claisen review

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Claisen Rearrangement over the Past Nine Decades

Ana M. Martn Castro*

Departamento de Qumica Organica, Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain

Received February 18, 2003

Contents

1. Introduction 29392. Definition and Historic Overview of the Claisen

Rearrangement2940

3. Related [3,3] Sigmatropic Rearrangements 29413.1. Carroll Rearrangement 29413.2. Eschenmoser Rearrangement 29413.3. Johnson Rearrangement 29423.4. IrelandClaisen Rearrangement 29423.5. ReformatskyClaisen Rearrangement 29423.6. ThioClaisen Rearrangement 2943

3.7. AzaClaisen Rearrangement 29433.8. Chelate Claisen Rearrangement 29433.9. DiosphenolClaisen Rearrangement 2944

3.10. MetalloClaisen Rearrangement 29443.11. Retro-Claisen Rearrangement 2944

4. Mechanistic and Kinetic Aspects 29454.1. General Remarks 29454.2. Factors Affecting the Reaction Rate 2945

4.2.1. Influence of the Substituents 29454.2.2. Influence of Charged Intermediates 29474.2.3. Catalyzed Claisen Rearrangements 29494.2.4. Other Parameters 2954

5. Enzymatic Claisen Rearrangement 2956

6. Stereoselective Claisen Rearrangement 29566.1. General Aspects 29566.2. Intraannular Diastereoselectivi ty 2956

6.2.1. Transition-State Geometry 29566.2.2. Vinyl Double-Bond Geometry 29586.2.3. Allyl Double-Bond Geometry 29606.2.4. Configuration at C-4 2961

6.3. Diastereoselective Synthesis of AchiralProducts

2963

6.3.1. Diastereoselective Synthesis ofCycloalkane Derivatives

2963

6.3.2. E/Z Selectivity 29636.4. Diastereoselective Synthesis of Chiral

Products

2963

6.4.1. Chiral Auxiliary at the Allyl Fragment 29646.4.2. Chiral Auxiliary at the Vinyl Fragment 2965

6.5. Enantioselective Claisen Rearrangement 29686.5.1. Chiral Catalysts 29686.5.2. Chiral Solvents 2972

7. Application of Claisen Rearrangement Productsto the Synthesis of Organic Building Blocks

2973

7.1. Heterocyclic Compounds 2973

7.2. Carbocyclic Skeletons 29807.3. Dienes 29827.4. Condensed Aromatic Structures 29847.5. Carboxylic Acid Derivatives 29847.6. Quaternary Carbons 29887.7. Polysubstituted Alkenes 29897.8. Sugar Derivatives 2989

8. Application of Claisen Rearrangement to theSynthesis of Natural Products

2990

9. Other Applications 299810. Conclusion 299811. Acknowledgments 299912. References 2999

1. Introduction

The discovery of the Claisen rearrangement almosta century ago1 offered a potentially useful synth etictool to the organic chemist. Over the decades thisusefulness has been realized and the reaction hasdrawn the attention of numerous research groups,which h as been r eflected in t he n umber of papers onthe topic published in the l i terature.2 In the 1970sand 1980s several general r eviews appeared on thetitle reaction or related processes.2a-g However, inrecent year s only specific issues r elated t o this typeof rearran gement have been addressed,2k-m the stud-ies on the stereochemical aspects of th e reactiondeserving special mention. This review provides ageneral overview covering the most relevant topicsrelated to the Claisen rearra ngement, starting fromits first publication by Ludwig Claisen in 1912 as anew [3,3] reorgan ization of allyl ar yl (or vinyl) eth ersup to its most recent applications in different organicchemistry fields. First , a brief description of t herea ction along with its h istoric profile ar e given. Thisleads to the presentation of other [3,3] rearrange-ment s closely related to th e title rea ction, which areof relevant interest for having been largely exploitedas synthetic methods. Next, mechanistic and kineticaspects are discussed with attention focused on themain factors affecting the reaction rate, basically thepresence of different substituents at the 1,5-hetero-diene skeleton, the use of catalysts, and changes inthe physical parameters affecting the reaction. Thefollowing section in the review briefly deals with thee n zy m a t ic v er s ion of t h e C la i se n r e a r r a n g em e n t ,which is of relevant interest in metabolic routes.

A significant section of the review is constitutedby th e study of th e stereoselective version of th erear ran gement. After a presenta tion of some general* E-mail: mar tin.castro@uam .es.

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a s p ect s r e ga r d i n g c h ir a l it y t r a n s fe r i n t h e s e p r o-cesses, different strat egies to control intraan nulardiastereoselectivity as well as methods to performdiastereoselective synth esis of both achiral a nd chiralcompound s a re examined. The enan tioselective Clais-e n r e a r r a n g em e n t i s a l so t h o r ou g h ly con s id e r ed .Fina lly, in t he last sections of th e review a selectionof the most outst an ding applications of the r eactionis presented. A number of examples illustrating theuse of the Claisen rearrangement in the preparationof a wide r an ge of synth etically interesting buildingblocks and natural or biologically active compounds

are considered. Some other potentially interestingapplications of the rearrangement in further fieldsof organic chemistry are also presented.

2. Definition and Historic Overview of the ClaisenRearrangement

The [3,3] sigmat ropic rear ra ngement of allyl vinylethers, which allows the preparation of,-unsatur-ated carbonyl compounds, is worthy of study due toits special synthetic relevance as well as the largenumber of theoretical studies generated. This reac-tion, first r eported by Ludwig Claisen in 1912,1 wa soriginally described as the thermal isomerization of

an allyl vinyl ether 1sor of i ts nitrogen or sulfurcontaining ana logue der ivat ivessto afford a bifunc-tionalized molecule 2 (Scheme 1) in a [2s + 2s +2s] process.

This first paper essentially described the tra nsfor-m a t i on of a l ly l p h e n y l e t h e r i n t o C-allyl phenol.

However, i t also dealt with the formation, startingfrom O-allylat ed eth yl acetoacetate (3), of its C-allylisomer 4 after distillation in the presence of NH 4Cl(Scheme 2) in a process which adopted the general

denomination ofClaisen rearrangement. As we shallsee, th is is a reaction exhibiting all t he essentialproperties required by a synthetic procedure to beconsidered as efficient: i t can be chemo-, regio-,diastereo-, an d enan tioselective,3 can be performedunder mild conditions, and affords potentially usefulpolyfunctionalized molecules.

The synt hetic potent ial of the process encour aged,in the following years after i ts f irst publication, anu mber of resear ch groups t o make significan t effortsto find the experimental conditions which wouldallow the generalization of the reaction to a widevariety of substrat es. To verify that the conditionsinitially r eported by Claisen to perform the rear-rangement on aromatic substrates 4 could be success-fully a pplied to aliphatic skeletons, independentlyBergman a nd Corte in 19355a and Lauer and Kilburnin 19375b studied the rearra ngement in th e presenceof NH 4Cl of ethyl cinnamyl oxycrotonate (5). Thissubstrate was generated either by reaction of cin-na myl alcohol an d ethyl 3-ethoxy-2-crotona te 5a orfrom sodium cinnamylate and ethyl -chlorocrotonate5b

(Scheme 3). The formation of the rearranged product

afforded a formal way of S N2 C-alkylation of cin-namyl halides with the anion derived from aceto-acetates.

The interest of this new rearra ngement promptedthe development of different meth ods for th e prepa -ration of the starting materials. Hurd and Pollack6

described the synthesis of allyl vinyl ethers by acidicor basic elimination as well as the rearrangement ofsuch compounds into the corresponding ,-unsatur-ated carbonyl compounds (Scheme 4). However, thismeth od did not provide genera l access t o allyl vinylethers.

Ana M. Martin Castro was born in Madrid, Spain, in 1964. She receivedher B.S. (1988) and Ph.D. (1994) degrees under the supervision ofProfessors J. L. Garcia Ruano and J. H. Rodriguez Ramos at theUniversidad Autonoma of Madrid. As a postdoctoral fellow she joined thegroups of Professor P. R. Raithby at the University of Cambridge (U.K.,1997) and Professor V. K. Aggarwal at the University of Sheffield (U.K.,19982000). She retuned to Professor Garcia Ruanos group as anAssistant Professor. Her present research interests include the develop-ment of novel asymmetric methodologies assisted by a chiral sulfinylgroup, particularly hydrocyanation processes and DielsAlder and 1,3-dipolar cycloadditions.

S c h e m e 1

S c h e m e 2

S c h e m e 3

S c h e m e 4

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Several years later t his procedure for the synthesisof allyl vinyl ethers was improved by the interchangeof a l coh ol s wit h a l k yl v in y l e t h e r s ca t a l y ze d b yHg(OAc)2.7 Those compounds once again proved tobe excellent substr ates to under go a [3,3] rearra nge-ment (Scheme 5). This mercury-catalyzed reaction

ha s become one of th e typical meth ods of prepar at ionof allyl vinyl ethers despite that the yields of thesereactions are often low.

The development of the aliphatic Claisen rear-rangement was simultaneous with the study of thearomatic version of t he reaction.2a,b,8 T h u s , i n t h eClaisen rearrangement of an allyl aryl ether, the first[3,3] step affords a n ortho dienone which usuallyenolizes into an o-allylphenol. I t is the reactionknown as the ortho Claisen rearrangem ent(Scheme

6). When the rearrangement takes place on an ortho

position bearing a substituent, a second [3,3] rear-rangement (Cope rearra ngement) takes place fol-lowed by enolization. This reaction, usually called thepa ra Cl ai sen rear ra n gem ent, leads to the correspond-in g p-allylphenol.

The product resulting from t he ortho Claisen rear-rangement is usua lly obtained from th e r eaction,although the para process can compete even whenboth ortho positions are unoccupied.2b The proposedmechanism for the aromatic Claisen rearrangementhas been corrobora ted by t he pr oduct r esulting fromthe rearrangements of allyl phenyl ether and allyl2 ,6 -d i m e t h y lp h e n y l e t h e r , b ot h com p ou n d s 14 C-

labeled on the carbon of t he allyl chain8a (seeScheme 6). The result of the ortho r e a r r a n g e m e n tshows that the rear rangement with inversion at theallyl group is the only reaction taking place. In thecase of the para rearra ngement, the migrat ion onlyproceeds without inversion of the allyl group. Thismeans that during the course of the reaction such agroup is never free enough to undergo resonance.8b

3. Related [3,3] Sigmatropic Rearrangements

The interest generated by the Claisen rearrange-ment prompted the development of a considerablenumber of different versions of [3,3] sigmatr opic

rearrangement. Some of the most noteworthy oneswill be considered next.

3.1. Carroll Rearrangement

The Carroll reaction, initially described in 1940, 9

is a thermal rearrangement of allylic -ketoestersfollowed by decarboxylation 10 to yield ,-unsaturatedk e t on e s (S ch e m e 7 ). T h is r e a ct i on h a s n ot b ee n

widely developed du e t o th e dr astic conditions (tem-peratures of 130-220 C after in situ preparation oft h e -ketoester) which are required to perform thetransformation.

After the publication of these results, i t was re-

ported that dianions derived from allylic acetoace-tates, prepared by treatment of acetoacetates with 2equiv of LDA, rear ran ged under milder therm al con-ditions to give easily isolated -keto acids (Scheme8). 11

A dependence of the reaction rate on the substitu-tion pattern on the allylic fragment (R, R ) H, a lkyl,aryl) has also been detected. Thu s, a cetoacetatesderived from prima ry alcohols rear ra nge more slowlyt h a n t h os e d e r iv ed fr om s e con d a r y a n d t e r t ia r yalcohols.

3.2. Eschenmoser Rearrangement

In 1964 Eschenmoser,12 based on observationspreviously reported by Meerwein 13 on the interchangeof amide a cetals with allylic alcohols, described the

[3,3] r earran gement of N ,O-ketene acetals to yield,-unsaturated amides (Scheme 9).

S c h e m e 5

S c h e m e 6

S c h e m e 7

S c h e m e 8

S c h e m e 9

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This reaction allows the formation of a carbon-c a r b o n b o n d a t t h e position to a nitrogen atom,which is of great applicability in alkaloid syn thesis,although it has the inconvenience of th e difficultyinherent to the preparation of more elaborated N ,O -ketene a cetals, which usua lly requires elevated tem-peratures leading, in some cases, to decompositionof th e resulting amides.

Several years later an Eschenmoser rearrangement

by reaction of lithium allyl alkoxides with acyclic14

and cyclic15 s a lt s of N ,N-dialkylalkoxymethylene-iminium was reported to proceed in excellent yields(Scheme 10). The high tempera tur es reported for t he

Eschenmoser rear ran gement ar e usu ally required forthe alcohol exchange reaction, not for the actualrearra ngement. Therefore, the mild conditions em-ployed for th e prepa ra tion ofN ,O-ketene acetals suchas those depicted in Scheme 10 increased the syn-thetic interest of the m ethod.

S im i la r r e s u lt s a r e ob t a in e d b y t h e y n a m in e-Claisen rearr angement,16 a l so k n own a s F i ci n i-Claisen rearrangement, by reaction of an allylic alco-hol with 1-(diethylamino)propyne (Scheme 11). This

is a process whose stereochemical course may bemodified by th e r eaction conditions, as discussed insection 6.2.2. When the N ,O-ketene acetal is obtainedby addin g t he alcohol slowly t o a refluxing solutionof the ynamine in xylene, the rearrangement takesplace via the kinetically formed (E)-isomer. In thepresence of a Lewis acid, equilibration to the ther-modyna mically favored (Z)-stereoisomer occurs beforerearra ngement. Transformat ion of th e kineticallyfavored (E)-N ,O - k e t e n e a c e t a l t o t h e threo ,-un-saturated amide can be considered as complementaryto the Eschenmoser rearrangement, which evolvesthrough the (Z)-isomer affording the erythro product.

3.3. Johnson Rearrangement

First reported in 1970,17 t h e J o h n s on r e a r r a n g e-ment, which may afford trans-trisubstitut ed alkenes,was originally described as the process consisting ofthe heating of an allylic alcohol (6) with an excess ofethyl orthoacetate in t he presence of trace amountsof a weak acid (typically propionic acid). The initiallyformed mixed ortho ester (7) loses eth an ol to generat ethe ketene a cetal 8, which undergoes rearrangementleading to a ,-u n s a t u r a t e d e s t er (9) (Scheme 12).

Subsequently the Claisen rearr angement of orthoesters wa s shown t o be compatible with th e presenceof a h eteroatomic substituent directly bonded t o theallyl vinyl ether moiety. One of th e few reported ex-amples of Johnson rearr angement with heteroatomicsubstitu tion (OCH 3) is the reaction of allylic alcoholswith methyl methoxyorthoacetate that gives methylR-methoxy-,-unsaturated esters in a process thatoccurs under acidic conditions (Scheme 13).18

3.4. IrelandClaisen Rearrangement

In 1972 Ireland reported the rearrangement of allyltrimet hylsilyl ketene a cetals,19 prepar ed by reactionof allylic ester enolates with trimethylsilyl chloride,to yield ,-unsaturated carboxylic acids (Scheme 14).

As compared with other reported rearrangements,this reaction proceeds under mild basic or neutralconditions.

These conditions have allowed the preparation ofpolyfunctionalized st ructur es, such as the vinylstan-n a n e s r e p r es e n t ed i n S ch e m e 1 5.20 This example

p r ov id e s a m e t h od of fu n c t ion a l iz in g t h e n e wlyformed double bond due t o the h igh synth etic versa-tility of organotin compounds.

3.5. ReformatskyClaisen Rearrangement

W e h a v e s o f a r s e en t h a t a l ly li c e st e r e n ol a t esrearrange quite easily. [3,3] Sigmatropic rearrange-

S c h e m e 1 0

S c h e m e 1 1

S c h e m e 1 2

S c h e m e 1 3

S c h e m e 1 4

S c h e m e 1 5



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ment of zinc enolates, kn own as the Reformat sky-C la i se n r e a r r a n g em e n t , h a s a l so b ee n r e p or t e d .21

These zinc enolates (10 ), generated by Reformatskyreaction ofR-haloesters (11) with zinc dust, lead tothe corresponding ,-unsatu rat ed zinc carboxylates(12 ) (Scheme 16) in good yields under neither acidicnor basic conditions.

Similar reaction conditions, in the presence of trimethylsilyl chloride, allowed the synthesis of 2,2-difluoro-4-pentenoic acid starting from allyl chlorodi-fluoroacetate 22 (Scheme 17). This silicon-induced

Reformatsky-Claisen reaction did not occur in theabsence of chlorotrimethylsilane. This indicates thatthe ketene acetal depicted in Scheme 17 is most likelya reaction intermediate.

3.6. ThioClaisen Rearrangement

Thermolysis of allyl phenyl sulfides (13 )23 leadingto a [3,3] sigmatropic rearrangement contrasts withthe classic Claisen rearr angement: it requires higher

temperatur e to pr oduce the corresponding thiols,i n t er m e d ia t e s wh ich a r e n ot e a s il y i s ol a t ed a n dusua lly evolve into t he corresponding diallyl deriva-tives due to a S N2 displacement by the intermediatethiolate on the starting sulfide (Scheme 18). 24

I n con t r a s t , t h e a l ip h a t i c v er s ion of t h e t h i o-Claisen rearrangement may proceed under milderconditions than those reported for oxygenated sub-strates (Scheme 19).25

Nevertheless, the low applicability of this method-ology is a consequence of the instability of the prod-ucts. This prompted the development of conditionst o t r a p a n d t r a n s for m t h e m i n t o m or e s t a b le com -pounds such as, for example, the hydrolysis of theintermediate thioaldehyde into the correspondingaldehyde (Scheme 20).26

3.7. AzaClaisen Rearrangement

The [3,3] sigmat ropic rear ra ngement ofN-allyl-N-a r y la m i n es , k n o wn a s t h e a z a-Claisen rearrange-ment (Scheme 21),27 usually requires more drastic

conditions than those required for the classic Claisenrearra ngement of oxygenated substrates (this r ear-rangement occurs at 200-350 C). In addition, i taffords the corresponding anilines along with undes-ired byproducts.

Similar energetic conditions are needed for thealiphatic aza-Claisen rearrangement to take place(Scheme 22).2a The thermal process requires higher

t e m p er a t u r e s t h a n t h o se n e e de d for ox yg en s u b -stra tes. In a n umber of cases t he r eaction only evolvesun der Lewis-acid cata lysis.

3.8. Chelate Claisen Rearrangement

Chelated enolates derived from amino acid estersu n d e r go C l a is e n r e a r r a n g em e n t u p on s t a n d in g a troom t emperat ure t o produce ,-unsatu rated aminoacids (Scheme 23).28 Start ing from E-allylic esters,

syn products a re obtained in a diastereoselectivefashion. These reaction conditions are based on thefact that, in general, chelation sharply increases thetherma l sta bility with no negative influence on thereactivity of those enolat es. As a consequence of th erigid geometry of the enolate and the predictablegeometry of the transition state, any transformation

S c h e m e 2 0

S c h e m e 2 1

S c h e m e 2 2

S c h e m e 2 3

S c h e m e 1 6

S c h e m e 1 7

S c h e m e 1 8

S c h e m e 1 9



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will tend to take place with a very high stereoselec-tivity (see section 6.2.2).

3.9. DiosphenolClaisen Rearrangement

This variety of Claisen rearrangement uses allylethers (14 ) derived from diosphenol, with an endocy-clic vinyl double bond, t o give rise t o a bond betweena fu n c t ion a l iz ed ca r b on m oi et y a n d a s t e r ica l lyhindered carbon which is part of a cyclic structure

(Scheme 24).29 The resulting bisketone usua lly ta u-tomerizes into the ketoenol derivative.

3.10. MetalloClaisen Rearrangement

Several studies focused on the development of

synth etic applicat ions ofgem

-dimetallic compounds,

30

which were prepared by carbometalation of an al-kenyl organometallic magnesium, lithium , or a lumi-n u m d e r iv a t iv e wi t h a n a l ly l z in c b r om i de . T h einitially accepted pathway for the carbometalationconsists first in the formation of an allyl vinyl zinccompound (15) (Scheme 25), which next undergoes a

[3,3] rearrangementsa p r o c e s s k n o wn a s t h e m e t -allo-Claisen rear rangement 30ast o a ffor d t h e 1 ,1 -bimetallic species 16 . Howev er , t wo m e ch a n i s t ic

rationales, a metallo-ene reaction and a metallo-Claisen r earran gement, account for the resultingproducts as shown in Scheme 25. Density functional(B3LYP) stu dies on t his rea ction have demonstr atedthat the process is a n endothermic Lewis-acid-as-sisted metallo-C la i se n r e a r r a n g em e n t wit h s om echaracter of metallo-ene reaction of the vinylmag-nesium species (MXn ) MgCl in Scheme 25).31 Th ehigh diastereoselectivity of the reaction has beenexplained by the short length of the forming C-Cb on d i n t h e l a t e t r a n s i t ion s t a t e of t h e m e t a ll o-Claisen process.

These organic gem -dimeta llic compound s are ableto react successively with two different electrophiles

to pr oduce var ious gem -difun ctionalized str uctur es30b-d

(Scheme 26).

Several years later this methodology was expanded

to th e rearra ngement of allyl a llenyl derivatives togive access to gem -dimetalated dienes30e,f (Scheme27).

As ment ioned, r ecently a series of theoretical cal-culations has supported a mechanism in which thereaction of an allyl zinc bromide with a vinylmagne-sium bromide initially proceeds through a fast trans-metalation process to generate an allyl vinyl zinc

intermediate A, which undergoes a MgBr 2-assistedmetallo-Claisen rearrangement through transitions t a t e B , which generates the 1,1-dimetallic speciesC. T h e r e a ct i on p r od u ct D r e s u lt s fr om a fi n a loligomerization step31 (Scheme 28). An equilibrium

mixture of (E / Z)-allyl zinc bromide affords a singlediastereomer r esulting from r eaction of the m inor (Z)-allyl isomer. This result is explained by compar isonof the relative energies of the diast ereomeric tra nsi-tion states since the pathway through the (Z)-isomeris favored over that evolving through the (E) reagent.

3.11. Retro-Claisen Rearrangement

The Claisen rearrangement, as in any other [3,3]sigmatr opic rearra ngement, takes place un der th er-modynamic contr ol. This reaction is irreversibletoward the format ion of th e carbonyl compounds(S ch e m e 2 9) d u e t o t h e ir h i gh e r t h e r m od yn a m i cstability.

S c h e m e 2 6

S c h e m e 2 7

S c h e m e 2 8

S c h e m e 2 9

S c h e m e 2 4

S c h e m e 2 5



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However, some structural features have been iden-tified a s being r esponsible for in version of th e norm alsitua tion, favoring the t ra nsforma tion of th e car bonylcompound into the vinyl ether. In this sense, botht h e p r e se n ce of a n y s u b st i t u en t a t a b r id ge h ea dposition and vicinal quat ernary carbons in the car-bonyl compound shifts the equilibrium toward theretr o-Claisen isomer as a result of a r elief in t orsiona ls t r a i n (S ch e m e 3 0).32 This effect is particularly

mar ked in t he pr esence of a cata lytic amount of Lewisacid (BF 3.OEt 2). This r etro-Claisen process is genera lfor a num ber of substrat es conta ining contiguousq u a t e r n a r y c e n t er s wh e n ev er t h e R-carbonyl sub-stituent is not an electron-releasing group.

A similar thermolabili ty h as been detected forvinylcyclopropa ne carboxaldehydes, which evolve into2,5-dihydrooxepines by ret ro-Claisen rea rr an gement,

a s i n di ca t e d i n S ch e m e 3 1 a . I n t h i s e x a m p le t h e

ther modynamic sta bility of the carbonyl group, whichis favored at equilibrium, compensates for the un-stabilizing strain of the cyclopropane ring.33a Th eready retr o-Claisen r eaction of this type of vinylcy-clopropanes is evidenced by a number of examplesreported in the literature (see, for example, Scheme

31 b33b ).

4. Mechanistic and Kinetic Aspects

4.1. General Remarks

The term Claisen rearrangement was originallya p p l i e d t o r e a r r a n g e m e n t s o f a l l y l a r y l e t h e r s t oafford ortho- and occasionally para-substituted phe-nols. Afterward it expanded to analogue rearrange-ments of allyl vinyl ethers into unsa tur ated carbonylcompounds, which were classified as [3,3] sigmatropicrearrangements.34 Initially a synchronic evolution forthese reactions through aromatic transition states

was accepted,35,36 formed by a combination of a n doverlap of 2p atomic orbitals of the carbon atomsof both allyl fragments. It wa s concluded th at, out ofthe two feasible geometries for the transition state,the reaction proceeded through chairlike intermedi-a t es (17 ) i n st e a d of b oa t l ik e i n t er m e d ia t e s (18 )(Figure 1).37 Both transition states (17 a n d 18 ) a r e

th e only ones corresponding to supra-supra processesand, therefore, allowed by Woodward-Hoffmannrules.34

The intramolecular cyclic character of th e rear-rangement is generally accepted. However, the re-s e a r c h t o u n d e r s t a n d t h e p r e c i s e n a t u r e a n d t h egeometry of the tran sition state continues. A largenum ber of th eoretical calculations aiming t o pre-dict the structures of the tran sition states involved

in the Claisen rearrangement have been reported.38-41

M os t of t h e m a cce p t a con ce r t e d r e a r r a n g em e n tthrough a chairlike t ransition state. H owever, re-cently Houk used quantum mechanical calculationsto rat ionalize the stereoselectivity of t he Ireland-Claisen rearra ngement of cyclohexenyl silyl enole t h e r s f r om t h e ch a i r or b oa t p r e fe r e n ce s i n t h etransition state which derived from the substituentson the cyclohexenyl ring.38c In addition, there is nogeneral agreement about the structure of this transi-tion state (Figure 2).42

Ove r t h e d e ca d e s s ev er a l e xp e r im e n t a l s t u d ie sbased on k inetic isotopic effects h ave been reportedin order to determine the geometry of the transitionstate of aliphatic and aromatic Claisen rearrange-ments.42-44 However, this has not proved to be aneasy task, an d despite th e nu merous pa pers dealingwith the Claisen rearrangement in different fieldsr e la t e d t o or g a n ic ch e m is t r y , t h e r e i s n o g en e r a lagreement about such a geometry from theoreticalpredictions. The difficulty of describing such a ge-

ometry still persists.

4.2. Factors Affecting the Reaction Rate

The most frequently reported Claisen rearrange-mentsthermal isomerization of allyl vinyl etherssi s a p r o c e s s t h a t r e q u i r e s h i g h t e m p e r a t u r e s a n dproceeds quite slowly at atmospheric pressure. Totransform this reaction into a synthetically usefulprocedure, nu merous at tempts to find milder experi-menta l conditions have been reported. The intr oduc-tion of different substituents in the carbon skeletonof the substrate as well as variations of the catalystare worth mentioning.

4.2.1. Influence of the Substituents

I n t h e l a st 2 0 y e a r s a con s id e r a bl e n u m b e r of s t u d ie s t o d e t er m i n e t h e i n du ct i ve or m e s om e r iceffects of electron-withdrawing or electron-donatingsubstituents located at different positions of t hecar bon skeleton ha ve been m entioned. These effectsare qualitatively described in Scheme 32.

Carpen ter stu died the effect of the cyan o group a tdifferent positions of allyl vinyl ethers. Such an effectwas interpr eted a s ba sically electronic.45 In th e caseof substrates substituted a t positions C-2 (kre l 111),C-4 (kre l 270), and C-5 (kre l 15.6), an acceleration ofthe rearrangement was detected, whereas substitu-

S c h e m e 3 0

S c h e m e 3 1

F i g u r e 1 .

F i g u r e 2 .



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t i o n a t C - 1 a n d C - 6 r e s u l t e d i n a d e c r e a s e i n t h ereaction rate. These observations were rationalizedfrom Hu ckel molecula r orbital (HMO) th eory, whichallowed evaluation of the effect of a substituent int h e t r a n s it i on s t a t e a n d i n t h e g r ou n d s t a t e .45b Th ecomparison of the difference of energy of HMO(E) b et we en t h e g r ou n d s t a t e a n d t h e t r a n s i t ions t a t e wi t h t h e v a l u e o f E for the unsubstitutedanalogue compound allowed them to predict the signand magnitude of the effect of the substituent in theactivation ent ha lpy of the r eaction. In t his model theelectron-withdra wing and -donat ing substituent s a rerepresented as carbocations and carbanions, respec-

tively. Fr om t he delocalized model of the tra nsitionstat e, some qu alitative predictions about t he effectsof t h e s u b st i t u en t s i n t h e C la i se n r e a r r a n g em e n tcould be m ade. Th e ma in inconvenience of th is modeli s t h a t t h e cy a n o g r ou p i s n o t on l y a n e le ct r on -withdra wing group, but also a radical-stabilizinggroup, so that the acceleration resulting from thepresence of a cyano group at C-2 an d C-4 may n ot bea consequence of its electron-withdrawing character.

To different iate th e indu ctive electron-withdra wingcha ra cter an d th e result of a combinat ion of indu ctiveand mesomeric electron-withdra wing effects, thebehavior of allyl vinyl ethers bearing a trifluorom-e t h yl g r ou p a t C -2 a n d C -4 wa s s t u d ie d .46 A CF 3

group is an electron-withdrawing substituent withan inductive chara cter but with no mesomeric one;it is n ot able to sta bilize radicals. Hen ce, th e Claisenrearrangement of allyl vinyl ethers bearing a CF 3group at C-2 su ffered a n accelera ting factor of 73 inrelation with the unsubstituted substrate, in com-parison with the value ofkre l 111 observed for cyanoderivatives at C-2.45a In i ts turn, a CF 3 group at C-4e xe r t e d n o i n fl u en ce i n t h e r e a ct i on r a t e . T h e seresults allowed Gajewski46 to suggest that the electron-withdrawing character of the substituent at C-4 isnot tha t responsible for the increase in the rate butits a bility to stabilize r adicals, which is r eflected inthe stabilization of the transition state. Similarly,

quite recently it h as been reported that a CF 3 groupat C-1 does not modify the reaction rate, whereas theeffect of a fluorine atom at the same position willdepend on the influence of an alkyl substituent R atC-2 (Figure 3).47

Different theoretical models predicting the effectsof several substituents in t he Claisen r earra ngementrate have been proposed. The model suggested byGajewski48 assumes that the stru cture of the tra nsi-t i o n s t a t e a d o p t s t h e f e a t u r e s o f t h e s u b s t r a t e o rproduct depending on the exothermic properties ofthe reaction. In addition, it will have an associativeor dissociative character according to the way thatthe su bstituent s can sta bilize such a char acter. Also,recently some theoretical calculations on the effectsof cyano, amino, an d t rifluoromethyl subst ituent s ont h e r a t e , wh os e r e s u lt s a r e coi n ci de n t wit h t h os eattained from experimental studies, have been re-ported.49

The effect of alkoxy groups has been largely studiedb y C u rr a n .50,51 An electron-donat ing substituent(alkoxy group) at C-6 sharply accelerates the Claisenrearrangement. 50 This effect seems to contra dictCar pent ers model,45 which predicts a deceleration inthe presence of a donating substituent at C-6, despitethe loss of resonan ce energy from the ground stateto the tra nsition sta te. To compensate for th is effect,t h e m od e l p r op os e s a f * sta bilization by avinylogous an omeric effect of th e O3-C4 bond of th evinyl ether as r esponsible for the Claisen r earr an ge-ment acceleration by donating substituents at C-6.The tra nsition state of the Claisen r earra ngement (eq2 in Scheme 33) can be understood in a similar way

to the double bond-no bond resonance explainingthe vinylogous anomeric effect (eq 1 in Scheme 33).

The process goes through an early transition statewhere the bond breaking is more advanced tha n t hebond formation.45 As ca n b e s e en , a n ox yg en a t e dsubstituent at C-6 must decrease the energy of thetransition statesan d, ther efore, accelera te t he r eac-tionsas it makes the breaking of the weakened O3-C4bond easier.

A similar a ccelera tion wa s detected with t he pr es-ence of an a lkoxy group a t C-4. In addition, the r at esof th e rearra ngements of 4- a nd 6-alkoxyallyl enolether s were quite sensitive to the solvent polarity andconsiderably increased in hydrogen bonding sol-vents51sit could not be detected from unsubstituteds u bs t r a t es . T h es e r e su lt s w er e a t t r ib u t ed t o a n

S c h e m e 3 2

F i g u r e 3 .

S c h e m e 3 3



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enhanced dipolar character of the transition state oft h e C la is en r e a r r a n ge m en t . I n ot h e r w or d s, t h epart ial delocalization of a nonbonding electr on pairat the donating substituent generates a significantdegree of enolat e-oxonium ion pa ir, which st abilizesthe transition state (Scheme 34).

A tr imethylsilyloxy group at C-2 of th e a llyl vinylether (Ireland-Claisen rear rangement 19) c a u s e s adecrease in t he activation free energy of about 9kcalm ol-1 i n r e la t i on wit h t h e u n s u b s t it u t e d s u b -s t r a t e .19b As the rearra ngement rat e is independentof the solvent polarity, in this case the mechanisticinterpretation mu st be based upon a neutra l transi-tion state.52 Ho we v e r , i t h a s b e e n a d m i t t e d t h a t aMe 3S i O g r o u p a t C - 2 g e n e r a t e s a t r a n s i t i o n s t a t e

where the degree of bond breaking is much higherthan that in an unsubstituted substrate. Therefore,to account for the easier Ireland-Claisen rearrange-m e n t a s com p a r e d wit h t h e cl a ss ic C l a is e n r e a r -rangement, one mu st invoke t he h igher stabili ty of the 2-(trimethylsilyloxy)-1-oxallyl moiety. This dif-ferent stability influences the structure of the tra nsi-tion state.

The results reported by Wilcox53 on r e a r r a n g e-ments of O-allyl silyl ketene acetals ar e worth men-tioning. Accordingly, an increase in th e st eric volumeof the subst ituent at C-5 produces an a cceleration ofthe reaction, whereas the electron-donating characterof a substituent at the same position decreases the

rate. The study of the influence of alkyl groups wasp r op os e d t a k i n g i n t o a ccou n t t h a t t h e s e s u b s t it -uents should not substantially affect the geometryand the electronic structure of the transition state.From these effects the influence of more polar sub-stituents in t he rear rangement r ate could be evalu-ated. In fact, the different tra nsition stat es (synchro-nic, fra gment ed, or 1,4-diyl) which ha ve been proposedfor the Claisen rearrangement can be more or lessstabilized according to th e nat ure of the substitu ents(Figure 4).

Therefore, it can be concluded that donor and ac-ceptor substituents at positions 1, 2, and 4 increasethe r at e in compar ison with a h ydrogen at om. At po-sitions 5 an d 6 t he effects a re complementa ry. A rat eacceleration is observed with donor groups at position6 a n d a cce p t or g r ou p s a t p os it i on 5 , wh e r e a s t h ereaction is decelera ted wh en t he donor an d acceptorgroups are interchanged at those positions. The de-

celerating effect of a methoxy group has been ac-cepted as evidence against a 1,4-diyl transition state.

Finally, in t he case of the ortho-Claisen r earra nge-ment, chan ges in the reaction rat e for differentlysubstitut ed aromatic substrat es have been observed.Schmid 54 explained this behavior as a consequenceof a differen t 1,2-bond order of the a romat ic fra gmentof th e allyl aryl ether, wher eas Tar bell an d Wilson55

proposed a directional electron flow du ring t he rear -

rangement both for substituted and unsubstitutedsubstrates (Figure 5).

The polar na tu re of th e reaction wa s reinforced bythe fact that the rate of the rearrangement of allylp-tolyl ether gradually increased as the polarity of the solvent was higher (reactions were faster whenthe solvent was phenol instead of diethyl ether). 56

There are several possible explanations accountingfor the effect of the su bstituen ts in t he rea rra ngement

rate.57 If concert ed, th e rea ction could be ra tionalizedas taking place almost as simultaneously at both thepa ra a n d meta positions relative to th e substitu ents;b on d for m a t i on a n d r u p t u r e wil l e x h ib it a p ol a rn a t u r e a n d s h ou l d n o t b e e qu a l ly i m p or t a n t i n t h eactivated complex. White proposed that the overallelectronic cha nge could be sum mar ized a s indicatedin Figure 6.58

Another plausible mechanism implies the forma-tion of ionic pairs (with a mar kedly oriented char-acter) as an intermediate step between the allyl arylether and the dienone, so that the allyl group willi o n i z e a s a n a n i o n a n d t h e a r o m a t i c m o i e t y a s acation (Figure 7).

Undoubtedly, the mecha nism for t he Claisen rear -rangement l ies, for a number of substrates, some-w h er e b et w ee n t h e se t w o e x t r em e s (F ig u r es 6

and 7).

4.2.2. Influence of Charged Intermediates

On the basis of the empirical observations that-electron-donating groups at the C-2 position of anallyl vinyl ether accelerate the Claisen rearrange-ment, Denmark studied the effect of the strongest-donating group, a carbanion (Scheme 35).

S c h e m e 3 4

F i g u r e 4 .

F i g u r e 5 .

F i g u r e 6 .

F i g u r e 7 .

S c h e m e 3 5



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Carba nions st abilized by cyano or alkoxycarbonylgroups (Z ) CN or CO2E t ) e xe r t e d n o p os it i vei n fl u en ce i n t h e r e a ct i on r a t e , m a y be d u e t o t h eextensive charge delocalization and the covalentnature of the anions. However, a carbanion on anarylsulfonylmethyl group at the C-2 position of anallyl vinyl ether accelerates the Claisen rearrange-ment about 300 times (Scheme 36);59 this has been

attributed to the inductive charge-stabilizing effectof the sulfonyl group. This acceleration has not beenobserved in the presence of other sulfur functionalgroups.59c The r eaction can be considered a s a regio-and stereoselective procedure capable of creatingvicinal quaternary centers in high yields.

The above-ment ioned diosphenol-

C la i se n r e a r -rangement 29 was considerably a ccelerated by thetra nsforma tion of the su bstra tes int o carbomethoxy-hydrazones, whose sodium salts rearra nged morethan 200 times faster than the corresponding carbo-nyl der ivatives60 (Scheme 37). This reaction pro-

ceeded in high yields and allowed th e creation of sterically hindered bonds such as the bond betweentwo quaterna ry carbons.

Similarly, the so-called anionic oxy-Claisen rear-ran gement of enolat es derived from R-allyloxyketoneshas been reported.61 This reaction, which took placeat unexpectedly low temperatures, was influenced bythe counterion and solvent (Table 1).

The enolates derived from R-allyloxyketones ar eable to evolve thr ough two possible sigmatr opicrear ra ngement s (Scheme 38). Resonance form 19 a (R-allyloxy-R-ca r b a n i on ) i ll u st r a t e s h ow i t i s a b le t oundergo a [2,3] rearra ngement (Wittig rear ran ge-ment) to yield the R-alkoxyketone 20 . In i ts turn, 19 b

can be consider ed a s a 1-oxy-3-oxa-1,5-hexa diene a bleto evolve th rough a [3,3] sigmatropic rearra ngementresulting in the isomeric alkoxyketone 21 .

As can be deduced from the data collected in Table1 , t h e r e a r e s om e con d i t ion s fa v or i n g t h e [3 ,3 ]process. A considerable acceleration was indeedobserved as a function of the electron-donating abilityo f t h e g r o u p OM a t C - 1 . T h u s , wh e r e a s t h e r e a r -rangement evolved at -23 C with potassium hydride

in toluene, there was practically no reaction withs od iu m h y dr i de u n d e r t h e s a m e con d it i on s . T h isaccelera tion of th e Claisen rea rr angement evidencesthe effect of the alkoxy anion in the tra nsition stat e.As we have already seen, the rearrangement proceedst h r o u g h a n e a r l y t r a n s i t i o n s t a t e q u i t e c l o s e t o aradical pair r esulting from the homolytic fragment a-tion of the O 3-C4 bond. In the case of the anionicoxy-Claisen rea rra ngement, th is fragment ation willg en e r a t e a p a ir for m e d b y a n a l ly l r a d ica l a n d astable oxy-oxallyl radical 22 (Figure 8). Therefore,

the rate-accelerating effect can be attributed, to alarge extent, to th e contr ibution of the extraordina rilystable radical anion 22 to the t ransition state of thereaction.

An anionic oxy-Claisen rearrangement has beenr e por t e d a s t h e k e y s t ep in t h e s yn t h e sis of t h eskeleton existing in a family of natural sesquiterpe-nes derived from campherenone (Scheme 39).62

S c h e m e 3 6

S c h e m e 3 7

Table 1. Oxy-C l a i s e n R e a r r a n g e m e n t u n d e r D i f f e r e n tE x p e r i m e n t a l C o n d i t i o n s

en t r y solven t M t em p (C) t1/2 (h )

1 t olu en e K -23 3.32 t olu en e Na 0 2.6

3 t olu en e Li +96.5 1.14 t olu en e Me3Si +71 0.55 TH F K -42 6.26 TH F K -23


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T h e r a t e o f t h e a z a-Claisen rear rangement of N-allylamines has been considerably increased bytreatment of allylamines with acid fluorides in thepresence of Me3Al.63 The zwitterionic rearra ngementimplies either the format ion of a complex of th eacylammonium salt with the Lewis acid or the directformation of the zwitterionic intermediate as a resultof a nucleophilic attack of the amine to the ketene-Lewis-acid complex (Scheme 40). In an y case, t he

reaction took place in high yields for a wide range ofsubstrates under milder conditions than those re-ported for the aza-Claisen rearrangement.

This reaction exemplifies how a positively chargedheteroatom decreases the activation energy of the

r e a r r a n g e m en t . T h is r e s u lt p r om p t e d t h e s t u d y o f 1,3-dipolar intermediates in the reaction (Scheme 41),

which were easily formed by reaction of allyl ethers,sulfides, or selenides with haloketenes.64

It is generally admitted that the reaction productsa r e ob t a in e d b y [3 ,3 ] r e a r r a n g e m en t of a d ip ol a roxonium intermediate 23 . Although intermediate23 is s u p pos ed t o b e le ss s t a ble t h a n t h e cor r e -sponding sulfur der ivative (due t o stabilizat ion of thelatter through d orbitals), the yields ofO-esters ar ehigher than those of the S esters. The results from

open chain allylic esters prompted the study of thereaction of vinyl-substitu ted heter ocyclic systemswith electrophilic haloketenes, which afforded me-dium-sized lactones, although in moderate to lowyields (Scheme 42). Subsequen t meta l (Zn, F e) reduc-tion allowed the elimination of the chlorine atoms ofthe molecule.

This ketene-Claisen variant could be recognizedas an importan t Claisen r earran gement class on thebasis of the number of syntheses that have used thischemistry and the enantioselective and Lewis-acid-catalyzed examples reported on this methodology (seelater).

Finally, another type of Claisen r earran gementaccelerated by charged substra tes is th e [3,3] rear-

rangement of the intermediates obtained by treat-ment of dienones 24 wit h t r i -n -butyltin hydride(Schem e 43).65 These reactions, which provided a

considerable increase in rate, proceeded under neu-tral conditions. The rearra ngement mechanism h asbeen studied independently by Enholm 65a a n d C u r -r a n ,65b resulting in two different mechanistic propos-als. En holms hypoth esis supp orts t he so-called an ion-rad ical mechanism, wher eas isotopic-labeling ex-periments with n -Bu 3SnD led Curran to defend themechanism reported as a stannyloxy-Claisen mech-an ism or an an ionic mechan ism (Scheme 43).

4.2.3. Catalyzed Claisen Rearrangements

Allyl aryl ethers with n o electr on-withdr awing su b-stituents undergo [3,3] sigmatr opic rearra ngement

S c h e m e 3 9

S c h e m e 4 0

S c h e m e 4 1

S c h e m e 4 2

S c h e m e 4 3



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in the presence of boron trichloride at low tempera-ture to afford the corresponding o-allyl phenols ingood yields.66,67 The charge induced at the reactionsite by the catalyst generates a rate increase of ca.10 10 relative to the therma l Claisen rearr angement.The rearrangement of allyl aryl ethers bearing anortho alkyl group, in the presence of boron trichloride,produced a mixtur e ofo- a n d p-allyl phenols, the ratioof th e para product being higher than tha t r esulting

from t he t herm al rea ction (Scheme 44).67

This par a

effect was especially marked for o-alkyl R-methyl-allyl aryl ethers.

In the presence of boron trichloride, 2,6-dialkyl allylaryl ethers gave products resulting from a sequenceof ortho-Claisen rearrangement followed by a [1,2],[3,3], or [3,4] r earran gement of the allyl m oiety.T h es e r e a r r a n g em e n t s , wh ich wer e s t u d ie d wit hdeuterium- or 14C isotopically-labeled subst ra tes, a rerepresented in Scheme 45. In the presence of protic

acids there was always a [3,3] rearrangement of theallyl group of 2,6-disubst itu ted 6-allylcyclohexa -2,4-dien-1-ones, whereas the use of boron trichlorideproduced the [3,3] rearrangement product along withthose compounds resulting from the [1,2] and [3,4]processes, although the latter ones were obtained asthe minor reaction products.

The mechanism which was proposed to explain thebehavior of a llyl ar yl ethers under boron chloride

catalysis 67 i m pl ie s a fr a g m en t e d t r a n s i t ion s t a t e ,similar to the one proposed un der th erma l conditions,as depicted in Scheme 46.

From th e above results i t should be deduced th atuse of BCl3 as the catalyst of the aromatic Claisenr e a r r a n g e m e n t h a s a r e s t r i c t e d s y n t h e t i c a p p l i c a -bility since i t provokes undesired side r eactions.However, in the case of complex systems such a s 25(Scheme 47), BCl3 catalysis afforded the Claisen

rearrangement product, while under thermal condi-tions the star ting ma terial only evolved with decom-position.68

The ar omat ic Claisen rearra ngement of allyl phen-yl ether was reported in the presence of alkylalumi-num halides under mild conditions.69 Treatment of a llyl p h en yl e t h er in h e xa n e w it h a n e xce ss of diethylaluminum chloride at room temperature pro-

duced o-allylphenol almost quantitatively (Scheme48). Similar results were attained in the presence ofethylaluminum dichloride.

In contra st with the cata lyst boron trichloride,these a lkylaluminum derivatives are able to catalyze[3 ,3 ] r e a r r a n g em e n t of a l ly l a r y l e t h e r s b ea r i n g

electron-withdra wing groups on the aromatic ring.Thus, allyl o-, m -, a n d p-chlorophenyl ethers rear-ranged in high yields into the corresponding allyl-chlorophenols bearing the allyl group in ortho posi-tion relative to the hydroxy group.69

Despite the large number of reported examples ofcatalysis of the aromatic Claisen rearrangement,66

the number of published results on the influence ofaluminum Lewis acids in the aliphatic Claisen rear-rangement is quite low. Nevertheless, it was reportedthat in the presence of organoaluminum compoundsof the type R3Al or R2AlX, or Et 2AlSPh or Et 2AlCl-P P h 3, a series of allyl vinyl ethers rearranged undermild conditions, although the overall results were

S c h e m e 4 4

S c h e m e 4 5

S c h e m e 4 6

S c h e m e 4 7

S c h e m e 4 8



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closely dependent on the catalyst nat ure (Scheme49).70 Thus, in the presence of trialkylalanes, therearra ngement pr oduct un derwent n ucleophile a t-tack, either by the alkyl group or by a hydride. Incontr ast, use of Et 2AlSPh or Et 2AlCl-P P h 3 producedthe aldehydes or ketones derived from the rearrange-ment with no nucleophilic attack.

The use of especially bulky aluminum reagentsallowed control of the regiochemistry of the Claisenrearr angement in compounds bear ing two allyl frag-ments.71 Un d e r t h e r m a l con d it i on s t h e r e a r r a n g e-ment evolved through the less hindered allyl group.In contrast, in the presence of aluminum reagents

s u c h a s A or B (Scheme 50), t he minimization of

steric repulsions between the more substituted allylg r ou p a n d t h e L ewis a ci d a ffor d e d t h e op p os it eregioselectivity.

Triisobutylaluminum-catalyzed Claisen rearrange-ments with concomitant reduction of the resultingcarbonyl group a llowed ring en largement processes.72

From the above-mentioned results on the rearrange-ment acceleration in the presence of charged inter-mediates, alkylaluminu m-cata lyzed rearra ngements

may be considered as the cationic analogues of thean ionic oxy-Claisen rear rangements. The tran sfor-mat ion of26 into 27 may be un derstood consideringthat the rearra ngement t akes place through a chair-like transition state such as that depicted in Scheme51 .

Many [3,3] sigmatropic rearrangements of allylicesters, allyl imidates, an d S-allyl thioimidates in thepresence of Hg(II) or Pd(II) salts have been reported.These reactions proceeded by a cyclization inducedrearra ngement, which explains the effect of t hemetal catalysts (Scheme 52).

Nevertheless, the number of reported examples ofHg(II)- or Pd(II)-catalyzed Claisen rearrangements

of 3-hetero-1,5-dienes, such as allyl vinyl ethers (X) O, Y ) CR 2, Z ) H, alkyl, aryl), is quite low. This

fact was explained a s a consequence of th e irrevers-ible binding of the electrophilic meta l catalyst a t th estr ongly nu cleophilic vinyl ether , which pr evented itsbinding at th e allylic double bond.74 In contrast, thosesubstrates bearing a vinyl moiety protected by alkylsubstitut ion from th e att ack of the metal catalyst areable to rearrange in the presence of PdCl2(CH 3CN )2,75

whereas they are unstable under thermal conditions(Scheme 53).

The Pd(II)-catalyzed Claisen rearra ngement of 2-alkoxycar bonyl-substitu ted allyl vinyl et hers (28 )was reported.76 Whereas under thermal conditionsthe reaction required heating at 150 C in a sealedtube, in the presence of PdCl2(PhCN)2, 2-alkoxycar -bonyl-substituted Z ,E- a n d E ,E-allyl vinyl ethersexhibited mar kedly different reactivities. Thus, (E ,E)-28 rearra nged through a boatlike tra nsition sta te toafford anti-,-alkyl-substituted R-ketoesters, while(Z ,E)-28 d id n ot r e a r r a n g e a t r oom t e m p er a t u r e .However, the latter rearranged at higher tempera-tures through a chairlike transition state to producethe same anti product (Scheme 54).

Similarly, some thio-Claisen rearran gements cata-lyzed by transition metals [Pd(II), Ni(II)] under mild

S c h e m e 4 9

S c h e m e 5 0

S c h e m e 5 1

S c h e m e 5 2

S c h e m e 5 3

S c h e m e 5 4



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conditions ar e kn own.77 Ketene N ,S-acetals 29 a a n d29 b un derwent tra nsition-meta l-promoted [3,3] sig-matropic rearrangements, under smooth conditions,to yield the corresponding t hiolactams (Scheme 55),

whereas the thermal rearrangement required heat-ing at 140 C. Although in t he pr esence of a cata lystth e exo diaster eoselectivity dra mat ically decreased ascompared with th e th erma l process, the isolat ed yieldof th e ma jor exo diastereomer was higher than underthermal conditions.

PdCl2(MeCN)2, P d C l2(PPh 3)2, and Pd(OAc)2 werePd(II) derivatives able to catalyze the rearrangementa t 2 5 C . P d ( P P h 3)4 wa s u s e d a t 2 5 C a s a P d ( 0 )catalyst. The results with NiCl2(PPh 3)2 should alsobe considered. Coordination of the metal with thed ou b le b on d (E i n S ch e m e 5 6) wa s p r op os ed t oexplain the stereochemical results obtained from 29 ain t he presence of Pd(II). Nu cleophilic atta ck of thethioenol ether generated an intermediate six-mem-bered palladate (F), which underwent Pd(II) elimina-tion to afford the [3,3] product. The Pd(0) reactionwa s p r op os ed t o p r oce ed v ia t h e for m a t i on of a-allylpalladium complex (I) (Scheme 56).

The catalytic effect of oth er Lewis acids (ZnCl2,

TiCl4, AgBF 4) in th e Claisen rear rangement ra te hasbeen stu died. However, only moderate rat e a ccelera-tions an d/or poor yields h ave been observed. This isprobably due to the formation of byproducts or to thedecomposition of the rearranged products under thereaction conditions.66 On the other ha nd, i t has beenreported that ytterbium triflate catalyzes the Claisenrearrangement of aromatic allyl and crotyl ethers togive the corresponding C-allyl phenols with an in-crease in the rate relative to the uncatalyzed reaction(Schem e 57).78 The increase in t he ra te was evidentfrom th e results obtained on increasing th e substitu-

tion at th e olefinic position. R-Naphthol was alsoobtained as a byproduct (15-30% yield).

E u (I II ) w a s a ls o r e p or t e d a s a ca t a ly st of t h eC la i se n r e a r r a n g em e n t of t h e p r e n yl e t h e r 30 t oafford the phenols resulting from the migrations toortho a n d para positions (Scheme 58).79 These com-pounds, after basic treatment, gave rise to flavonoids6-(1,1-dimet hylallyl)na rin genin (31 ) a n d 8 -p r e n yl -naringenin (32 ), r espectively.

Zwitterionic a za-C la i se n r e a r r a n g em e n t s wer ealso studied in the presence of a number of Lewisacids, an d a remarka ble catalytic effect was deter-mined.80 Allyl vinylam monium complexes, genera tedby the reaction of ketenes with tertiary allylaminesin t he presence of a Lewis acid, rear ranged to give2,3-disubstituted Claisen products in good yields(>75%) and excellent stereocontrol (>99:1 anti:sy nratio), the best results having been obtained with Yb-(OTf)3, AlCl3, Ti(Oi-Pr)2Cl 2, and TiCl4THF (Scheme59).

Similarly, the Ireland-Claisen rearrangement of allylic aryl acetates has been reported to proceed inhigh yields a nd diastereoselectivities by a ddition of

catalytic amounts of Lewis acids such as TiCl4 orSnCl4.81 However, t he na tu re of th is Lewis-acid effectcould not be sa tisfactorily explained by spectroscopicmethods.

Claisen rear ran gements promoted by rh odium car-benoids have recently been shown to be a generalstereoselective method for the synthesis of tertiaryalcohols.82 The reaction occurs when the diazosub-strat es a re combined with allylic alcohols in thepresence of a Rh(II) catalyst. The process takes placethrough a mechan istic pathway where the insertionin the O-H bond generates a reactive enol interme-diate wh ich will und ergo rearra ngement (Scheme 60).This r eaction proceeds with a highly efficient stere-

ochemical transfer from enantiomerically enrichedallylic alcohols to the resulting R-hydroxy carbonylcompounds. This st ereochemical outcome of th e r ear-rangement is rationalized by a chairlike transitions t a t e w i t h a (Z)-enol fragment a nd an equatorialmethyl substituent.

In the context of the use of Lewis acids as catalystsof the Claisen rear ran gement, in the last few month sthe allenoate-Claisen rearrangement has been re-ported as a general method for the diastereoselectiveprepar at ion of 4,5-disubstitut ed--enamino esters.83

As depicted in Scheme 61, the reaction of a Lewis-

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acid-activated allenic ester with a tertiary allylamineproceeded with a high -facial discrimina tion t o givean allyl vinylammonium complex exhibiting (E)-stereochemistry at the enamine double bond. Thiscomplex evolved t hr ough a cha irlike t ran sition stat eto afford the [3,3] rear ranged product. Excellent

yields an d st ereoselectivities were obtained in t hepresence of Yb(OTf)3, Sn (OTf)2, Cu(OTf)2, or Zn(OTf)2.

Recently, a new catalytic system able to acceleratea type of aromatic Claisen rearrangement was re-ported. Thu s, the Ag-KI/HOAc system promoted thereductive rearrangement of allyloxyanthraquinones(Scheme 62).84 The reduction of the anthraquinone

m oi et y t o i t s h y d r oq u in on e s t a t e b y Ag /KI wa sproposed as being responsible for the acceleration oft h e r e a r r a n g em e n t .

Trifluoroacetic acid considerably increases the allylaryl ether Claisen rearra ngement rate, although theresulting allylphenols generally u ndergo furthertran sformat ions under the acidic reaction condi-tions.66 Thus, the reaction of crotyl tolyl ether (33 )in trifluoroacetic acid afforded, as the major product,c u m a r a n e 34 , resulting from the cyclization of the[3,3] rearranged product 35 (Scheme 63).85 Similar

mixtures were obtained by using su lfur ic acid as t hecatalyst.

Aza-Claisen r earran gements of N-(-ketovinyl)-isoquinuclidines have also been described underprotic acid (p-toluenesulfonic acid) catalysis to givestructures which afforded polycyclic skeletons bear-ing the hydroisoquinoline core (Scheme 64). 86

The thio-Claisen r earra ngement wa s considerablya cce le r a t e d i n t h e p r e se n ce of n e u t r a l or a n i on i cnu cleophiles (amines, P hS-, P h O-, MeCOO-).87a

The proposed m echan ism for this tran sformat ion,tested by the secondary kinetic deuterium isotopeeffect and the substituent rate effect,87b implies aconcerted bimolecular process where the nucleophileapproaches the substrate to reach a chairlike [3,3]tran sition state, where t he nucleophile is weakly

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bonded to the substrate. As the reaction advances,the nucleophile detaches, as depicted in Scheme 65.

T h e r a t e of t h e C la i se n r e a r r a n g em e n t of a l l ylphen yl ether into 2-allylphenol is enha nced (ca. 15%)by an increase in the solvent viscosity. A considerablea cce le r a t i on wa s r e p or t e d b y a d d i t ion of s m a l lamounts of low molecular weight polyethylene intothe reaction solvent.88 The viscous but amorphousnat ur e of th e polyethylene cata lytic fra gment was ofhigh importance. I t was concluded that in the caseof enzymes, regardless of th e t raditionally accepted

role played by th e tra nsition-stat e binding, th e higherviscosity of the active center also contributes signifi-cantly to the enzymatic catalysis.

4.2.4. Other Parameters

To increase the Claisen rearrangement rate, sev-eral ph ysical param eters a ffecting th e reaction h avebeen investigated with successful results in manycases. Next some of the most noteworthy exampleswill be described.

The empirical reaction acceleration observed oni n c r e a s i n g t h e p r e s s u r e m e a n s t h a t t h e t r a n s i t i o nstat e, which includes not only the rea cting at oms butalso the solvent molecules surrounding them, oc-

cupies a smaller volume than the reactants. Bond-forming r eactions are prone to un dergo an increasein their r ates on increasing the pressure. The volumeof activation (Vq) is generally assumed as merely avolume term. However, i t has been suggested thatVq derives only partially from the volume, since apressure increase may induce kinetic effects whichare not a result of chan ges in the volume. The termphant om activation volume has been coined todenote any change in the rate induced by pressurewh ich , a l t h ou g h d e fi n ed a s Vq, a ct u a ll y is n otrelated to the volume.89 One example is the Claisenrearra ngement, which is accelerated by pressure,90

a l t h ou g h t h e r e i s n o s ig n ifi ca n t d e cr e a s e i n t h e

volume along the reaction coordinate. One examplemay be illustrative. The molar volume of allylacetal-dehyde is only 6 mL/mol (5.4%) smaller t ha n tha t ofallyl vinyl ether . This fact is n ot surpr ising since thenu mbers of bonds an d rin gs are not modified, whichmeans t hat the Claisen r earran gement pr oducts getno thermodynamic advantage over the reactants froma n i n cr e a s e i n t h e p r e ss u r e . T h er e for e , on l y o n ekinetic factor related to the volume will be consid-

ered: th e fact tha t th e cyclic tra nsition sta te ha s onemore ring than the substrate. Hence, the ensemble[transition state + solvent ] is sma ller th an [reacta nt+ solvent], and the activation volume will be nega-t i ve . F or e xa m p le , [3 ,3 ] r e a r r a n g em e n t s of a l ly lphenyl ether at 160 C and ethyl (1-ethylpropenyl)-allylcyanoacetate a t 119 C ha ve been reported t o bepressure-accelerated.90b

Polar solvents increase the rearrangement rate.The contribution of the polar effects to the increasein the reaction rate was first observed in the orthoClaisen rearra ngement of allyl p-X-phenyl ether s(Scheme 66).91

The a ccelera ting influence of water as the solventof t h e r e a ct i on of a l ip h a t i c s u b s t r a t e s h a s b ee n

demonstrated by measuring the first-order rate con-stant s of the r earran gement of the allyl vinyl ether36 (R ) Na, Me) in solvents of increasing polarity(Scheme 67).92 T h e r e l a t iv e r a t e d e cr e a s es i n t h e

order water > trifluoroacetic acid > methanol >ethanol > 2-propanol > acetonitrile > acetone benzene > cyclohexane, which reinforces the polar

char acter of the t ransition state.A similar accelerating effect has been observedwith other substrates (Scheme 68).93

The us e of polar solvents u nder mild conditions h asgiven rise to rearrangement products unable to be

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obtained under classical conditions due to t hermaldecomposition (Schem e 69).93

Theoretical calculations have corroborated the roleof polar s olvent s.94 The incorpora tion of two moleculesof water leads to th e conclusion th at hydrogen bond-ing with t he oxygen at om of the solute is stronger inthe tra nsition stat es than in th e substrates. In addi-tion, the presence of two molecules of water affordsmore dissociative and polarized transition states.

Microwave irradiation strongly accelerates theClaisen rearrangement. This fact contributes to solvethe problem of the long thermal treatments impliedby th e classical conditions reported for th e r eaction.

In this sense, th e first reported studies pointed outa combined effect of microwave irradiation and tem-perature, the latter directly dependent on the sol-vent, tha t allowed a considerable decrease in t hereaction time, as deduced from th e r esults collectedin Table 2.95

However, wha t is synth etically more int eresting isthe fact t hat compounds which decompose or areinert under thermal conditions react with excellentregiocontrol upon microwave irradiation. Such is thecase, for example, of the aromatic Claisen rearrange-ment that, with microwave irradiation, allows theregioselective isoprenylation at th e para position offlavonoids (Schem e 70).96

Similarly, microwave irr adiation successfully a f-forded the key step of the synthesis of R,R-dialkylamino acids derived from benzocyclohepten e. Th etransformation, which had been unsuccessful underthermal conditions, implied a double Johnson rear-rangement from 2-butyne-1,4-diol (Scheme 71).97

A microwave-induced Claisen rear ra ngement of th epropargylic enol ether 37 wa s a l s o t h e k e y s t e p i nthe synthesis of the skeleton present in the triterpe-noid a zadirachtin 38 (Scheme 72).98 Once again, this

tra nsforma tion under ther mal or cata lytic conditionsdid not take place at all.

In recent years the main feature of the evolutionof combinatorial chemistry has been the building of

polyfun ctionalized librar ies of sma ll organ ic mol-ecules on solid supports.99 Some param eters such a stime and temperature of solid-phase organic reac-tions may be critical. Recently, microwave irradiationhas been used to perform t he Claisen rea rra ngementin th e solid phase ofO-allyl aryl ethers derived fromsalicylic acids anchored to a Merrifield resin, afford-ing the corresponding trisubstituted aromatic sys-tems (39 ) in 4-6 min (in contrast with the 10-16 hrequired un der therma l conditions) in high yields(Scheme 73).100

An Ireland-Claisen rear ran gement of silyl keteneacetals an chored t o a polystyrene-diethylsilane (40 )was also reported.101 This reaction proceeded under

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T a b le 2 . A ro m a t i c C l a i s e n R e a r r a n g e m e n tA c c e l e r a t e d b y M i c r o w a v e I r ra d i a t i o n a

e n tr y i rr a d ia t ion t im e t e mp (C ) s olv en t y ie ld (%)

1 6 h 220 852 W 10 m in 325-361 213 W 6 m in 3 00-315 DMF 92

a Ada pte d with pe r m ission fr om r e f 95. C opyr ight 1986Elsevier.

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mild conditions (50 C, 5 h) to produce the corre-sponding silyl esters in h igh yields (Scheme 74).

The results of the Carr oll rearran gement of 41 onthe surface of an a dsorbent su ch as alumina shouldbe considered. The corresponding ,-unsaturatedketone 42 was obtain ed in good yield (Schem e 75).102

T h e r a t e e n h a n c e m e n t a s c o m p a r e d wi t h t h a t r e -port ed in solution h as been at tribut ed to restrictionsof the conformational mobility imposed by the inter-action with the surface adsorption centers.

5. Enzymatic Claisen Rearrangement

Chorismic acid is a key intermediate in the shiki-mate biosynthetic pathway. Sigmatropic rearrange-ment of chorismat e (43 ) into prephenate (44 ) (Schem e76) represents the first step in the transformation of

chorismate into phenylalanine and tyrosine. Thisprocess is a Claisen rearrangement, in vivo catalyzedby the enzyme chorismate muta se, which generatesa rate increase of 2 10 6 at 37 C.103 It is the onlyknown formal enzyme-catalyzed pericyclic reactionand is widely reported in the literature.104 Althoughthe comprehensive scope of the present review justi-

fi es a b r ie f m e n t i on of t h e r e p or t e d e xa m p l es of enzyme-catalyzed Claisen rearra ngements, t he pe-culiar features of these processes as well as theirspecial relevance in m etabolic routes m ake advisorytheir detailed study elsewhere.

6. Stereoselective Claisen Rearrangement

6.1. General Aspects

The h ighly order ed cyclic tr an sition sta tes in volvedin the Claisen rear ran gement, a long with t he restric-tions imposed by the orbital symmetry rules, allowone to predict excellent stereochemical resu lts. Twostra tegies h ave been developed t o contr ol the stereo-selectivity of the reaction: either the stereogenicelement s a ccounting for the selectivity are intra an-nular (i.e., they are incorporat ed into the cyclics t r u ct u r e of t h e t r a n s i t ion s t a t e ) or t h e y a r e e x-tr aa nn ular (therefore, lacking any cyclic rest riction).

The strategy of intraannular stereoselection con-siders the use of an achiral auxiliary inherent to thestereochemistr y of the allyl or vinyl double bond or

else a chiral auxiliary, derived from the presence ofa stereocenter directly bonded to th e heteroatom.This stereocenter disappears as a consequence of thecha nge in the h ybridization. The extra ann ular controlis represent ed by the pr esence of a chiral element inthe allyl or vinyl fragment of the starting structure.In an y of th e above situat ions, t he diast ereoselectivityof the Claisen rea rra ngements is considered. The useof chiral catalysts or solvents determines the enan-tioselectivity of these processes.

It is also possible to find conditions making theClaisen rearrangement a stereoselective process re-gardless of the optical purity of the newly createdchiral center. In these cases, the E / Z selectivity of

the new double bond is considered.

6.2. Intraannular Diastereoselectivity

6.2.1. Transition-State Geometry

The generally accepted geometry for the transitionstate of the Claisen rearrangement is a chair confor-mation, controlled by the steric105 and electronic106

featur es of the system. The gas-phase r earra ngementof (1Z,2E)-, (1Z,2Z)-, (1E,2E)-, and (1E,2Z)-propenylbut-2-enyl ether [(Z,E)-, (Z,Z)-, (E,E)-, and (E,Z)-45 ]into erythro a nd threo-2,3-dimethylpent-4-enal (eryth-ro- a n d threo-46 ) proceeds preferentially thr ough

chairlike transition states in order to minimize repul-sive steric interactions, as depicted in the Newmanprojections represented in Scheme 77.

Therefore, the chairlike transition state determinesthat the relative stereochemistry (erythro/ threo) a tthe newly generated vicinal stereocenters is con-trolled by t he relative geometr y of the double bondsa t t h e s t a r t in g m a t e ri a l. H e n ce , (Z ,Z) a nd (E ,E)substrates afford threo products, whereas (E ,Z) a n d(Z ,E) substrates yield erythro products.107

In the presence of a substituent R 4 * H at C-4, thedifferent sta bility of both chair conform at ions for th etransition state determines a clear predominance ofE alkenes as the reaction products (Scheme 78).

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Diastereofacial selectivity of the Claisen rear ra nge-ment has also been explained by considering elec-trostat ic interactions.106 The chairlike structure pro-posed for the tra nsition stat e of the Claisen r earra nge-ment, especially the Ireland-Claisen rearra ngement,could be conceptually divided into a nucleophilicester enolat e allylic fragment an d an electrophilichydrocarbon allylic fragment (Figure 9).

As a consequen ce of the lat ent dipolar natu re ofthese rear ran gements, their stereochemical path wayderives from the electrostatic requirements of bothallyl components, so th at th e m ost electrophilic faceof the relatively electronically poor component com-bines with th e electronically r ich nu cleophilic frag-ment (Figure 10). In the presence of allyl alcohols orethers on the electrophilic fragment, the addition

of the n ucleophilic ester enolat e takes place in t heanti position with respect to the electronically richallyl oxygen of the most r eactive (more electrophilic)conformer where the allyl C-H bond eclipses th eCdC double bond.

Despite the clear predominance of the chair con-formation in the cyclic transition state of the Claisenrearra ngement, some examples have been reportedto produce the isomers resulting from a boat confor-mation in the transition state, as a consequence of either t he stru ctura l features of the substrate or thereaction conditions. In the context of the stereose-lective synt hesis of nonactic acids (47 ), the Claisenrear ran gement of the involved het erocyclic systemstakes place through a boatlike transition state fromthe silyl ketene acetal derived from the glycal 48(Scheme 79).108

A similar explanation has been proposed for the

[3,3] rear ra ngement of carbocyclic systems where th esteric interactions may destabilize a chairlike transi-tion st ate, thu s shifting the J ohnson rearr angementof cyclic ortho esters toward a boat conformation forthe tran sition state (Scheme 80).109a Thus, whereasacyclic allyl alcohols evolve thr ough a chairliketransition state (J ), destabilizing 1,3-syndiaxial in-teractions present in the chair conformation J de-rived from cyclohexenols determine that the Johnsonrearrangement proceeds through a boatlike transi-tion state (K).

It is even possible to invert the conformation of thet r a n s i t i o n s t a t e o f a n I r e l a n d-Claisen rear range-ment thr ough inversion of the st ereochemistry of the

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enol double bond,11 0 a s d e du ce d fr om t h e r e s u lt scollected in Table 3.

To explain the operativity of the chair and boattransition states in these rearrangements, bicyclicstructures L a n d M d e pi ct e d i n F i gu r e 1 1, wit hdifferent steric interactions in each, should be con-sidered. In the chair conformat ion L, t h e r e i s a nunfavorable interaction between the substituent Xand the cyclohexenyl ring, which leads to a preferencefor the boat conformation M (see Table 3, entry 2).O n t h e ot h e r h a n d , w h e n R c ) m e t h y l , t h e b o a tconformat ion is unsta bilized because this methylgroup and an allyl methylene are eclipsed (entry 1).

From cyclic enol etherssa n d , t h e r e for e , wi t h adefined E stereochemistrysit is possible to direct th eClaisen rearr angement toward t he diastereoselectiveformation of syn or anti (erythro or threo) productsby th e suit able choice of cata lyst (Scheme 81).111 Th e

E f anti diastereoselectivity of the rearrangementin the presence of a catalytic amount of 2,6-dimeth-

ylphenol is explained by a chairlike transition state(N ), whereas the E f syn selectivity of the Pd(II)-catalyzed rearrangement can be understood by as-s u m in g a b oa t l ik e t r a n s i t ion s t a t e (O) w h e r e t h ediene a cts a s a bidentate l igand.

6.2.2. Vinyl Double-Bond Geometry

As a consequence of the chairlike transition stateof the rearra ngement, th e relative configuration of the stereogenic center at the new CsC single bondca n b e p r e di ct e d fr om t h e g eom e t r y of t h e v in y ldouble bond of th e sta rting 1,5-diene system. In th iscon t e xt t h e s t u d ie s o n t h e I r e la n d-Claisen r ear-r a n g em e n t a r e p a r t i cu l a r ly i n t er e s t in g .112 I t w as

demonstrated that the silyl ketene acetal 49 (X )t-BuMe2S i , R ) alkyl) a fforded acid 50 , wh e r e a sstar ting from 51 the major reaction product was acid52 (Scheme 82).

T h e r e a r r a n g e m en t of (E) - a n d (Z)-crotyl propi-onates proved the stereochemical outcome of t heenolization, where a marked influence of the solventpolarity was observed (Scheme 83).112 When (E)-crotylp r o p i o n a t e wa s e n o l i z e d i n T HF a n d t h e n t r e a t e dunder rearrangement conditions for the enolate orthe corresponding silyl ketene acetal, the erythro acidwas diastereoselectively formed. In a more coordina-tive solvent (HMPA-THF), the enolization followeda different pathway and the threo acid was obtained.

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Table 3. Ireland-C l a i s e n R e a r r a n g e m e n t o f 2 - C y c l o h e x e n o l s

favoredi nt ermedi at e

en t r y con dit ion s X Rc Rt 48 a :48 btransition

s t a t eyield

(%)

1 L DA, T HF ;t-BuMe2SiCl;

OSiR3 Me H 85:15 ch a ir 47

2 LDA,

HMPA/THF;t-BuMe2SiCl;

OSiR3 H Me 75:25 boa t 36

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The rearr angement of (Z)-crotyl pr opiona te proceededwith the opposite diastereoselectivity, which led tothe conclusion that the selectivity determining stepis th e enolization. In fact, Z enolates (P ) are prefer-

entially form ed in TH F, while th e isomeric E enolates(Q) are obtained in HMPA-T HF .

Among the methods allowing the synthesis of,-unsaturated amino acids, the above-mentioned Clais-en rearra ngement modification evolving thr oughchelated enolates derived from amino acid estersshould be considered.28 As the enolate geometry isdetermined by the chelation and the chairlike tran si-tion state is preferred, compounds exhibiting a synrelative configurat ion ar e formed diaster eoselectively(Scheme 84).11 3 When esters derived from optically

pure allyl alcohols were u sed, enan tiomerically pureamino a cids were obtained (vide infra).

The effect of a halogen on the vinyl fragment of the sta rting material for th e Claisen rearr angementwas also investigat ed t o check the influence of sucha s u bs t it u e n t in t h e g eom e t r y o f t h e t r a n s it ionstate.114 The rear ran gement of allyl trans-bromofluo-rovinyl ether s 53 took place at low tempera tur e withhigh diastereoselectivity to produce ,-unsaturated-substituted R-bromoacids 54 in a process with a

marked internal stereocontrol (Scheme 85). The in-fluence of a halogen in the geometry of the vinylgroup of the ethers 53 , and therefore the selectivityof th e a cids 54 , could also be investigated. The trans-bromofluorinated ether 53 l e d t o t h e a n t i a c i d 54through a chairlike tr ansition state.

Similarly, E enolates, prepar ed by st ereoselectivedeprotona tion of allyl fluoroacetates, un derwent adiastereoselective Claisen rear ra ngement (Scheme86).11 5

The Claisen rearrangement promoted by rhodiumcar benoids ha s alrea dy been considered as a genera lstereoselective method for the synthesis of enantio-merically pure ter tiar y alcohols, whose configura tionis a consequence of the stereochemistry of the rear-ran ged enol (Scheme 87).82

Closely related t o these results, it h as been r ecentlyd e m o n s t r a t e d t h a t (E)-silyl ketene acetals, diaste-reoselectively generated by treatment of allyl acry-lates with [(cod)RhCl]2 and 1,2-bis(dimethylphosphol-an o)benzene (Me-DuP hos) in th e pr esence of a silane,underwent reductive Ireland-Claisen rearra ngementwith good diastereocontrol to give ,-unsaturatedcarboxylic acids (Scheme 88).116 The control of the

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s il yl k e t en e a ce t a l g eom e t r y wa s cr u ci a l for t h econtrol of the overall stereoselectivity.

T h e a z a-Claisen rearrangement of enolates de-

rived from N-2-butenyl-N-butylpropana mides pro-ceeded with high diastereoselectivity to generateN-butyl-2,3-dimethyl-4-pentenamides (Scheme 89).117

This excellent diastereoselectivity shows both th eexclusive formation ofZ enolates and the participa-tion of a chair conformation for the transition stateof the aza-Claisen r earr an gement. The formation oft h e Z enolate was r ationalized by assuming th at thesteric repulsion between methyl and dialkylaminogr ou p s in t h e E e n ola t e w a s s t r on ge r t h a n t h einteraction of the methyl group with the negativelycharged oxygen atom in the Z enolate (Figure 12).

The repulsion of the butyl group when eclipsed byone of the a llyl hydrogen at oms in t he boat conforma -tion may account for the preferred chairlike transi-t i on s t a t e . T h i s i n t er a ct i on d oe s n ot e xi st i n t h ereaction of ester enolat es.

The sa lts der ived from alkylat ion of propiona midesreacted with the l ithium alkoxide of (E) o r (Z)-2-butenol to afford the product of Eschenmoser rear-rangement of the corresponding N ,O-ketene acetals(Scheme 90).118

The diaster eoselectivity of the rear ran gement wa sexplained by u nfavorable ster ic intera ctions, inh erentt o t h e v in y l d ou b le -b on d g eom e t r y, b et we en t h enitrogen substituents and the enamine substituenta t t h e position (Figure 13). This shows that themost stable (Z)-enolate reacts faster than the (E)-

enolate. However, in this reaction it is actually thegeometr y about t he a llylic alkoxide th at leads to th eselectivity, as discussed in section 6.2.3.

The ynamine-Claisen rearrangement can be con-sidered t o be complementar y t o th e Eschenmoser-C la i se n r e a r r a n g em e n t d u e t o i t s s t e r eoch e m ica loutcome. Ynamine-Claisen r earran gements beginwith the addition of a n alcohol (or alkoxide) to aketeniminium intermediate (Scheme 91).119 As t h e

alcohol must approach this intermediate onto th eplane of the CdC double bond, t he st eric int eractionwith the methyl group will favor the formation of the(E)-N ,O -ketene acetal. The rearrangement of the Eisomer, formed under kinetic control conditions,yielded the threo product. In t he pr esence of a Lewisacid, the initially formed adduct equilibrated to thethermodynamically favored Z stereoisomer to gener-ate, upon rearra ngement, the same isomerserythrosthat would result from t he classical Eschenmoserrearrangement.

6.2.3. Allyl Double-Bond Geometry

The highly ordered cyclic transition state of the

Claisen rearrangement results in the high observedstereoselectivity. With in t he cont ext of the stereospe-cific control of the C-20 configuration of cholesterol(F i gu r e 1 4), fr om t h e a n a l ys is of t h e r e s pe ct i vetransition states of the rearrangement of both pos-sible allyl alcohols (55 a n d 56 ) it can be deduced th at

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F i g u re 1 2. Reprinted w ith perm is sion from ref 117.Copyright 1990 Elsevier Science.

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t h e E isomer (55 ) will produce the natural configu-ration (20R ) at C-20, whereas from t he Z isomer (56 )the unnatural isomer at C-20 will be obtained (Scheme92).120

T h e u s e of t h e C a r r ol l v e r si on of t h e C la i se nrearrangement of the corresponding allyl ketoace-tat es led t o complete diastereocontrol in t he process(Scheme 93).120

Carbanionic Claisen rearrangement can also ex-hibit high diastereoselectivity. This is directly con-trolled by the most favored chairlike geometry of thetra nsition st ate, which is dependent on the geometryof the allyl double bond (Scheme 94). 12 1

The high diastereoselectivity observed in thesereactions, as well as their stereochemical results,similar to those obtained under thermal conditions,suggested a chairlike tra nsition sta te. Under th ermalconditions th e isomer T rearra nged twice as fast asU , whereas under anionic conditions (Na+ salt) thereaction of T w a s 1 2 t i m e s f a s t e r t h a n t h a t o f U(Figure 15). This suggests an increase in the steric

volume of the sulfonylmethyl group due to i ts as-sociation with the cation and the solvent.121b

6.2.4. Configuration at C-4

In the Claisen rearrangement, if the substrate isa chiral molecule due to the presence of a substituentat C-4 of the allyl vinyl ether, particularly in the caseof acyclic molecules, this chirality can be transferredto the 1 and/or 6 positions through a cyclic transitionstate (Scheme 95).122

T h es e ch i r a l s u b st r a t e s u s u a l ly u n d e r go r e a r -ran gement t hrough a chairlike tra nsition sta te wherethe bulkiest group bonded to th e ster eogenic carbona d op t s a n e qu a t o r ia l a r r a n g e m en t (S ch e m e 9 6).

Similarly, the substituent at the double bond alsoa r r a n g e s i n a n e qu a t o r ia l p os it i on . T h e a b s ol u t estereochemistry and the double-bond geometry of theproduct must be those depicted in Scheme 96.

Magnesium en olates are extraordinarily useful forpeptide transformations through Claisen rearrange-ments of chelated enolates.123 This methodology isespecially interesting for esters derived from chiralalcohols. As the vicinal amino acids had no significanti n f l u e n c e o n t h e r e a r r a n g e m e n t , t h e u s e o f c h i r a le st e r s, in t h e p r es en ce of L iH M DS a s t h e b a se ,afforded diastereomerically pure peptides (Scheme97). This rear ra ngement also allowed th e generat ionof S or R amino acids through an intramolecularchirality transfer.

A chirality 1,3-migration thr ough a chairlike tr an-sition state was also reported from acetates derivedfrom chiral allyl alcohols under Ireland-Claisen rear-

S c h e m e 9 2

S c h e m e 9 3

S c h e m e 9 4

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claisen review

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