotonation is relatively fast, the concentration of the base will influence the rate, and the reaction displays pseudo second-order kinetics (Figure 5).

EWG

H

X

Base

EWG

X

EWG

k2k1

k−1

Figure 5 E1cb(reversible).

Such reactions are sensitive to the nature of the base and leaving group and are called E1cb(reversible) eliminations.In some cases, reprotonation is very slow and therefore anion formation is essentially irreversible. These reactions are relatively

insensitive to the nature of the leaving group, but the electron-withdrawing group has a large effect on the behavior of the reaction.Reactions of this type are designated as E1cb(irreversible) (Figure 6).

EWG

H

X

Base

EWG

X

EWG

k2k1

Figure 6 E1cb(irreversible).

From a synthetic point of view, E1cb reactions tend to give complete regioselectivity because the electron-withdrawing groupdetermines the site of anion formation. This factor also promotes lower reaction temperatures and relatively mild reactionconditions. Stereoselectivity is kinetically controlled, but product distribution can often be predicted by the consideration ofproduct stability. Because anion formation produces an intermediate enolate, stereochemical information may be lost, andproduct distribution is typically established during leaving group removal. Interactions in the transition state of this latter processtend to favor E-alkenes in the product. These reactions are very common in aldol processes.11

If the groups are removed in opposite order (leaving group first), a carbocation is implicated as an intermediate and themechanism is designated as an E1 elimination. These types of reactions become dominant when conditions are favorable forthe formation of carbocations. If the leaving group is located on a highly substituted carbon or if extensive delocalization of thecarbocation is possible, E1 reactions are often encountered (Figure 7).13

H

X

HBase

Figure 7 E1 Mechanism.






From a synthetic point of view, E1 reactions are usually avoided because they tend not to afford high levels of control. E1processes are typically accompanied by significant amounts of substitution products, unless the base and solvent are extremelyweak nucleophiles. Because E1 eliminations involve carbocations, rearrangements are also common side reactions. Stereochemicalinformation is typically lost or attenuated in these reactions because of the planar nature of the intermediate carbocations. Somestereochemical memory may be retained if the departure of the leaving group can be impeded relative to the rate of hydrogenabstraction. Structural features that favor carbocations, such as increased substitution, resonance, or anchiomeric assistance, tendto favor E1 eliminations. Higher temperatures generally result in increased amounts of elimination relative to substitution.3

Because of the selectivity issues associated with unimolecular eliminations, these reactions are encountered less frequentlythan bimolecular processes in synthesis; however, E1 eliminations are commonly found in protecting group removal andinstallation.14,15 For example, the commonly encountered tert-butoxycarbonyl and tert-butyl ester groups are both removed byperforming E1 eliminations on the departing protecting function.

6.18.2.1 Mechanistic Drift

Because the degree of control and selectivity that is characteristic of each of these modes is highly variable, it is important toconsider the mechanistic pathway that will most likely evolve from a chosen reaction when designing a synthesis.12 Syntheticissues associated with these reactions typically revolve around issues of reliability, competition with substitution, stereoselectivity,and the control of regiochemistry. Many eliminations proceed by processes that are blends of more than one pathway. To describethese situations, More O'Farrall–Jencks plots were developed.16–18 These plots are contour maps of potential energy surfaces forelimination reactions, plotted with respect to the bond orders of the departing groups (Figure 8).

H

X

X

H

rC�-X

rC�-H

E1cb

E1

E2

� �

�

��

�

��

Figure 8 More O’Farrall–Jencks plot.

The vertical axis represents the bond order between the β-carbon and hydrogen, whereas the horizontal axis describes thedissociation of the bond between the α-carbon and leaving group. The plot is a projection of the potential energy surface of thesubstrate, and this energy is usually read along the third axis of the plot (above the plane and toward the reader), often shown incontour. An ‘ideal’ E2 reaction (C–H and C–X bonds break simultaneously) proceeds along an energy pathway that follows thediagonal between the starting material (located on the lower left-hand corner) and the products (on the upper right-hand corner)on the diagram (Figure 9).

Mechanistic drift may arise if either of the bond-cleaving events proceeds faster than the other. Reactions in which the C–Hbond becomes elongated show deviations in the potential energy curve toward the top of the plot. If this proceeds to an extent thatresults in fracture of the C–H bond, an E1cb mechanism is followed. The mechanistic pathway for the E1cb, therefore, wrapsaround the left and top outside axes of the plot through the intermediate carbanion (Figure 10).

Reactions in which the leaving group is initially removed produce deviations toward the bottom of the plot. This is thesituation for an E1 mechanism, in which (as in the case of the E1cb) the reaction follows a path toward the outside axes of the plot(Figure 11).


H

X

X

H

rC� -X

rC�-H

� �

�

��

�

��

Figure 9 More O’Farrall–Jencks plot of an E2 reaction.

H

X

X

H

rC� -X

rC�-H

� α

�

��

�

β�

E1cb

Figure 10 More O’Farrall–Jencks plot of an E1cb reaction.


Many reactions do not follow these ideal limiting situations, but instead occupy reaction coordinate trajectories that areintermediate between two extremes. An elimination reaction may exhibit characteristics of more than one reaction path, and thepractitioner will have to take steps to ensure that enough control can be exerted in the reaction to ensure selectivity and conversion.

6.18.2.2 Elimination Versus Substitution

Because of the presence of leaving groups on the substrate, substitutions often compete with β-elimination reactions. The pro-duction of these side products is particularly problematic with E1 processes. If a nucleophilic solvent is used on a substrate capableof unimolecular elimination, the SN1 pathway is usually faster and will dominate over the E1 sequence. This lack of control in E1reactions makes the process an uncommon choice to produce unsaturation in synthetic sequences. However, E1 reactions arefrequently encountered in protecting group chemistry.

Substitution is usually easier to suppress in the E2 and E1cb cases. In the E2 sequence, choosing a nonnucleophilic base canensure that the elimination dominates and substituted products are minimized. Substitution is also disfavored if the leaving group



H

X

X

H

rC� -X

rC�-H

� �

�

��

�

��

E1

Figure 11 More O’Farrall–Jencks plot of an E1 reaction.


is located on a hindered position. Increasing the concentration of the base or using reverse addition of the substrate to the base isan effective strategy to limit substitution in E2 reactions. Other reaction conditions can generally be tuned to ensure high yieldsand stereoselectivity. These factors render E2 reactions suitable for synthesis; however, E2 reactions frequently require vigorousreaction conditions.2–6

The presence of electron-withdrawing groups on E1cb substrates usually ensures that the substrate behaves in the desiredmanner and eliminates rather than substituting. Elimination in E1cb-type substrates can also be promoted by increasing thestrength and concentration of the base and by the presence of stronger electron-withdrawing groups. The products of E1cbreactions are often conjugated olefins, and these products are susceptible to Michael-type additions of extraneous nucleophiles.This type of product formation may be difficult to suppress.10,11 However, such indirect substitutions are frequently employed, asthe elimination/addition sequence is often more efficient than a standard SN2 substitution (Figure 12).

R

X

RO

O

RRO

O

R

Nu

RO

OBase Nu

Figure 12 Elimination/addition sequence.

6.18.2.3 Regiochemical Control

The selective formation of regioisomers from elimination processes is frequently a significant concern from a synthetic point ofview. If more than one β-hydrogen is available for removal, there arises the possibility that regioisomers may be obtained.Ensuring proper control from an elimination reaction can be complex, as many reaction parameters can influence the finallocation of the unsaturation. E1cb reactions represent the most straightforward case, because the most acidic hydrogen is the onethat is removed. Regioselectivity is, therefore, dictated simply by the location of the electron-withdrawing group.

In other β-elimination processes, the products are usually differentiated by the degree of substitution on the resulting doublebond. The product with the most substituents on the double bond is called the Zaitsev product,19 whereas the compound withfewer groups on the unsaturation is labeled as the Hofmann product.20,21 Resonance may override substitution and thereforeconjugated olefins are usually preferred products when their formation is possible (Figure 13).

X

Zaitsev Hoffmann

Figure 13 Zaitsev and Hofmann products.





The E1 reaction presents the most difficulties for regioselectivity and affords the least amount of control. Zaitsev's rule predictsthat eliminations conducted under basic conditions will predominately produce the more highly substituted alkene.22 Therefore,product distribution can be predicted by considering product stability. It should be noted that product ratios are often somewhatlow in these reactions (less than 4:1 is typical). This selectivity is actually a result of kinetic control when basic conditions are used,proceeding more readily through the transition states leading to the more substituted products.

If acidic conditions are employed, the regiochemistry of an E1 reaction will often revert to thermodynamic control becausereprotonation of the alkene may occur to regenerate a carbocation. Substitution generally stabilizes double bonds, and so theZaitsev product is usually favored in these reactions. Unfortunately, the tendency for reprotonation tends to promote rearran-gements. These rearrangement processes are extremely common in E1 reactions and this can further erode selectivity.

Predicting regiochemistry in E2 reactions is more complex. Bimolecular elimination in acyclic systems generally favors theZaitsev products. This is because the transition states for E2 reactions carry significant double bond character, and factors thatstabilize double bonds, therefore, stabilize the transition states leading to them. Product distribution is also affected by statisticalfactors, which erode selectivity for the Zaitsev products, and so the ratios of products obtained may be somewhat low(Figure 14).23

Br KOEt

HOEt+

75% 25%

Br KOtBu

HOtBu

+

27% 73%

Figure 14 Effect of base sterics on product distribution.

Regioselectivity in E2 eliminations may be reversed to favor production of the less substituted olefin (Hofmann product) whenbulky bases are used to remove the proton. The large base becomes encumbered when approaching highly substituted carbons,and so removal of a hydrogen from the less substituted position becomes more favorable, resulting in the production of theHofmann product. Using stronger bases will also often lead to the selective formation of Hofmann isomers.24,25 Hofmannproducts may also be obtained from E2 reactions when positively charged leaving groups, such as tetralkylammonium andsulfonium salts, are employed.26 These processes may proceed via ylide formation. Experiments suggest that selectivity is primarilydue to steric effects wherein gauche interactions are avoided in the transition state leading to the less-substituted alkene, as the useof large leaving groups (charged or neutral) generally leads to the production of Hofmann products (Figure 15).27,28

S EtO

26% 74%

Figure 15 Charged leaving groups produce Hofmann products.

Reactions that proceed through cyclic transition states tend to produce Hofmann products. The Cope elimination provides away to produce π bonds of less-substituted regiochemistries.29 The N-oxide removes the β-hydrogen through a cyclic transitionstate that favors substitution. Other leaving groups that can provide cyclic mechanisms also produce Hofmann products.30 The useof sulfoxide or sulfone-leaving groups may afford the Hofmann product if used to prepare alkenes. Hydrogen removal is achievedby the sulfoxide oxygen (Figure 16).

S

H

R O

Figure 16 Cope elimination.

Hindered sulfoxides provide an interesting case of regiocontrol by the elimination of diastereomeric leaving groups. Usingcholestanes as rigid scaffolds, and adamantyl substituted sulfoxides as leaving groups, complete regiocontrol could be exerted atsecondary positions. The selectivity in these reactions was proposed to be a consequence of conformational restrictions dictatingthe trajectory of base approach in E2 reactions (Figure 17).31




H

HS

O

Ad

H

HAd

O

H

H

H

H

H

HS

O

Ad

H

HO

Ad

H

H

H

H

Figure 17 Stereochemical effects in sulfoxide eliminations.


Selenoxide elimination is a popular method for the introduction of unsaturation onto molecules. The phenylselenide group isreadily introduced through the use of standard carbanion chemistry and provides a convenient installation tool for double-bondassembly. Selenium is readily oxidized and the eliminations themselves require relatively little thermal persuasion.32,33 Otherfunctional groups such as esters, xanthates, and sulfoxides have also been used, although these functionalities may require highertemperatures for elimination.

Regioselectivity in cyclic systems is often dependent on orbital alignment. The E2 reaction is stereospecific and usually proceedsfrom conformations in which the hydrogen and leaving group are antiperiplanar to each other. In such conformations, thecarbon–hydrogen σ bond is able to overlap the σ⁎ orbital of the carbon-leaving group bond achieving a smooth flow of electronsduring the course of the reaction (Figure 18).

H

RHX

HR

RH

HR

H

Base

RR

�*

Figure 18 Orbital alignment in E2 eliminations.

Antiperiplanar conformations are normally easy for acyclic molecules to sample, and these materials typically follow a reactionpathway that implicates antiperiplanar conformations. This alignment affords the best overlap between the fracturing carbon–hydrogen σ bond and the accepting σ⁎ orbital and provides a staggered transition state; therefore, conformers that provide thesealignments give eliminations.

In cyclic systems, the requirement for orbital alignment dictates that the hydrogen and leaving group adopt a trans-diaxial (orpseudo trans-diaxial) alignment. This tends to decelerate those eliminations in which the leaving group is equatorial in the low-energy conformer. In conformationally restricted systems, these reactions may proceed extremely slowly or not at all. Geometricalconstraints dictate that regiochemistry in ring systems will depend on the relative configuration between the hydrogen and leavinggroup. A classic example is that of the E2 elimination of menthyl and neomenthyl chlorides.34 Menthyl chloride eliminates slowlybecause the conformer in which the chlorine is antiperiplanar to a hydrogen is relatively unpopulated. Only one hydrogen isavailable to react in this compound; therefore, the E2 elimination is completely regioselective (Figure 19).

Cl

Cl

H

EtO

Menthyl chloride

Slow

Figure 19 E2 Elimination of menthyl chloride.





The most stable conformer of neomenthyl chloride is also the reactive one, and so neomenthyl chloride reacts much morerapidly than menthyl chloride does. In the reactive conformation, two hydrogens are available for removal, resulting in theproduction of a mixture. Note that regioselection follows Zaitsev's rule; however, the selectivity is not large (Figure 20).

ClCl

Ha

HaHb

Hb

−Ha −Hb

EtO

22% 78%

Neomenthyl chloride

Fast

Figure 20 E2 Elimination of neomenthyl chloride.

6.18.2.4 Stereoselectivity

The selective formation of E- or Z-isomers from elimination processes is a significant concern from a synthetic point of view.Not only does low selectivity impact yields, but also E- and Z-olefins are often very difficult to separate from each another.This challenge can significantly erode the purity of final products and may produce unwanted effects in subsequenttransformations.

Unimolecular eliminations show preference for E-isomers.2–5,13 In the final transition states leading to products, both the E1and E1cb processes must proceed through conformations that align filled and empty orbitals. In the E1 reaction, the C–H σ bondmust align with the empty p orbital of the carbocation to complete the formation of the double bond. This creates stericinteractions in the transition state leading to the Z-isomer, resulting in a preference for the E-product. Ratios of Z- to E-productsare, however, normally low (Figure 21).

RR

H

X

RR

R

R

RR

H

RHHR

H

HRHR

H

Figure 21 Stereochemical preference in E1 eliminations.

In the E1cb process, a similar situation exists. This reaction requires that the filled π orbital of the enolate become coplanar withthe empty σ⁎ orbital of the leaving group. This alignment produces steric interference in transition states leading to the Z-isomers,and so E-products are favored (Figure 22).



R

H

X

RO

O

R

X

RO

O

H

X

R H

O

ORH

X

HR

O

RO

RRO

O

RO

O R

Figure 22 Stereochemical preference in E1cb eliminations.


The prediction of stereochemistry in E2 reactions may require conformational analysis.5 For acyclic systems, if two hydrogensare available for removal, the base will tend to remove the hydrogen that results in E-isomer formation, because of stericinteractions that are generated in the Z-selective transition states (Figure 23).

RR

H

X

RR

R

R

RH

HRH

H

XHR

HRH

X

Base Base

Figure 23 Stereochemical preference in E2 eliminations.

If the removal of only one hydrogen is possible, the stereochemical disposition between the two carbons will determine thestereochemistry of the final product. Examination of a Newman projection can be used to predict the stereochemical outcome ofthe product.

In some cases, antiperiplanar alignment is difficult, and so a synperiplanar attitude is adopted during elimination. Thissynperiplanar route is typically disfavored because such conformations are eclipsed, but these pathways can become dominant ifthe leaving group is capable of undergoing elimination through a cyclic intermediate or transition state. The syn pathway is oftenencountered in cyclic systems that disfavor antiperiplanar orientations of hydrogen and leaving group.35,36 This may occur whentetraalkylammonium-leaving groups are employed. In these cases, the positively charged group may interact with the negativelycharged base, resulting in removal of the hydrogen in a synperiplanar reaction (Figure 24).

Cope-type eliminations must also follow the synperiplanar pathway.37 Oxidation of a fully substituted amine to produce theN-oxide followed by heating results in synperiplanar hydrogen abstraction through a cyclic transition state.



NMe3

HO

H

Figure 24 Stereochemical preference with charged leaving groups.


Selenoxide eliminations are commonly used in modern synthesis. The selenide is easily installed and eliminates readily onoxidation. In the example below, the exocyclic double bond is formed preferentially by virtue of the synperiplanar route.38

Synperiplanar elimination is only possible with a methyl hydrogen. In other cases, the eclipsed nature of the conformers in thetransition state may make alignment difficult (Figure 25).38

OO

H

H SePh

1. m-CPBA2. Δ O

O

H

H

Figure 25 Synperiplanar eliminations of selenoxides.

6.18.3 a-Eliminations

The elimination of two geminal atoms typically involves carbene processes, although some reactions can utilize the β-eliminationmanifold. Exposing 1,1-vinyl dihalides to organolithiums brings about a Fritsch–Buttenberg–Wiechell rearrangement.39–41 Thisprocess passes through a carbene intermediate that then rearranges to form an alkyne or, in some cases, an allene (Figure 26).

Br

Br BuLiC

Figure 26 α-Elimination reactions.

These reactions can be carried out with a variety of bases and metals. Lithium is particularly popular, as the initial lithium–

halogen exchange is often extremely fast.42,43 Geminally substituted dibromocyclopropanes can be converted into allenes througha related mechanism. Exposure to magnesium or sodium will trigger the formation of a carbene via metal–halogen exchange.44

Using other bases, such as methyllithium, will bring about the formation of the same intermediate. Regiochemical and stereo-chemical issues are not normally problematic in α-eliminations because of the nature of the products.

6.18.4 Stereoselective Methods

6.18.4.1 Eliminations to Form E-Alkenes

E-Alkenes are found in a variety of biologically and synthetically valuable compounds. The ability to make E-alkenes stereo-selectively is significant in synthesis, as the separation from the Z-isomers is often not a trivial task. There are a variety of differenteliminations that produce doubly substituted E-alkenes from nondiastereopure precursors. Stereoselectivity in most of theseprocesses is a consequence of unfavorable interactions in transition states leading to the Z-isomers. This influences the selection ofthe removed hydrogen by favoring productive substrate conformations. In the case of synperiplanar elimination, the E-product isalso preferentially formed in acyclic systems (Figure 27).

6.18.4.1.1 Doubly substituted alkenes from alkyl halidesSecondary and tertiary alkyl halides can be eliminated to form the corresponding olefins by heating in the presence of anappropriate base.5 Eliminations of primary halides are usually difficult because competition with substitution processes dom-inates.45 Regiocontrol can usually be achieved by careful base selection because bulky or very strong bases tend to produce the less-substituted (Hofmann) materials, whereas smaller bases favor Zaitsev products. In either case, product ratios are normallysomewhat low. When stereoisomers are possible, the E-isomer is normally produced in excess, although the level of selectivity maynot be spectacular. Alkoxide bases are commonly used in the appropriate alcohol solvent to bring about these transformations,




RR

X

RR

R

R

RH

X

H

H

H

R

Base Base

HR

X

H

H

R

RR

X

RR

R

R

RH

HRH

H

XHR

HRH

X

Base Base

Antiperiplanar elimination Synperiplanar elimination

Figure 27 E2 Elimination to form E-alkenes.


although tertiary amines are also popular choices.5 In recent applications, amide bases such as lithium diisopropylamide (LDA)have been increasingly employed.46,47

Strong hindered bases, such as 1,5-diazabicyclo(4.3.0)non-5-ene (DBN) or 1,8-diazabicycloundec-7-ene (DBU), have beenpopular choices in synthesis.48–50 DBN or DBU are usually required in excess,51 and their use often results in only moderate yields.To address some of these downfalls, the commercially available nonionic superbase P(CH3NCH2CH2)3N has been employed toperform dehydrohalogenations on primary and secondary alkyl halides.52 Both alkyl and aryl alkenes were synthesized by thismethod. Notably, the use of this base gave exclusive access to the E-isomers (Figure 28).

R1 R3

R2

Br

R1 R3

R2

N

NP

N

N

CH3CN, r.t.

90−92%Single isomer

Figure 28 Dehydrohalogenation with nonionic superbase.

An extension of this method used a modified procatalyst53 that was less expensive and more stable than the original base(Figure 29).

H3CR1

Br

H3CR1

NaHCH3CN, r.t.

65−95%Single isomer

Cl

N

NP

N

N

Figure 29 Dehydrohalogenation with nonionic superbase procatalyst system.

6.18.4.1.2 Doubly substituted alkenes from alcoholsThe dehydration of alcohols may require strongly acidic conditions that tend to encourage unimolecular (E1) mechanisms.54,55

This can erode the synthetic utility of the method because rearrangements and substitutions become competitive processes.Regioselectivity can also be a problem in these transformations. Many of these issues can be alleviated through conversion of thealcohol to a sulfonate ester or other efficient leaving group. This expedient provides access to bimolecular pathways for morecontrol and milder reaction conditions.56,57

Terminal epoxides can be transformed into E-alkenes by the use of a lithium amide base in combination with a variety oforganolithiums or Grignard reagents58,59 to prepare diverse alkenes both stereo- and regioselectively. By adding the hindered baselithium 2,2,6,6-tetramethylpiperidide (LTMP), the researchers were able to selectively deprotonate the epoxide trans to the existing





substituent. Addition of an organolithium then opened the epoxide, setting the stage for syn elimination of Li2O and formation ofan E-olefin (Figure 30).

R1LiR2LTMP

Hexane0 °C to r.t. up to

100:0E:Z

O

R1O

LiR1 Li

OLi

R2R1 R2

OLi

Li

R1 R2

71−73%

Figure 30 Conversion of terminal epoxides into E-alkenes.

The stereochemistry of the α-lithiated epoxide was important for controlling the geometry of the alkene product.60 This wasdemonstrated through the use of isotopically labeled epoxides. When a cis deuterated epoxide was subjected to the reaction, theproduct was obtained as a 98:2 mixture of E- and Z-isomers, both of which had high deuterium content (94% and 96%,respectively). This suggested that the initial lithiation had occurred trans to the alkyl group (Figure 31).

C8H17

O

D

LiPh, LTMP

C8H17Ph

D/H

E:Zcis

Hexane0 °C to r.t.

(94% D):(96% D)98:2

Figure 31 Isotopic labels show site of initial lithiation.

Employing the trans-labeled epoxide resulted in much lower E/Z-selectivity. Significantly, the E-isomer contained very littledeuterium, consistent with trans deprotonation. The Z-isomer had very high deuterium content, suggesting that a kinetic isotopeeffect had resulted in significant cis lithiation that was the pathway leading to the Z-isomer (Figure 32).

LiPh, LTMP

trans

C8H17D

O

Hexane0 °C to r.t.

DO

Li

D

(92% D)

Ph

C8H17

C8H17 C8H17

C8H17Li

O

H

Ph

(1% D)

85

:

15

Figure 32 Kinetic isotope effect favors the Z-isomer.

The dehydration of alcohols to form E-alkenes has been performed with reagents such as anhydrous CuSO4,61 POCl3,

62

SOCl2,63 or I2.

64 As an example, β-methylstyrene was prepared, with a 91:9 E:Z ratio in 69% yield with only catalytic CuSO4 andthe neat alcohol (Figure 33).61

Ph

OH CuSO4

125 °C

Ph

91:9 (E:Z) 69%

Figure 33 E-Alkenes from alcohol dehydration.

A mild, efficient method for the stereoselective production of E-aryl alkenes65 using ethers in neutral ionic liquids andmicrowave irradiation has been developed. The reactions minimize the formation of unwanted by-products that often arise when






dehydrations are carried out under more harsh conditions.66 Dimethylsulfoxide (DMSO) has also been used to accomplish themild dehydration of alcohols by simple heating (Figure 34).67,68

OR

Ar

Ar

80−96%Single isomers

Figure 34 Alcohol dehydration in DMSO.

6.18.4.1.3 Doubly substituted alkenes from vicinal dihalidesThe dehalogenation of vic-dihalides is a common method for the synthesis of alkenes. The reaction may be considered by some tobe a deprotection because the vicinal halides are normally prepared from alkenes, and so sometimes serve as protecting groups fordouble bonds.69 The sequence of halogenation and then dehalogenation has also been employed for the purpose of olefininversion.60 Many organometallic reagents70,71 and metal catalysts72–74 have been used for this purpose. A few of the reportedmethods favor E-isomers, but many are nonselective.6

An example of an organometallic approach to vic-dehalogenation utilizes organodisodium reagents to produce the corre-sponding alkenes with high yields (more than 90%) and stereoselectivities (up to 100:0 for the E-isomer).75 The reaction wasthought to proceed through a single-electron transfer process (Figure 35).

R1 R2

Br

Br

R1 R2THFPh

Na

Na

N+ Ph N+

R1 R2

Br

Br

R1 R2

PhAr + R1 R2

BrPh

Ar +

PhAr R1 R2

Br

++PhAr

>90%up to 100:0

E:Z

Figure 35 E-Alkenes from vicinal dihalides.

6.18.4.1.4 Doubly substituted alkenes using other leaving groupso-Nitrophenyl sulfoxides have been employed as leaving groups76 to give rise to both terminal and disubstituted alkenes, as well asα,β-unsaturated esters with high E-stereoselectivities. A particular advantage of this method is the facile purification of the alkenethrough precipitation of the sulfenic acid salt during the course of the reaction (Figure 36).

S

R1

R2

HONO2

NaOAc

Toluene110 °C

S

NO2

ONa


R1 R2

Figure 36 E-Alkenes from nitrophenyl sulfoxides.

Sulfone-leaving groups have been used to prepare olefins using the elimination of arenesulfinic acids to produce E-alkenes aswell as trisubstituted alkenes. Both alkyl–aryl-substituted and alkyl–allyl-substituted alkenes were produced via this arenesulfinicacid elimination reaction (Figure 37).77




R2

SR3O

O

R1

KOSiMe3

THF70 °C

R2 R3 S OK

O

up to 100:0E:Z

Figure 37 E-Alkenes from sulfones.


The use of samarium to promote eliminations which form E-nitroalkenes with selectivities higher than 98:2 E:Z has beendescribed.78 Eliminations to provide E-α,β-unsaturated esters79 and primary amines80 stereoselectively were also possible. Addi-tionally, the use of manganese to provide alkenes stereoselectively by elimination has been disclosed.81,82 The selectivity for theE-isomer in this process was thought to be a consequence of a half-chair transition state operating under chelation control, inwhich the R group was located in a pseudoequatorial position (Figure 38).

OO

SmI2

N

H

R

O

HR H

O

Br NO2

NaI(cat)

RNO2

Br

OHSmI2

RNO2

> 98:2E:Z

55−96%

Figure 38 Samarium promoted eliminations to form E-Alkenes.

E-Alkenes have been produced from an interesting method involving acetylenes.83 Various alkyl, aryl, and cyclic alkynes couldbe converted into their respective alkenes via vicinal borane intermediates. Selectivities ranged from 78:22 in favor of the E-isomerto up to complete E-selectivity (Figure 39).

RR1. BH3•THF

2. Ag2NO3(Alkaline)

R

R

up to100:0

E:Z

BH3

RR

BH2

BH2

Ag2OHRRH

72−89%

Figure 39 E-Alkenes from alkynes.

The removal of nitro groups from nitroalkanes using radical conditions has been employed as a way to prepare E-alkenes withsome selectivity.84 The carbon radicals were generated using a Barton ester, and E-selectivities of up to 6:1 E:Z were realized(Figure 40).

S NO2

R1 R2

EtS

S N

S

O R3

O

BenzeneΔ/h�

up to6:1E:ZR1

R2

88−94%

Figure 40 E-Alkenes from radical eliminations.

A stereoselective formation of polyenes that consisted of a double elimination involving β-acetoxy sulfones using potassiumtert-butoxide as base was reported.85 Polyenes, diynes, and enynes were obtained in good yields, and moderate to excellentselectivities were obtained in the case of the polyenes. This method was used to synthesize dienamides and dienic estersstereoselectively in excellent yields (Figure 41).86





R1 R2

OSO2Ph

OAc

KOtBuR1 R2

OSO2Ph

R1 R2

OSO2Ph

R1 R2

O

52−88%

up to 95:5E:Z

Figure 41 Stereoselective eliminations forming polyenes.


Application of the method to a dienamide-containing natural product resulted in a facile and efficient synthesis of a larvicide,isolated from Spilanthes mauritiana, which had previously been used to control the population of Anopheles mosquitoes.87 The keystep involved a double elimination reaction to form a key intermediate in the sequence. A similar method has been used in thesynthesis of d,l-muscone as well as methyl retinoate (Figure 42).87

OH

OSO2Ph

O

O

KOtBu

HN

O

82% one isomer

Figure 42 Stereoselective elimination in the synthesis of a natural product.

An E-stereoselective synthesis of α,β-unsaturated esters and ketones using sulfides was reported88 involving the sulfenylation–dehydrosulfenylation of enolates. This method produced α,β-unsaturated esters and ketones in good yields and completeE-selectivity (Figure 43).

R R

O1. i-PrNLiCy2. CH3SSCH3

3. Δ R R

O

One isomer,71−90%

Figure 43 Stereoselective elimination of sulfides.

This thermal elimination of β-ketosulfoxides was employed89 to make a key α,β-unsaturated ketone intermediate, as a singleisomer, that was used in the synthesis of C-ring-modified estrogen derivatives (Figure 44).

Eliminations involving β-acyloxysulfones are generally associated with the Julia–Lythgoe olefination.90 The elimination step inthese olefin-forming reactions is typically initiated reductively by either Na/Hg amalgam91 or by the use of samarium iodide and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU).92 Both methods generally give high selectivities for the E-isomer.The latter method has been recently applied in the synthesis of haminol A, an alarm pheromone found in cephalospideanmolluscs. The stereoselective installation of two of the alkenes in the triene was accomplished by treatment of the benzoylox-ysulfone with samarium iodide in THF/DMPU (Figure 45).

The Julia–Lythgoe93,94 and Kocienski95 syntheses are popular ways to construct alkenes, involving elimination reactions in thefinal step. Related methods for olefin production that employ eliminations are named reactions such as the Wittig,96 Peterson,97–99

Seyferth–Gilbert,100 and Horner–Wadsworth–Emmons 101 homologation. Some aldol processes have been employed to preparealkenes by in situ E1cb processes.102,103

6.18.4.2 Eliminations to Form Z-Alkenes

Elimination methods for the stereoselective preparation of Z-alkenes are considerably less common than methods that afford theE-isomers. Z-alkenes can be found in many biologically important molecules104,105 and their preparation is commonly achieved




S

O

MeO

O

S

O

MeO

O

MeO2C

Dioxane

Reflux

CO2Me

MeO

O

CO2H OH

HH

H

82%

Figure 44 Thermal elimination of β-ketosulfoxides.

N

OBz

SO2Ph OBz

OTBS

SmI2, DMPU

THF, 98%( )3

N

OTBS

( )3PhO2S

Figure 45 Eliminations involving β-acyloxysulfones.


by methods such as alkyne reduction or Wittig-type processes. Nevertheless, some success has been realized in the development ofZ-selective eliminations.

6.18.4.2.1 Disubstituted Z-alkenesThe stereoselective synthesis of unfunctionalized Z-alkenes was accomplished by utilizing nondiastereopure O-acetylchlorohydrinsand samarium iodide.106 Using this method, Z-alkenes were obtained in selectivities of up to 98:2 Z:E, bearing simple alkylsubstituents. The use of aryl-substituted O-acetylchlorohydrins resulted in a reversal of selectivity to produce the E-isomer, withratios as high as 8:92 Z:E being observed in these cases. The authors proposed a mechanism for this observation that involvedchelation of the SmIII center with the oxygen of the carbonyl in the acetoxy group, giving rise to a six-membered transition state.The high Z-selectivity was rationalized by assuming that there was one diastereomer that had a conformation that more readilycoordinated to the SmIII, whereas the other diastereomer slowly epimerized into the reactive form (Figure 46).

Cl

R1OAc

R2SmI2

h�, ΔR2

R1

R1OAc

R2 OSmO

H

R1

H

R2

98:2Z:E

Figure 46 Samarium promoted elimination of acetylchlorohydrins to give Z-alkenes.

Samarium iodide has been employed to obtain a variety of functionalized Z-alkene products stereoselectively, includingZ-vinyl halides,107 Z-vinylsilanes,108 Z-allylsilanes,109 and Z-β,γ-unsaturated nitriles.110 All have been prepared with good yieldsand selectivities using this technology.

The stereoselective preparation of nonfunctionalized Z-alkenes has been carried out by utilizing a zinc homologation–elimination reaction.111 In this method, α-sulfinyl carbanions were reacted with zinc carbenoids and subsequently eliminated togive Z-alkenes with up to 20:1 Z:E selectivity (Figure 47).

The total synthesis of (+)-crocacin A was carried out by employing an elimination reaction as the final synthetic step in orderto provide the product enamide with complete Z-selectivity.104 This key step utilized a Peterson elimination112–114 processemploying tetra-n-butylammonium fluoride (TBAF) to afford an oxyanion intermediate that underwent the elimination to affordthe Z-enamide (Figure 48).




H23C11 S

O

1. LDA, −70 °C

2. CuBr, −30 °C

I

IPh

Bu2Zn, 2LiBrH23C11 Ph

60%20:1Z:E

Figure 47 Elimination of sulfinyl groups to give Z-alkenes.

NH

OMe OMe O

TMS

OTMS

O NH

O

OMe

TBAF, THF 0 °C86%

NH

OMe OMe O

O NH

O

OMe

Figure 48 Z-Selective elimination in the synthesis of (+)-crocacin A.


6.18.4.3 Trisubstituted Alkenes

The stereocontrolled synthesis of trisubstituted olefins has applications in the preparation of many bioactive molecules.β-Elimination reactions are often preferred to alternative methods of stereoselective alkene construction, such as the Wittig reactionfor these processes, and are often associated with aldol processes.11

The stereoselective conversion of Baylis–Hillman adducts into trisubstituted alkenes has been investigated by a few differentresearch groups in recent years to obtain trisubstituted olefins with complete E-stereoselectivity.115 The observed selectivity couldbe rationalized by consideration of the transition states leading to the formation of the E- and Z-products, respectively. In the caseof the transition state leading to the Z-alkene, A(1,3) strain was operative. When nitriles were employed as electron-withdrawinggroups, the selectivity favored the Z-alkene product (Figure 49).

R

OH O

OMe

NaBH4/CuCl2 H2O

MeOH, r.t.R

O

OMe

H3C

OH

R H O

OMe

R

O

OMe

H3CO

OMe

OH

H R

O

OMe

R


Figure 49 Stereoselective eliminations during the Baylis–Hillman process.

An alternative method of stereoselectively converting Baylis–Hillman adducts into trisubstituted E-alkenes was investigatedrecently.116,117 In this method, SmI2 was used with Baylis–Hillman adducts, or the corresponding acetates were treated with Smpowder in the presence of a catalytic amount of I2, to furnish the desired trisubstituted alkenes with exclusive E-selectivity. Thehigh E-selectivity was rationalized by a model employing chelation control (Figure 50).

The E-stereoselective synthesis of trisubstituted nitroolefins was accomplished using a copper-mediated addition–eliminationreaction.118 The authors found that the addition of cuprates onto 2-nitro-1-phenylthiopropene derivatives gave the corresponding




Ar

OH O

OMeSmI2, THF, Δ

Ar

O

OMe

Ar

OAc O

OMeSm, I2, THF, Δ

Ar

O

OMe



Ar

O O

OMe

H SmI I

SmI2

Ar

O

OMe

SmI2

Ar

O

OMeH

Figure 50 Samarium promoted stereoselective eliminations in Baylis–Hillman reactions.


trisubstituted nitroalkenes. Oxophillic reagents such as Grignards or organolithiums tended to produce only addition, with nodetected elimination products.

Nitroalkenes can be useful synthetic intermediates in Michael additions and cycloaddition reactions119; therefore, stereo-selective methods of preparing these compounds can be very important. The origin of the E-stereoselectivity was proposed by theauthors to arise from a conformation in which allylic strain was minimal (Figure 51).

H3C N

SPh

R H O

O

RNO2

H3C NO

O

SPh

H R

NO2

R

PhSNO2 R

NO2RCu(CN)MX

THF


Figure 51 Stereoselective eliminations to E-nitroalkenes.

Dihaloalkanes can be used as a protection strategy for syntheses involving vulnerable alkenes,60 provided that a stereoselectivedehalogenation reaction exists for unmasking the alkene. Toward this end, a stereoselective radical debromination utilizing Ru(bpy)3Cl2 as a visible light photoredox catalyst120 was developed to obtain the E-trisubstituted olefins stereoselectively from aseries of dibromoalkanes. Stereoselectivity was rationalized by the authors as arising from a radical intermediate which could breakdown to form the thermodynamically more stable E-alkenes (Figure 52).

R1 OEt

OR2 Br

R3 BrR1 OEt

OR2

R3

Ru(bpy)3Cl2DMN

MeOH:H2O(10:1)

27−70%up to 95:5

E:Z

Figure 52 Elimination of vicinal dihalides to trisubstituted alkenes.

Methods to produce trisubstituted fluoroalkenoates have become somewhat popular in recent years, owing to thehigh importance of fluorinated derivatives in medicinal chemistry,121 crop protection,122 and modified pheromones.123 Anearly approach to synthesizing Z-fluoroalkenoates stereoselectively was demonstrated in 1991.124 In this method, α-fluorinatedarylsulfinyl acetates were alkylated and subsequently heated to promote elimination, giving rise to a variety of Z-fluoroalkenoates.





The method was shown to be compatible with functional groups such as esters, acetates, silyl ethers, imides, and amides(Figure 53).

PhS F

O

CO2Me

R I

BasePh

S

O

CO2Me

RF

Δ MeO2CR

F

20−90%

Figure 53 Elimination of α-fluorinated arylsulfinyl acetates.

The selectivity was rationalized by comparison with nonfluorinated Z-alkenes that had been prepared using a similarmethod.125 The stereoselectivity was said to have risen because of the lack of steric interactions between the substituent group andthe ester in the transition states leading to the Z-alkene isomers. Ratios of up to 495:5 in favor of the Z-isomer were obtained bythis method (Figure 54).

SPhO

H

RF

CO2Me

MeO2CR

F

SPhO

H

RF

CO2Me

MeO2C

R

F

Figure 54 Rationalization of stereoselectivity for Z-fluoroalkenoates.

Another method for the stereoselective synthesis of Z-fluoroalkenoates involved a three-step process starting from a fluor-osulfide.126 This preparation gave rise to Z-fluoroalkenoates with selectivities up to 98:2 Z:E, in yields ranging from 50% to 60%overall. Both aromatic and aliphatic aldehydes could be used in the reaction, and each class of reactant gave comparable overallyields. The authors suggested a radical or anionic elimination mechanism, due to the high Z-selectivity obtained (98:2), even fromdiastereomeric mixtures (Figure 55).

F

S CO2Me1. LDA, RCHO

2. mCPBA

FOS

CO2Me

OH

R SO2Cl2CO2Me

R

F

50−60%

Figure 55 Z-Fluoroalkenoates from sulfoxide elimination.

The preparation of both tri- and tetrasubstituted fluoroalkenoates was achieved using diethylzinc to facilitate the addition ofethyldibromofluoroacetate to various aldehydes and ketones,127 which produced tri- and tetrasubstituted fluoroalkenoates,respectively. High Z-selectivities were obtained with both aldehydes and ketones (Figure 56).

Br2FCCO2Et + Et2Zn

RCHO

R

HF

CO2Et

+R

OH

CO2Et

Br F

up to 99:1 Z:E43−96%

R1 R2

O R1

R2 F

CO2Et

up to 99:1 Z:E52−97%

Figure 56 Eliminations in Reformatsky reactions.






An E2 elimination mechanism was proposed for the aldehyde derivatives, in which a chair-like transition state involving a zinc-aldolate intermediate held the bromine atom antiperiplanar to the leaving group. This transition state produced selectivity for theZ-isomer. These reactions also gave rise to a syn-α-bromo-α-fluoro-β-hydroxyester by-product in varying amounts. This materialwas thought to arise from the diastereomeric zinc aldolate intermediate, in which the bromine atom and leaving group were notantiperiplanar and so elimination was not possible. On workup, this intermediate was converted into the hydroxyester product.For ketones, an E1cb mechanism was proposed using a similar transition state model (Figure 57).

OZnO

F

H

RBr

OEtEt2Zn

R

HF

CO2Et

OZnO

Br

H

RF

OEt

R

OH

CO2Et

Br F

Figure 57 Reformatsky elimination stereoselectivity.

The stereoselective synthesis of unfunctionalized trisubstituted alkenes was carried out by using an iron-promoted eliminationof β-thioalkoxy alcohols.128 This method consisted of ring opening of propargylic dithioacetals with n-BuLi and subsequentreaction with aldehydes to obtain homopropargylic alcohols as a mixture of diastereomers. These alcohols were then treated withFe(acac)3 and MeMgI to afford the corresponding enynes with excellent stereoselectivities. The selection was thought to be aconsequence of equilibration between the intermediate iron complexes (Figure 58).

R1

SS

R2

1. n-BuLi

2. R3CHO

S

R2

R1

R3

OH

SBu

R2

R1

H

R3

up to 32:1 Z:E62−78%

Fe(acac)3

MeMgI

Figure 58 Iron-promoted elimination of β-thioalkoxy alcohols.

Unfunctionalized trisubstituted Z-alkenes have also been selectively prepared by utilizing selenophosphates and thiophos-phates.129 In this method, NaBH4 was added to the seleno- or thiophosphate to obtain diastereomeric oxyanions, whichunderwent phosphoryl migration. This was followed by cyclization to produce episelenides or episulfides, which subsequentlyunderwent spontaneous loss of selenium (or sulfur) to produce alkenes with high stereoselectivity. The selective formation ofZ-isomers was rationalized by invoking the Felkin–Anh model (assuming that the (EtO)2P(O)Se group was the largest) in thereduction step (Figure 59).

R1 XP(OEt)2

O

R2 R3 O

NaBH4 R1 XP(OEt)2

O

R2 R3 O

R1 X

O

R2 R3

P(OEt)2

O

R1

R2

R3XR1

R2

R3up to 100:0 Z:E

46−63%

X = S or Se

Figure 59 Stereoselective elimination of β-thioalkoxy alcohols.





A variety of disubstituted unfunctionalized olefins were prepared with good stereoselectivities from episulfides.130 Conjugateddienes were synthesized in near complete stereoselectivity for the E-isomers using thio-and selenophosphates.131 A similar methodallowed the preparation of alk-2-enenitriles with excellent stereoselectivity.132 Tetrasubstituted enynes and conjugated dienynescould also be accessed using this technology, albeit with lower selectivities.133,134

The construction of α,β-dehydroamino acids135–137 was carried out with up to complete Z-selectivity in the case of trisub-stituted examples.138 The trisubstituted olefins were synthesized by E2 eliminations of the corresponding carbonate derivatives.The authors proposed that the Z-selectivity may arise from equilibrated intermediates that break down to give the thermo-dynamically more stable Z-olefins (Figure 60).

CO2RNH

RO

OO O

O

R TBAF

CO2RNH

RO

O

81−88%

Figure 60 Z-Selectivity in eliminations to form α,β-dehydroamino acids.

6.18.4.4 Tetrasubstituted Alkenes

Only a few methods exist that can stereoselectively prepare tetrasubstituted olefins via elimination reactions.139 Methods involvingE2 processes can give rise to selectivity, but the hydrogen and leaving group must have an antiperiplanar arrangement for thereaction to proceed. In the case of tetrasubstituted olefins, the rotation needed to achieve an antiperiplanar arrangement may bedifficult due to the fact that vicinal tertiary and quaternary centers are implicated. The resulting steric interactions can promote E1processes instead, resulting in poor stereoselectivity or rearrangements. Because of this danger, elimination processes that producetetrasubstituted olefins are uncommon (Figure 61).

R2R1

X

H

R4R3R1

R2

R3

R4

Figure 61 Eliminations to give tetrasubstituted olefins.

One method involved the E-stereoselective preparation of tetrasubstituted alkenylboronates.140 This method enabled thepreparation of various alkenylboronates from the addition of 1,1-diboronates to carbonyl compounds (Figure 62).

R1 Bpin

Bpin

1. LiTMP

2. O

R3R2

R1R3

Bpin

R2

70−98%>99:1 E:Z

Figure 62 E-Selective elimination forming alkenylboronates.

The resulting alkenylboronates could be further elaborated via Suzuki–Miyaura coupling to produce all-carbon tetrasubstitutedalkenes. This idea was applied to the synthesis of a tamoxifen derivative, which had previously not been prepared in a stereo-selective fashion. The stereoselectivity was rationalized by performing density functional theory calculations on the lithiumalkoxide intermediates. The results supported the observed experimental data by suggesting that one boron atom was specificallyinvolved in a syn-elimination process, regardless of which boron's pinacol group was chelated to the lithium (Figure 63).

PhBpin

Bpin

1. LiTMP

2.

Ph Et

OPh

Bpin

Et

Ph

Pd(PtBu3)2NaOH

I

ON

O

76%

Et

Ph

Ph

ON

O

Figure 63 Stereoselective elimination in synthesis of tamoxifen derivative.






In 2004, an example of a stereoselective synthesis of a tetrasubstituted alkene en route to a synthesis of the alkaloid eupo-lauramine was reported.141 One of the key steps in the synthesis involved an elimination of a benzotriazolyl unit promoted byanchimeric assistance, followed by the stereoselective formation of the olefin through proton removal. The Z-isomer was obtainedin a ratio of 80:20 Z:E, in an 86% yield. The E- and Z-isomers were separable, and the Z-isomer was used for a subsequentoxidative radical cyclization reaction. Final replacement of the pivaloyl group with a methoxy group led to the producteupolauramine (Figure 64).

NN

O

OPv

Br

Bt

pTSA, Δ

86%N

N

O

OPv

Br

8:2Z:E

Figure 64 Stereoselective elimination in eupolauramine synthesis.

6.18.5 Stereospecific Methods

There are a variety of stereospecific methods to prepare alkenes through eliminations of stereodefined precursors. The stereo-chemical information in the starting materials translates in a predictable manner to the alkene products in these protocols, andsuch stereospecific eliminations can be used to prepare a variety of polysubstituted olefins. There are numerous types of substratesthat can be used to prepare olefins in a stereospecific manner. Many methods involve vic-dihalides, but there are other interestingmethods starting from precursors such as vic-diols (and related materials), halohydrin derivatives, β-hydroxy selenides, epoxides,episulfides, aziridines, epi-phosphonium, and phenylsulfide derivatives. The use of these methods for the preparation of sub-stituted olefins is discussed below.

6.18.5.1 Alkenes from Vicinal Dihalides

Vicinal dihalides can act as protecting groups for alkenes.60 This attribute makes eliminations that form alkenes from vic-dihalidesparticularly useful, provided that the stereochemistry of the resulting olefin can be controlled. Some stereoselective methods forthe elimination of vic-dihalides were discussed below, but there are a variety of stereospecific methods for the ‘unmasking’ of vic-dihalides to alkenes.

Many of these methods involve the use of metal reductants to effect the dehalogenations. Several metal–metal salt systems havebeen developed for this purpose in recent years, including NiCl2·6H2O/In,142 FeCl3·6H2O/In,143 BiCl3/In,

144 CoCl2·6H2O/In,145

Cp2TiCl2/Ga,146 and BiCl3/Ga.

147 These systems constitute inexpensive, mild conditions and generally give high yields of dis-ubstituted E-alkenes. α,β-Unsaturated aldehydes, ketones, carboxylic acids, and esters, as well as a variety of aryl-substitutedalkenes were prepared using this strategy as well as terminal and cyclic alkenes. The mechanism of the process is still unclear;however, the authors speculate that it occurs in two stages: the metal salt is reduced by the metal and this reduced specieseliminates bromide from the substrate (Figure 65).

R1 R2Br

Br

Metal–metal salt

R1 R2

E-only85−96% yield

Figure 65 Stereospecific elimination of vicinal dihalides with metal-metal salt systems.

The stereospecific debromination of vic-dibromides using only DMSO was investigated in 2007.148 This method consisted ofsimply heating the vic-dibromides in DMSO. The reaction tolerated a variety of functional groups such as esters, acids, amides,nitro, and keto groups and afforded good yields in most cases. Phenyl, pyridyl, and thiophenyl alkenes were also prepared;however, with certain derivatives, the bromoolefin was obtained as well (mostly in the thiophenyl series). The reaction mechanismwas thought to proceed from attack of the DMSO oxygen atom in an SN2 fashion onto one of the bromide positions, followed bythe loss of Br+ (to form the olefins) or H+ (to form bromoolefins). The reactions were often completely E-selective; however, thecarboxylic acid derivatives did show some erosion in stereointegrity. In general, this procedure was a mild, efficient way to obtainolefins from their vic-dibromide precursors (Figure 66).



ArR

Br

Br

DMSO

75 °CAr

R

up to E-only selectivity19−97% yieldAr = Ph, pyridyl, thiophenyl

R = CO2H, CO2Et, C(O)Ph,C(O)NH2, NO2

Figure 66 Stereospecific elimination of vicinal dihalides using DMSO.


6.18.5.2 Vicinal Diols or Dialkoxy Derivatives

The synthesis of alkenes from elimination reactions of vic-diols, or related derivatives, has been investigated by various researchgroups over the years. Most methods involve converting the vic-diols into leaving groups, such as the thiocarbamate derivatives ofthe Corey–Winter reaction149 or xanthate derivatives such as those described by Barton.150 vic-Dimesylates have also been con-verted to alkenes in a stereospecific manner by a few different research groups as discussed below.

In 1996, a variety of vic-dimesylates were eliminated to afford the corresponding alkenes stereospecifically using telluride orselenide dianions.151 In this method, the dimesylates were treated with either Li2Te or Li2Se to afford the corresponding alkenes.The dianions could be made from the direct addition of Et3BHLi to the metal or by treating the metals with sodium in liquidammonia. The reaction mechanism was thought to proceed via a three-membered ring intermediate, after ‘double attack’ of thedianion on the dimesylated compound. The reaction was especially useful for the synthesis of dideoxynucleosides; however, thetechnology could also be used to prepare acyclic E- and Z-olefins stereospecifically (Figure 67).

R1R2

OMs

OMs

Li2M

THFr.t.

R1 R2

M = Te or SeOne isomer only

60−93% yield

Figure 67 Stereospecific elimination of vicinal dimesylates.

A related process has also been reported from dimesylates using lithium areneselenates, which had a similar substrate scope.152

A potential drawback to this method, however, was that a stoichiometric amount of the tellurium or selenium reagent was used,which could potentially be problematic on larger scale.150 In an effort to make this process more amenable to scale up, somereaction parameters were modified to use a perfluorinated diselenide derivative as a catalyst.153 This method had an excellentsubstrate scope and stereospecificity and allowed the use of a catalytic amount of the selenide derivative (a stoichiometric amountof NaBH4 was required). Additionally, the catalyst could be recovered by using continuous fluorous extraction (Figure 68).

R1R2

OMs

OMs

NaBH4

0.2 equivalent (CF3(CF2)5C6H4Se)2EtOH

Δ

R1 R2

One isomer only74−99% yield

(CF3(CF2)5C6H4Se)2

Recoveredup to 88%

Figure 68 Stereospecific elimination of vicinal dimesylates to Z-alkenes.

The use of both dimesylates and ditosylates with sodium hydrogen telluride to form alkenes stereospecifically in excellentyields was reported in 1996.154 This method was compatible with esters, amides, ketones, and nitriles, but not with halides.

The elimination of vic-diols has also been accomplished directly using a rhenium catalyst.155 In this method, Re2(CO)10 washeated to 170 °C in the presence of vic-diols to produce the corresponding olefins. Only syn vic-diols were compatible with theseconditions, and E-stereospecific examples were shown along with cyclic and terminal examples. The reaction mechanism isunknown as of yet; however, the authors suggested the intermediacy of a rhenium diolate species (Figure 69).

6.18.5.3 Halohydrin Derivatives

The conversion of halohydrin derivatives to alkenes has been demonstrated by a few different research groups. Generally, thesederivatives provide advantages over using vic-dihalides as substrates for the eliminations because the alkene can be formed in a




R1 R2

OH

OH

Re2 (CO)10

170 °CAir

R1 R2

One isomerup to 87% yield

Figure 69 Stereospecific elimination of vicinal diols to E-alkenes.


stereospecific manner. This method, however, cannot be used for olefin inversion reactions (anti-addition followed by anti-elimination leads to the starting alkene).

In 1996, a method of stereospecifically converting vic-alkoxyiodoalkanes into the corresponding olefins via a syn-eliminationprocess was disclosed,156 which provided a route for olefin inversion. BuLi was added to vic-alkoxyiodoalkanes to obtain alkeneswith selectivities of up to 96:4 for either the E- or Z-isomers, depending on the stereochemistry of the starting substrate. Yieldsranged from 64% to 85%, and the method could also be used for the preparation of trisubstituted olefins. The authors proposedan E2 syn-periplanar mechanism in which the oxygen of the methoxy group coordinated to BuLi, changing the conformation of themolecule so that a syn-elimination of the I atom and the methoxy group takes place (Figure 70).

R1R2

I2, MeOH R1R2

OCH3

In-BuLi

Hexane R1 R2

64−85%

Figure 70 Stereospecific syn-elimination of vicinal alkoxyiodoalkanes.

The process could be rendered stereoselective by using a Grignard reagent (BuMgBr in Et2O) as the base to afford E-alkenesexclusively (499:1 E:Z), regardless of the configuration of the starting alkoxyiodoalkane. Yields were generally good for thisprocess, ranging from 66% to 97%. The authors proposed that a single electron transfer from the Grignard reagent to the substrateprovided a radical intermediate that formed a single anion after accepting a second electron; this anion then eliminated themethoxy group to selectively afford the E-alkene.157

A stereospecific anti-elimination of alkoxyiodoalkanes has also been described, using an allylsilane–titanium tetrachloridesystem.158 This method provided alkenes in ratios up to 499:1 in favor of the E-isomers or 96:4 in favor of the Z-isomer,depending on the relative configuration of the starting substrate. Yields of up to 97% were obtained. The involvement of anintermediate iodonium ion (after coordination of the methoxy oxygen to titanium) was proposed, which was then attacked by theallyltrimethylsilane to obtain the alkene. This method has also been used successfully to convert epoxides stereospecifically intoalkenes using Bu4NI (Figure 71).159

R1R2

OCH3

I SiMe3

TiCl4DCM

R1 R2

up to 97%

Figure 71 Stereospecific anti-elimination of alkoxyiodoalkanes.

6.18.5.4 b-Hydroxy Selenides

In 1976, a method was described which converted β-hydroxy selenides into di-, tri-, and tetrasubstituted olefins.160,161 Theβ-hydroxy selenides could be prepared from a variety of different methods.

The epoxides were opened in a trans fashion by either phenyl or methyl selenol to provide the corresponding β-hydroxy selenide,which was then transformed to the alkene by a stereospecific elimination, using one of the methods described (Figure 72).

6.18.5.5 Epoxides

The elimination of epoxides to form alkenes has been known for many years, and epoxide formation is a strategy sometimes usedfor the protection of alkenes.162 Early methods usually employed a stoichiometric amount of a reducing reagent includingphosphines,163 silanes,164 iodides,165 or heavy metal reduction, especially those utilizing tungsten.166 More recent methods tendto focus on the catalytic deoxygenation of the epoxides to form alkenes.




OR1 R3

R2 R4RSeH RSe

OH

R3

R1

R2

R4 Method A−DR2

R3

R4

R1

Method A: pTsOH, pentane, refluxMethod B: HClO4, Et2O, r.t.Method C: TFAA, Et3N, DCM, r.t.Method D: SOCl2, Et3N, DCM, r.t.

70−94%

Figure 72 Stereospecific elimination of β-hydroxy selenides.


In the past few years, catalytic processes have been developed for the stereospecific elimination of epoxides to obtain alkenesusing either silver167 or gold nanoparticles as catalysts.168 These methods employed hydrotalcite (Mg6Al2(OH)16CO3)-supportedAg or Au nanoparticles in conjunction with alcohols and used CO/H2O or H2 as the reducing agent. Eliminations to form alkeneswith stereoselectivities of more than 99% and isolated yields between 69% and 95% were reported. The types of alkenes preparedincluded diaryl-, alkyl–aryl-, terminal, and α,β-unsaturated esters, ketones, and amides. The mechanism for these reactions wasthought to involve the coordination of the metal nanoparticle with the Lewis basic sites of the hydrotalcite, such that the metalhydride species and H+ (on the basic site) reacted with the epoxide, producing the alkene and water (Figure 73).

R1

R2O M/HT

CO/H2O oralcohols or

H2

R1

R2

up to 99% E isomerup to 95% yield

Figure 73 Catalytic elimination of epoxides.

The elimination of epoxides has also been affected stereospecifically using a combination of ZrCl4 and NaI.169 This methodenabled a variety of alkenes to be prepared with alkyl, aryl, ether, carbonyl, ester, and hydroxy functional group tolerance. Thetechnology was mainly employed for terminal alkene synthesis; however, both trans- and cis-stilbene could be prepared stereo-specifically from the corresponding epoxides. A mechanism involving coordination of the ZrCl4 to the epoxide, followed byopening by iodide was proposed. Subsequent iodide-mediated elimination of the leaving group produced the alkene (Figure 74).

Ph

PhO ZrCl4/NaI

CH3CN Ph

Ph

One isomerup to 94% yield

Figure 74 Stereospecific elimination of epoxides.

Despite the recent focus on catalytic methods, older methods are very reliable and are often encountered in synthesis. In 2006,the polyketide macrocycle (−)-kendomycin, which shows a variety of biological activities,170 was synthesized. During thissynthesis, it became necessary to protect an olefin function. This was accomplished by the simple expedient of epoxide formation.Deprotection to reveal the desired olefin was performed using Sharpless’ deoxygenation protocol,165 and the alkene was obtainedstereospecifically in 71% yield (Figure 75).

O

OMeTBSO

OTES

OMe

HO

WCl6, BuLi

THF0 °C to r.t.

71%

O

O

OMeTBSO

OTES

OMe

HO

Figure 75 Stereospecific epoxide elimination in kendomycin synthesis.






6.18.5.6 Episulfides

There are relatively few methods to convert episulfides into alkenes stereospecifically. In one report,171 both cis- and trans-episulfides were treated with phenyllithium or triethyl phosphite to obtain the corresponding cis- and trans-alkenes, respectively.Although this process was demonstrated only for cis- and trans-2-butene, it provided near quantitative yields of the correspondingolefins with almost complete stereospecificity. A similar method of desulfurization to afford the corresponding alkene that useseither an alkyllithium or an iron carbonyl compound as a base has been reported (Figure 76).172

R1

R2S

or

R1

S

R2

PhLi or P(OEt)3R1

R2

or

R1 R2

Figure 76 Stereospecific elimination of episulfides.

Another method of converting episulfides into alkenes that involves the treatment of 2-(1-chloroethyl)thiiranes with phe-nyllithium in order to obtain 1-phenylsulfanylbut-2-enes stereospecifically was demonstrated recently.173 Terminal alkenes, alongwith di- and trisubstituted alkenes were obtained by this method, and the disubstituted alkenes were obtained stereospecifically. Theauthors proposed an anti-elimination following the attack of the phenyllithium on sulfur with subsequent ring opening (Figure 77).

SCl

PhLi

Et2O−25 °C

Et2O−25 °C

PhS

62%

SCl

PhLi

PhS

44%

Figure 77 Stereospecific elimination from episulfide opening.

6.18.5.7 Aziridines

There are several different ways to obtain alkenes by the elimination of aziridines. Some of these reactions have been performedusing reagents such as N-nitroso-3-nitrocarbazole,174,175 nitrosyl chloride,174,176 methyl nitrite,174 and n-butyl nitrite.177

A more recent method involves the deamination of aziridines by exposing them to N2O4 under relatively mild conditions.178

This reaction could be applied to the synthesis of disubstituted alkenes as well as to a single trisubstituted olefin example. Aryl-and alkylaryl alkenes were also prepared stereospecifically, with yields ranging from 70% to 95%. The authors proposed anN-nitroso intermediate, arising from the nitrosating conditions (self-ionization of N2O4 to NO+ and NO3

− in solution) as beingoperative in the elimination (Figure 78).

NH

R1 R3

R2 R4N2O4, Et3N

−23 °C or −43 °CTHF

N

R1 R3

R2 R4

NO

(−N2O) R1

R2

R3

R4

70−95%

Figure 78 Stereospecific elimination of aziridines.

6.18.5.8 Epi-Phosphonium

There are a few examples of the elimination of epi-phosphonium species to yield alkenes.179–181 Recently, a method was intro-duced that converts the epi-phosphonium species stereospecifically into the corresponding alkene.182 Alkylaryl-disubstituted





alkenes were successfully synthesized using this method with good stereochemical ratios. The elimination method consisted of thetreatment of β-hydroxyphosphines with PCl3 and NEt3 to convert the hydroxyl function into a good leaving group thereby formingthe epi-phosphonium species, which then suffered elimination on treatment with NEt3 (Figure 79).183

R1R2

PPh2

OHPCl3, NEt3

DCMr.t.

P

R1 R2

Ph PhNEt3

R1 R2

up to 92% yieldup to 93:7 Z:E

R1R2

PPh2

OHPCl3, NEt3

DCMr.t.

P

R1R2

Ph PhNEt3

up to 97% yield>95:5 E:Z

R1

R2

Figure 79 Stereospecific elimination of epi-phosphoniums.

6.18.5.9 Phenylsulfides

Phenylsulfides can be useful for the synthesis of alkenes because they are generally tolerant to acidic and basic conditions andcan be readily eliminated in a syn-fashion once converted into the corresponding sulfoxides.184 These eliminations, however,must usually be carried out at approximately 100–150 °C. In an effort to eliminate phenylsulfides at lower temperatures, amethod that converted the phenylsulfides into their corresponding N–H sulfilimine derivatives was developed in 2006.This transformation then allowed facile syn-eliminations to take place at room temperature.185 The phenyl sulfides wereaminated using O-mesitylenesulfonylhydroxylamine (MSH) at 0 °C, and subsequent addition of K2CO3 at room temperatureprovided the alkenes stereospecifically. Trisubstituted alkenes were prepared with selectivities more than 99:1 for theZ-isomers and 40:1 for the E-isomers, depending on the configuration of the starting substrates used. The lower ratios forthe E-isomers were rationalized by invoking slow isomerization from E- to Z-products over time (longer reaction times gave lowerE:Z ratios). α,β-Unsaturated carbonyl compounds could be prepared using this method with complete selectivity for the E-isomers(Figure 80).

PhPh

OMe

SPh

1. MSH0 °C

2. K2CO3r.t.

2. K2CO3r.t.

MeO

Ph

Ph

>99:1 Z:E85%

PhPh

OMe

SPh

1. MSH0 °C MeO

Ph

40:1 E:Z79%

Ph

Figure 80 Stereospecific elimination of phenylsulfides.

6.18.6 Eliminations to Form Terminal Alkenes

The preparation of terminal olefins by elimination processes generally presents fewer selectivity issues than other eliminationmotifs. Regiochemical issues may arise for the production of Hofmann isomers, and many methods incorporate strategies toaddress this. Some methods favor the production of Hofmann products through steric influences. These include the Copeelimination186 and related eliminations involving sulfonium and ammonium salts.187




6.18.6.1 Preparation from Alkyl Halides

Primary halides do not normally provide a reliable method of elimination to form terminal olefins because of the tendancy ofthese materials to undergo substitution. To overcome this difficulty, extremely hindered bases must be used.188 Primary iodidescan be eliminated to give the corresponding terminal olefins by the use of nonnucleophilic bases such as TBAF in DMSO,189

conditions that minimize the formation of SN2 products.Vinyl bromides have been prepared through a selective elimination process developed for use on vicinal dihalides.190 A variety

of olefins could be converted into vicinal halides, which were then selectively eliminated to afford terminal vinyl bromides. DBUwas used as a base in these transformations; however, selectivity required the presence of additives such as K2CO3. Other additiveshave been employed together with DBU in related transformations (Figure 81).191

O

NO2

1. pyHBr3

2. DBU, K2CO3CH2Cl2

O

NO2

Br

Figure 81 Vinyl bromides from stereospecific eliminations.

6.18.6.2 Preparation from Alcohols

Reliably converting alcohols into terminal alkenes normally requires E2 chemistry, as the use of acidic conditions to remove thehydroxyl group tends to promote the formation of Zaitsev products and encourages rearrangements.

One interesting method to achieve β-elimination was developed specially for tertiary alcohols.192 Subjecting these materialsto conditions normally employed for Swern193 oxidations resulted in β-elimination (rather than the usual α-elimination) andsmoothly converted the tertiary alcohols into terminal olefins (Figure 82).

OHR

R 1. DMSO, (COCl)2

2. Et3NO

SH

RR R

R

59−85%

Figure 82 β-Elimination of tertiary alcohols under Swern conditions.

6.18.6.3 Preparation from Epoxides

A variety of methods have been utilized to convert epoxides and vicinal diols into terminal alkenes through elimination processes.Adding alkyl cerium reagents to substituted styrene oxides gave a variety of terminal alkenes under relatively mild conditions.194

This reaction worked very well for styrene derivatives, but selectivity was somewhat lower when alkyl epoxides were used(Figure 83).

Ar

O R4CeLiAr

R

65−84%

Figure 83 Terminal alkenes from epoxide eliminations.

Epoxides have also been electrochemically eliminated using zinc electrodes to afford the corresponding double bonds inexcellent yields.195 Terminal alkenes have been obtained by the eliminative deoxygenation of epoxides catalyzed by gold nano-particles (Figure 84).196

R

O

R

CO/H2O

Au/TiO296−99%

Figure 84 Electrochemical elimination of epoxides.






Vicinal diols can be converted into terminal olefins using a variety of methods. A common theme in this chemistry is theconversion of one of the hydroxy functions into a halogen. This transformation is then followed by metal-promoted elimina-tion.197 An example of this involved the selective conversion of vicinal diols into iodohydrins.198 These deriviatives could theneasily be converted into terminal olefins by exposure to BuLi at low temperature.199

6.18.6.4 Terminal Olefins from Selenium and Sulfur-Based Leaving Groups

Selenoxide chemistry provides a convenient and mild way to carry out eliminations.200 Selenium groups are easily introducedusing standard carbanion chemistry, and the eliminations usually proceed under very mild conditions once the selenium atom hasbeen oxidized. The selenoxide group eliminates via a synperiplanar mechanism, and this should be taken into account in synthesisas this factor can be manipulated to control regiochemistry.

A selenium elimination was employed during the synthesis of xenicane diterpenes to introduce a cyclic double bond. Thisevent was performed during the endgame of the synthesis, and so reliable and mild conditions were required. A phenylselenidewas introduced through enolate formation. This group was oxidized using meta-chloroperoxybenzoic acid (m-CPBA) and readilyeliminated at low temperature in the final step of the synthesis (Figure 85).201

O

HOH

PhSeO

1. m-CPBADCM−78 °C

2. NEt3−78°C to r.t.

O

HOHO

55%

Figure 85 Eliminations during xenicane diterpene synthesis.

A phenylselenide group was introduced by using a regioselective epoxide opening during a recent morphine synthesis.202 Theselenide group was then oxidized using NaIO4 and underwent a highly regioselective elimination (Figure 86).

NHO

SePh

O

OH

EtO

O

1. NaIO4, H2O, THF N

O

OH

EtO

O

Morphine

58%

OH

2. Na2CO3, toluene, H2O

Figure 86 Elimination of phenylselenides in morphine synthesis.

Endocyclic unsaturation was introduced into a five-membered ring intermediate during a recent synthesis of (+)-intricarene(Figure 87).203

O

I

O

OTBSSePh

O

I

O

OTBSH2O2, THF

0 °C to r.t.97%

(+)-Intricarene

Figure 87 Eliminations during intricarene synthesis.

A phenylselelenide elimination was also employed to achieve the construction of a key cyclopentadiene-containing inter-mediate during a total synthesis of absinthin (Figure 88).204

Methods using sulfur-based leaving groups usually employ the thermolysis of sulfoxides and sulfones. The departure of thesegroups is not as facile as other functionalities and thus higher temperatures and longer reaction times may be required.205–207

The Ramberg–Bäcklund reaction208 has a well established past in synthesis, installing double bonds by the extrusion of SO2.This reaction was employed during a recent synthesis of fawcettidine to introduce a double bond with high Z selectivity into amacrocyclic ring (Figure 89).209




O

AcO H

H

O

SeAr NaIO4, MeOHH2O, r.t.

66%O

AcO H

H

O

Absinthin

Figure 88 Eliminations during absinthin synthesis.

N

S

O

O

O

H

HH

O

OCBr2F2, KOH−alumina

t-BuOH, DCM

46%

N

O

O

O

H

HH (+)-fawcettidine

Figure 89 Eliminations during fawcettidine synthesis.


6.18.7 Eliminations to Form Allenes

In recent years, research toward the synthesis of allenes has become very popular. Allenes are highly useful as synthetic inter-mediates and also occur in natural products and biologically relevant molecules.210 Allenes can be prepared by a variety ofmethods including substitution, addition, rearrangement, and elimination. Elimination reactions to form allenes generally employan alkene precursor or involve an alkene intermediate.

6.18.7.1 Stereocontrolled Methods

There are relatively few methods to synthesize allenes in a stereocontrolled fashion, although the preparation of chiral alleneswould be useful for applications in natural product synthesis and in the synthesis of pharmacologically active compounds. Themajority of methods that have been developed for the production of chiral allenes involve propargylic alcohol derivatives asstarting materials.

In 1992, a method for preparing chiral allenes by the hydrostannation/deoxystannylation of propargylic alcohols was devel-oped.211 A variety of racemic-disubstituted allenes were prepared using this method, along with a single example of a chiral allenecompound. This asymmetric synthesis came about by oxidizing the racemic stannyl allylic alcohol, and then enantioselectivelyreducing the resulting ketone with the Corey-Bakshi-Shibata catalyst.212 This provided an enantiopure alcohol, which wasacetylated and then treated with Bu4NF to afford the chiral allene. This process involved the stereospecific elimination of the stanyland acetoxy groups, initiated by an attack of fluoride on the stanyl group. The allene was obtained with complete stereospecificityin 94% ee and 81% yield (Figure 90).

OAc

nC6H13

SnBu3

Bu4NF•

H

nC6H13

H

81% yield94% ee

Figure 90 Stereocontrolled elimination to form allenes.

This method was later applied to the synthesis of a series of allenic hydrocarbons that are found in Australian melolonthinescarab beetles (Figure 91).213

OAc

nC14H29

SnBu3

nC8H17 Bu4NF

DMSO•

nC8H17

nC14H29

H

67% yield76% ee

Figure 91 Elimination to form allenes hydrocarbons.






Another method, developed in 1996, employed a Mitsunobu reaction on both enantiopure and racemic propargyl alcohols,using arenesulfonyl hydrazides as nucleophiles. These transformations afforded the corresponding propargyl hydrazides that weresubsequently fragmented via a retro-ene reaction in methanol at room temperature to provide the respective allenes.214 A variety offunctional groups displayed tolerance to this method, including tertiary amines, tertiary alcohols, acetals, ketals, silyl ethers, andnitriles. An example demonstrating the synthesis of a trialkylsilyl allene was also reported, along with an allene-ene-yne example.Complete stereospecificity was observed in all examples of this transformation (Figure 92).

H•

R1

R2

H

R1

R2

H OH

ArSO2NHNH2

PPh3, DEAD−15 °C R1

R2

N HH2N

SO2Ar

r.t.

53−91%

Figure 92 Elimination of arenesulfonyl hydrazides.

The synthesis of chiral allenes utilizing a chromium (III) catalyst in the presence of propargylic alcohol derivatives has beenrecently reported.215 This method was developed for the synthesis of stereodefined 1,3-allenes, with good yields and highenantiomeric excesses reported for some examples. The mechanism was thought to involve syn-carbometallation followed by asyn-elimination to afford the corresponding allenes. Yields up to 83% and ee's of up to 86% were reported (Figure 93).

R

TBSOMe3Al

N CrCl2

DCMr.t. up to 83% yield

up to 86% ee

R •

HMe

Figure 93 Eliminations to form chiral allenes.

The use of alkynyl sulfoxides and sulfones for the preparation of allenes via a carbocupration-zinc homologation-β-eliminationsequence was described in 2000.216 This method was later applied to the preparation of a single example of a chiral allene.217 Thismaterial was obtained in 65% ee and 75% yield, starting from a chiral ethenyl p-tolyl sulfoxide. The enantioselectivity wasrationalized by invoking the intermediacy of an allylic zinc derivative that underwent epimerization to the morestable intermediate, in which the tolyl and butyl groups were anti to one another. A syn-β-elimination then took place to afford thecorresponding allene (Figure 94).

Bu

H

Cu

S O

Tol

BuI

I1.

2. Bu2Zn, 2 MgBr20 to 5 °C

Bu

H S O

Tol

ZnBuBu

Bu

H S O

Tol

ZnBuBu

H•

HBu

Bu

75% yield65% ee

Figure 94 Elimination of alkynyl sulfoxides.

The synthesis of bioactive chiral allenes was undertaken in 2010, using an i-PrMgBr mediated elimination of enantioenriched3-acetoxy-2-iodo-propene derivatives.218 The enantiomer of a sex-attractant of the male dried bean beetle was synthesized usingthis technology in 91% ee, starting from a propargylic alcohol derivative. The elimination step proceeded in 89% yield (Figure 95).

6.18.7.2 Other Methods

It is very difficult to synthesize chiral allenes stereoselectively, but methods to form allenes by elimination without concern forstereoselectivities are very common.




H

•

H

CO2Me

AcOI

CO2Mei-PrMgBr

THF−78 °C89%

91% ee

Figure 95 Chiral allene formation by elimination.


6.18.7.3 From Alkene Precursors

The synthesis of allenes by the elimination of alkene precursors constitutes the primary strategy of a large majority of the methodsused in the literature. One account described the preparation of 1,1-difluoroallenes from the β-elimination of an acetoxy groupafter a lithium–halogen exchange reaction.219 The allenes were produced in good yields, and a variety of aryl and alkyl–aryl1,1-difluoroallenes were produced (Figure 96).

F

F

Br

AcO

R1

R2Hexane

0 °C F•

R2R1F

65−90%

n-BuLi

Figure 96 Alkene precursors for elimination to allenes.

Magnesium-sulfoxide exchange was another method of preparing allenes by inducing eliminations from alkene pre-cursors.220,221 This process involved metal–halogen exchange to induce a 1,1-elimination of the S(O)-tol group. This was followedby an attack of 2-lithio-5-methoxyfuran on the carbenoid intermediate. This gave rise to an alkenyl anion that opened the furanring by a cascading elimination. This process provided a trienyl intermediate that tautomerized to give the corresponding allene inyields of up to 54% (Figure 97).

R1

R2 S

Cl

Tol

O

1. t-BuMgCl2. i-PrMgCl

THF−78°C

3.OLi OCH3

THF−78 °C to −10 °C

R2•

HR1

CO2Me

up to 54% yield

Figure 97 Magnesium-sulfoxide induced eliminations.

The synthesis of allenyl esters was achieved by dehydrating β-ketoesters using lithium bis(trimethylsilyl)amide (LiHMDS) as abase.222 After initial treatment with LiHMDS, the enolate was trapped with Tf2O. A second addition of LiHMDS would provide thecorresponding ester enolate. Hexamethylphosphoramide (HMPA) was then added, presumably to destabilize the lithium complexesthat can form between the enolate anion and HMDS and could result in anion quenching through intracomplex protonation.223 Therole of the ZnCl2 was unclear; however, this additive was shown to be necessary to form allenes in appreciable yields. Both disubstitutedand terminal allenes could be prepared with this method (Figure 98).

ROR2

R1

O O

1. LiHMDS2. Tf2O3. LiHMDS

4. HMPA5. ZnCl2

R•

CO2R2R1H

up to 78% yield

Figure 98 Dehydrations of β-ketoesters.

Another method which employed the intermediacy of enol derivatives for the construction of allenes was that utilizing silyl enolethers.224,225 This process involved the treatment of silyl enol ethers with LDA to generate an allylic carbanion, which would produce






the terminal allene by either direct elimination of –OSiR3 or sequential 1,3 O–C silyl migration–Peterson elimination. The allenecould then be transformed to the corresponding bislithiated allene by treatment with LDA, and then quenched with electrophiles.This method was mostly used for the preparation of bissilylated allenes; however, some examples of doubly stanylated andbismethylated allenes were shown. Overall yields ranged from 60% to 84% for these reaction sequences (Figure 99).

Ph

Ph

OSiMe2t-Bu

CH3

LDATHF0 °C

Ph

Ph

OSiMe2t-Bu

CH2Lior

Ph

Ph

OLi

CH2SiMe2t-Bu

Ph•

Li

LiPh E

Ph•

E

EPh

60−84%

Figure 99 Elimination of silyl enol ethers.

The use of β-chlorovinylsilanes to prepare terminal allenes has also been demonstrated.226,227 Treatment of β-hydro-xyvinylsilanes with either acids or bases surprisingly did not affect elimination. But when the β-hydroxyvinylsilanes were convertedinto their β-chlorovinylsilanes by exposure to thionyl chloride, elimination to the allene could be induced by treating with fluoridesalts. The yields were only moderate for this transformation (Figure 100).

Cl

R2R1

SiR3

R4NF

DMSOor

CH3CNR1

•H

HR2

20−60%

Figure 100 β-Chlorovinylsilane eliminations.

The use of Pd(0) in the presence of ZnEt2 was demonstrated to form both terminal and internal allenes from allylic alcoholderivatives.228 Terminal allenes bearing a neighboring protected amino group were synthesized along with alkyl- and aryl- sub-stituted allenes. Yields ranged from 47% to 90%. The reaction was proposed to proceed via a π-allyl palladium intermediate, whichthen eliminated the vinylic bromide to produce the allene and a PdII species (regenerated to Pd(0) with diethyl zinc). The possibilityof Zn/Pd transmetallation of the π-allyl palladium intermediate was not ruled out as a potential reaction mechanism (Figure 101).

R1

Br

R2

OMsPd(PPh3)4

ZnEt2THF

r.t.R1

•R2

47−90%

Figure 101 Palladium induced vinyl bromide eliminations.

The radical-based synthesis of allenes using vinylsulfoxides with azobisisobutyronitrile (AIBN) and tris(trimethylsilyl)silane(TTMS) has been described.229 The vinyl sulfoxides were prepared from the corresponding aldehydes and ketones. This methoddemonstrated the preparation of terminal, di-, and trisubstituted allenes in modest yields and was tolerant to aryl, ester, silyl, andether functionalities. Yields ranged from 30% to 80%. The mechanism was thought to proceed through a radical β-elimination ofthe vinyl sulfoxides (Figure 102).

R2 SAr

OR1

Br

AIBN, TTMS

Benzene R2•

R1

30−80%

Figure 102 Radical based eliminations to form allenes.






6.18.7.4 From Alkyne Precursors

The synthesis of tetraaryl-substituted allenes starting from aryl substituted propargylic alcohols was disclosed.230 This method useda Pd-catalyzed addition–elimination sequence to obtain the tetraaryl allenes. The mechanism for the reaction was unclear;however, the authors postulated that a β-hydroxyvinyl palladium intermediate was formed from insertion of Pd onto the alkynevia carbopalladation, which then eliminated the β-hydroxy group to produce the corresponding allenes (Figure 103).

R2

Ph

OHR1 ArI, Pd(TFA)2, PPh3NEt3

MeCN Ph•

R2

ArR1

42−86%

Figure 103 Palladium catalyzed addition-elimination involving alkynes.

The synthesis of α-allenic alcohols was demonstrated by the treatment of mono-O-tetrahydropyran (THP) derivatives ofalkynyl diols with LiAlH4.

231 This method provided access to the α-allenic alcohols in high yields. Applications to the synthesis oflinear and branched α-allenic alcohols as well as the synthesis of a sex pheromone were demonstrated. The mechanism of thereaction was proposed to involve an intramolecular hydride transfer after attachment of the aluminum hydride to the alcohol. Thehydride would attack the alkyne and expel the O-THP group on the other end (Figure 104).

R1

O-THPR2

H

OHH LiAlH4

R1

O-THPR2

H

OH

Al

H

H

H

R2 •H

CH2OHR1

78−87%

Figure 104 Elimination of alkynyl diols.

The synthesis of α-allenic aldehydes was demonstrated by the conversion of propargyl diol derivatives to give an intermediatetriene.232 1-Trimethylsilyloxy-4-methoxy-2-alkynes were treated with t-BuLi to induce deprotonation, which led to elimination ofthe methoxy group. Subsequent hydrolysis of the silyl group led to the formation of the α-allenic aldehydes (Figure 105).

R1

OMeR2

OSiMe3

HH t-BuLi

R2

• •R1 H

OSiMe3

H2O

R2

•HR1

HO

Figure 105 Elimination of propargyl diol derivatives.

6.18.8 Eliminations to Form Alkynes

Elimination reactions are popular methods to prepare triple bonds, and many strategies are available for these transformations.233 Moststrategies employ one or two β-eliminations to achieve the alkyne construction, but α-elimination protocols may also be followed.234

α-Eliminations have been extensively used in the preparation of polyconjugated systems235 including those of natural products.α,α-Dichloroalkenes can be transformed into alkynes by treatment with base. The process can occur by β-elimination followed

by halogen exchange or by halogen exchange followed by α-elimination. The latter process generates a carbene that rearranges toafford an alkyne. Two named reactions are associated with the use of α,α-dichloroalkenes, the Corey–Fuchs synthesis236 and theFritsch–Buttenberg–Wiechell rearrangement.40–42

α,α-Dichloroalkenes were recently employed to generate a key intermediate in the synthesis of tulearin C.237 In this synthesis,MeLi was used as a base to carry out a Fritsch–Buttenberg–Wiechell rearrangement by lithium–halogen exchange. The methylchloride that was formed from the initial exchange process then served as the electrophile to cap the alkyne product of the carbenerearrangement with a methyl group (Figure 106).

A series of alkynyl imines was prepared by treating α,α-dichlororketimines with either NaH in DMSO or KOtBu in THF.238

Other groups have transformed α,α-dibromoalkenes into terminal alkynes by using Cs2CO3 as a base.239 The authors postulatedthat the reaction proceeded by a β-elimination, followed by hydrogen exchange involving the base (Figure 107).240




OCl

Cl

CH3LiHO

CH3

Figure 106 α-Elimination in synthesis.

NR2

R1Cl Cl

R3

NaH

DMSO50−60 °C

NR2

R1

R344−78%

Figure 107 Alkynyl imines from α-elimination.


The elimination of vicinal dihalogen compounds to provide alkynes is a well known transformation in organic chemistry.3,6

This method can be used to transform double bonds into triple bonds by bromination followed by double elimination with avariety of bases. The first elimination to form a vinyl halide is normally facile, but the second elimination often requires the use ofstronger bases such as NaNH2, LDA, or BuLi.6 Recently, it has been shown that the eliminations can be carried out in warmdimethylformamide (DMF) using DBU241 or TBAF242–244 as a base.

A method has been disclosed for preparing alkynes through the TBAF-promoted elimination of β-fluorovinylsilanes.245 Theprocess was used to unmask protected alkynes during the synthesis of oligoynes. Exposing the materials to TBAF at 0 °C smoothlycarried out the transformation (Figure 108).

Ph2BuSi

FPh

F

SiBuPh2

Ph

TBAF, 88%

PhPh

Figure 108 Oligoynes from alkene elimination.

β-Eliminations involving ketones have been explored in the synthesis of S-alkynyl sulfoximines. In this chemistry, the treatmentof alkyl sulfoximines with Tf2O in pyridine was sufficient to bring about alkyne formation. These transformations involvedenolsulfonate formation followed by elimination (Figure 109).246

O

RS

Ph

TBSN O Tf2O

pyRS

O

NTBS

Ph

47−94%

Figure 109 Alkynes from β-elimination.

Aldehydes have been converted into terminal alkynes using similar reaction sequences that could be induced with nonaflategroups.247 The high leaving group ability of the nonaflate provided for extremely mild conditions, and the method waschemoselective for aldehydes. A specialized base was required for these transformations (Figure 110).248

A combination of sulfone- and phosphate-leaving groups was employed in an alkyne assembly strategy. Sulfones were con-densed with aldehydes using chlorophosphonates as a quench. In situ treatment with base-induced double β-eliminations toproduce a series of (1-propynyl)arenes (Figure 111).249





OO

( )3

CF3(CF2)3SO2F

N P N

3

O

( )3

Figure 110 Terminal alkynes from elimination processes.

Me

OS

O

Ph

1. BuLi2. ArCHO

3. CIP(O)OEt2

THF60−83%

4. t-BuOK

Et Ar

Figure 111 Alkyne assembly by sulfone elimination.


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comprehensive organic synthesis ii || 6.18 eliminations to form alkenes, allenes, and alkynes and...

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