synthesizing allenes today (1982–2006)...in tetrahydrofuran led to the desired allenylsilanes in...

REVIEW 795

Synthesizing Allenes Today (1982–2006)Synthesizing Allenes Today (1982–2006)Kay M. Brummond,* Jolie E. DeForrestDepartment of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, USAFax +1(412)6248611; E-mail: [email protected] 14 December 2006; revised 17 January 2007

SYNTHESIS 2007, No. 6, pp 0795–0818xx.xx.2007Advanced online publication: 28.02.2007DOI: 10.1055/s-2007-965963; Art ID: E17106SS© Georg Thieme Verlag Stuttgart · New York

Abstract: Allenes have allowed chemists to access a variety ofstructurally interesting and biologically active products. The emer-gence of these unique compounds in organic synthesis is a direct re-sult of the discovery and development of efficient protocols for theirpreparation. Moreover, efficient syntheses of the allenyl functional-ity are important to the synthetic community and will be reportedand discussed in this review.

1 Introduction2 Synthesis of Allenes with Aluminum Hydride Reagents2.1 Allenes from Propargyl Electrophiles2.2 Allenes from Enynes3 Allene Synthesis via Skeletal Rearrangement Reactions3.1 Allene Synthesis via Claisen Rearrangements3.2 Allene Synthesis via Other [3,3]-Sigmatropic Rearrange-

ments3.3 Allene Synthesis via [2,3]-Sigmatropic Rearrangements3.4 Allenes via Carbene Rearrangement: The Doering–Moore–

Skatteböl Reaction3.5 Allenes via Ene Reactions4 Allene Synthesis via Direct Homologation Reactions4.1 Wittig, Wittig–Horner, and Horner–Wadsworth–Emmons

(HWE) Reactions4.2 Peterson Allenation4.3 Crabbé Homologation Reaction5 Allene Synthesis via b-Elimination Reactions 5.1 b-Elimination of Enol Phosphates5.2 b-Elimination of Sulfoxide Derivatives5.3 Allenes via Deoxystannylation5.4 b-Elimination via Radical Intermediates5.5 Allenes from b-Chlorovinylsilanes5.6 Transition-Metal-Catalyzed b-Elimination6 Transition-Metal-Catalyzed Allene Synthesis6.1 Palladium-Catalyzed SN2¢ Substitution of Dienes6.2 Palladium-Catalyzed 1,4-Addition of Enynes6.3 Palladium-Catalyzed Hydrogen Transfer Reactions of Pro-

pargyl Amines6.4 Palladium-Catalyzed Carbonylation Reaction of Propargyl

Substrates6.5 Palladium-Catalyzed Cross-Coupling of Propargyl Deriva-

tives6.6 Indium-Mediated Allene Formation6.7 Chromium-Catalyzed Allene Formation6.8 Ruthenium-Catalyzed Allene Formation6.9 Rhodium-Catalyzed Allene Formation6.10 A Zinc Carbenoid–Vinyl Copper Coupling to Form Allenes6.11 Titanium-Catalyzed Allene Formation6.12 Copper-Catalyzed Coupling of Allenyl Halides with Amide

Derivatives 7 Conclusion

Key words: allenes, rearrangements, homologation, elimination,additions

1 Introduction

Allenes have allowed chemists to access a variety of struc-turally interesting and biologically active products.1–18 Theemergence of these unique compounds in organic synthe-sis is a direct result of the discovery and development ofefficient protocols for their preparation. Allenes can beobtained through a variety of synthetic methods, howeverthis review focuses only on new developments or thosenot covered in previous reviews.

This review is organized according to the type of reactionused to gain access to the allene functionality. Attemptshave been made to focus on the more recent syntheticmethods, or protocols that have stood the test of time;however, biases based upon our own research have alsoshaped the content of this review. Finally, in many cases,recent reviews have been written pertaining to a very spe-cific reaction used to access an allene; to the best of ourability all of these reviews have been cited within.

2 Synthesis of Allenes with Aluminum Hydride Reagents

2.1 Allenes from Propargyl Electrophiles

Aluminum hydride reagents, such as lithium aluminumhydride (LiAlH4), and diisobutylaluminum hydride(DIBAL-H), are widely used to form allenes from propar-gyl moieties such as ethers, halides, alcohols and ep-oxides. This aluminum-mediated reduction involves ahydride delivery from the aluminum species to the elec-trophile via an SN2¢ reaction, which results in the forma-tion of a new carbon–hydrogen bond and a new carbon–carbon double bond.19 This transformation can proceedwith either syn- or anti-stereoselectivity depending uponthe nature of the substrate, reducing agent, and reactiontemperature.20

Hydroxyl-directed hydride delivery with LiAlH4, since itsdevelopment in 1973 by Landor and co-workers,21 hasproven to be a reliable method of allene construction frompropargyl mono-O-tetrahydropyranyl ethers of but-2-yn-1,4-diols. This methodology is still widely used today toprepare a-hydroxyallenes.15,20,22 For example, Yoshidaand co-workers23 used an LiAlH4 reduction protocol totransform the tetrahydropyranyl propargyl ether 1 into a-hydroxyallene 3 in 83% yield (Scheme 1).

This method is not limited to a tetrahydropyranyl etherserving as a leaving group, as methyl24 and silyl ethers25

796 K. M. Brummond, J. E. DeForrest REVIEW

Synthesis 2007, No. 6, 795–818 © Thieme Stuttgart · New York

or acetals26 can also be used. An example of the latter isshown in Scheme 2, where the aluminum hydride first re-duces the acetate group of 4 to the primary hydroxylgroup, then upon coordination, displaces the tertiary ace-tal via an SN2¢ reaction to produce trisubstituted allene 6in 76% yield.

Scheme 2

Like propargyl ethers, propargyl chlorides, such as 7, areexcellent substrates for allene synthesis via alcohol-directed aluminum hydride reduction. For example, Cook

and co-workers27 found that reacting tetrayne 7 with sodi-um bis(ethoxymethoxy)aluminum hydride (Red-Al) un-der dilute conditions resulted in the formation of thedesired diyne-diallene 8 in high yield (Scheme 3). Whenthe reaction was performed at higher concentrations, SN2displacement of the chloride was observed. The use of themore reactive aluminum hydride reagent LiAlH4

19 led toa complex mixture of compounds containing the desiredallene in low yield. Propargyl chlorides such as 9, howev-er, can successfully be transformed into their allenylcounterparts with LiAlH4 in high yield. As shown inScheme 4, propyne 9 is converted into mono-substitutedhydroxyallene 10 in 95% yield.28

Scheme 3

Scheme 4

Scheme 1

OH OTHP

Ph

OH •

Ph83%

21

O OTHP

Ph

AlHH

HLi

LiAlH4

3

Kay M. Brummond hascontributed pioneeringwork in developing newmethods for synthesizingorganic compounds of im-portance to drug discoveryand medicinal chemistry, inparticular her discoveries inallenic transition-metal-catalyzed reactions.

The University of Nebraskaawarded Brummond herbachelor’s degree, andPennsylvania State Univer-sity her Ph.D. After coming

to the University of Pitts-burgh in 2001, she wasnamed a full professor ofchemistry this past Novem-ber.

Brummond has receivedmany honors including theChancellor’s DistinguishedResearch Award from theUniversity of Pittsburgh, the2006 ACS Akron SectionAward, the CarnegieScience Center EmergingFemale Scientist Award,and the Johnson & Johnson

Focused Giving Award. Shehas served as Chair of theGordon Research Confer-ence on Organic Reactionsand Processes, guest editorof Tetrahedron, is a memberof the Corporation of Or-ganic Synthesis, Inc., NIHSynthetic and BiologicalChemistry Study Section Aand is Vice-Chair of theCenter of Excellence forChemical Methodologiesand Library Synthesiswhere she is a project lead-er.

Jolie DeForrest was born in1981 in Princeton, New Jer-sey and received her Bache-lor of Science in Chemistryat the Pennsylvania State

University in 2003. She thencontinued her studies at theUniversity of Pittsburgh un-der the direction of Dr. KayBrummond. Her research

interests include syntheticmethodology and naturalproduct synthesis.

Biographical Sketches

76%

6

•

HO

THF, r.t. Li

4

LiAlH4

5

O

OAc

OEt

O

O

OEt

AlHH

H

7 8

•Cl

TIPSTIPS

Cl

OH

OH

Red-Al (3–4 equiv)

Et2O, 10–3 M,–30 to –20 °C 70%

•

OH

OHTIPS

TIPS

95%THF, 0 °C

OMe

Br

OH

Cl •

OHOMe

Br

9 10

LiAlH4

REVIEW Synthesizing Allenes Today (1982–2006) 797


Uang and co-workers29 have shown that chiral propargylalcohols such as 11 can be converted into optically activeallenes in good yields, ranging from 51–90%, when treat-ed with AlH3 (Scheme 5). It is noteworthy that substituentR must have no free hydroxyl groups in order to obtainhigh diastereoselectivity. This is particularly interestingwhen compared to the examples mentioned above as itdemonstrates that a free hydroxyl group can function as aleaving group.

Scheme 5

Other electrophiles such as acetylenic oxiranes are alsocommonly converted into hydroxyallenes via an alumi-num-mediated process.15,30,31 For example, Katsumuraand co-workers32 used DIBAL-H to reduce ethynylep-oxide 14 to triol 16 in 80% yield. As shown in Scheme 6,the aluminum hydride first coordinates to the epoxidefunctionality which facilitates the stereoselective hydridereduction.

Scheme 6

2.2 Allenes from Enynes

Aluminum hydride reagents have also been used to con-vert conjugated enynes into their allenyl counterparts. Theapplication of this method to enynes was first explored bySantelli and Bertrand in 197333 and later by Landor andco-workers in 1974.34 More recently in 1988, Bovicelliand co-workers35 made use of this methodology in theirsynthesis of b-allenyl alcohols 18a–d. Treatment of a va-riety of 1-silyl-enyne-ketones or esters 17a–d withLiAlH4 in tetrahydrofuran led to the desired allenylsilanesin yields ranging from 65–71% (Table 1).

3 Allene Synthesis via Skeletal Rearrangement Reactions

3.1 Allene Synthesis via Claisen Rearrangements

The Claisen rearrangement, a [3,3]-sigmatropic rear-rangement used for carbon–carbon bond formation,36 hasfound application in allene synthesis. This atom-economical37 rearrangement, and its many variants suchas the ortho-ester Claisen and Ireland–Claisen, allow forthe construction of many allenyl carbonyl compounds.

The thermal Claisen transformation has been used for thegeneration of allenyl aldehydes,38 ketones,39 and amides40

from propargyl alcohol precursors. Early studies38 on thesynthesis of allenic aldehydes via the Claisen rearrange-ment demonstrated that propargyl vinyl ethers of type 19could be converted into allenyl aldehydes in good yieldswhen subjected to high temperatures (Scheme 7). It wasfound that increased substitution led to faster rearrange-ment, indicating that steric hindrance is not important inthe transition state.

Scheme 7

More recently, Potáček and co-workers41 have appliedthis protocol to the synthesis of substituted homoallenylaldehydes 22. As shown in Scheme 8, the Claisen rear-rangement is tolerant of a variety of functional groups, aspropargyl vinyl ether 21 can posses different amino func-tionalities R at the 3-position. This rearrangement wascomplete in 5–10 minutes and pure allenes were obtainedvia Kugelrohr distillation under high vacuum in yields of70–88%.

OH

R

THF, 90 °C

1311

AlH3 O

R

AlH2

H2Al H

R = alkyl, CH2OBn, CH2CH2OBn12

•R

H

14

16

O

CO2Me

HO

DIBAL-H

80%O

HOAl

H

•

H

OHHO

15

OH

Table 1 b-Allenyl Alcohols from Oxygenated Enynes

Substrate Product Yield (%)

17a R = H, R1 = OMe 18a R = H, R1 = H 71

17b R = Et, R1 = OMe 18b R = Et, R1 = H 70

17c R = H, R1 = Me 18c R = H, R1 = Me 68

17d R = Me, R1 = Me 18d R = Me, R1 = Me 65

R1

TMS

OR1

R•

TMS

H RHOTHF

17 18

LiAlH4

O

19

140 °C

•

O

20

R1

R R

R1

R = R1 = H, 4 h, reflux, 70%R = R1 = Me, 15 min, reflux, 76%



Scheme 8

The ortho-ester Claisen rearrangement has been a popularmethod for the construction of allenyl esters since Cran-dall and Tindell42 published their pioneering work in1970. Typically, the reaction conditions include heatingpropargyl alcohols, usually between 80–160 °C, with tri-ethyl orthoacetate in the presence of a catalytic amount ofpropionic acid (Scheme 9). Using this methodology,Couty and co-workers43 were able to transform propargylalcohols attached to oxazolidine rings into various allenylesters. This rearrangement proved to be highly stereose-lective and produced diastereomerically pure allenes ingood yields, except when substituent R was a phenyl ring(Table 2).

Scheme 9

Allenyl amides can also be prepared from propargyl alco-hols in an analogous manner. Parker and co-workers44,45

have shown that treating propargyl alcohols with N,N-

dimethylacetamide diethyl acetal (DMA-DEA) at elevat-ed temperatures results in the formation of allenyl amidesin 80–86% yield (Scheme 10). This methodology hasmore recently been used by Trost and co-workers37 for thepreparation of various allenyl acetamides.

Scheme 10

Allenyl acids are often obtained from propargylic estersvia an Ireland–Claisen rearrangement. This particularmodification of the Claisen rearrangement involves for-mation a silyl ketene acetal, such as intermediate 32,which spontaneously undergoes a [3,3]-sigmatropic rear-rangement to produce the corresponding allenyl acid. Anearly example46 of this transformation is shown here inScheme 11, where allenyl acid derivatives 34 were ob-tained in yields of 50–70%.

Scheme 11

Brummond and You47 have since applied the Ireland–Claisen rearrangement to the synthesis of allenyl acid 36.As shown in Scheme 12, propargyl ester 35 underwent thedesired [3,3]-sigmatropic rearrangement to afford 36 as asingle diastereomer (determined by 1H NMR). These mildreaction conditions are unique, as lithium diisopropyl-amide and trimethylsilyl chloride are typically employedfor this transformation.46,48

Scheme 12

The ester-enolate Claisen rearrangement is a useful meth-od to access allenes with an a-hydroxyl or amide substit-uent. In 1985, Fujisawa and co-workers49 demonstratedthat 2-hydroxy-3,4-alkadienoic acids 40 could be ob-tained by treating esters 37 with lithium hexamethyldisil-azide and trimethylsilyl chloride (Scheme 13). The highdiastereoselectivity (> 92%) is attributed to the formation

Table 2 Rearrangement of Propargyl Alcohols into Allenyl Esters

Substrate R Yield (%)

27a C6H13 67

27b CH2OTBS 71

27c Ph 17

27d TMS 50

RO

21

200 °C•

R

O

22

R =N N N N

O

N

N

N

26

•R1 R

23

OHR2 R

O

OEt

MeC(OEt)3

cat. EtCO2H

25

O

EtO

R2R

R1

R1

R2

24

O

EtO

R2R

R1

OEt

– EtOH

27

MeC(OEt)3cat. EtCO2H

28

N

O OH

RBoc

Ph reflux, 4 h•

R

O

NPhBoc

CO2Et

R•

30

H

TMS

HR

OHTMS

OMe2N

EtO

N

OEt

R = H, Me

29

xylene, reflux

3431

R2O

R

OR31) LDA or

LHMDS

2) TMSCl R1

O

R

OTMS

R3R•

R1

R3Me3SiO

O

R = alkyl; R1 = alkyl, aryl, H; R2 = H, alkyl; R3 = alkyl, H

R1R2

R2H

R•

R1

R3HO

O

R2

32 33

36

•

OHO

35

O

O

i-Pr3SiOTf, Et3N

r.t., 14 h, 69%



of lithium enolate 38. This stable chelate is transformedinto disilylated intermediate 39, which is thought to existin a boat conformation and thus prevents unfavorable 1,3-diaxial interactions between the hydrogen and the large si-lyl group.

Scheme 13

The chelate-controlled Claisen rearrangement has alsobeen used for the synthesis of allenyl amino acids. Earlywork in this field was conducted by Kazmaier andGörbitz50 who transformed propargyl esters of amino ac-ids into allenes using lithium diisopropylamide and zincchloride. This methodology tolerates a variety of amineprotecting groups like benzyloxycarbonyl, tert-butoxy-carbonyl, and p-toluenesulfonyl, and high diastereoselec-tivity is often observed.50 More recently, Brummond andMitasev51 (Scheme 14) applied this protocol to ester de-rivatives 41, which were converted into diastereomerical-ly pure allenyl amino acids 44a and 44b in good yields.

Scheme 14

In 1988, Castelhano and Krantz52 developed alternativeconditions for the synthesis of allenyl amino esters via theClaisen rearrangement. As shown in Scheme 15, thismethod uses a dehydration protocol to transform propar-gyl ester 45 into propargyloxyoxazolone 46, which under-goes a Claisen rearrangement to produce allenyloxazolinone 47.

These reaction conditions have recently been employedby Brummond and co-workers53 for the formation of var-ious aromatic-substituted allenyl methyl esters in yieldsbetween 64% and 84% (Scheme 16). One limitation ofthis route is the requirement of the amine functionality tobe protected as a benzamide group; other protectinggroups such as tert-butoxycarbonyl, formyl, benzyloxy-

carbonyl, and trifluoroacetyl do not allow for allene for-mation.52

Transition metals are often used in organic synthesis asthey allow for milder reaction conditions, increased effi-ciency of synthetic transformations, and higher functionalgroup tolerance.54 An example that illustrates the utility ofmetal catalysis in allene synthesis is the gold(I)-catalyzedpropargyl Claisen rearrangement developed by Toste andSherry.55 This protocol is tolerant of functional groupslike electron-rich and electron-deficient aryl groups, aswell as linear and branched aliphatic moieties at the prop-argylic position (Scheme 17). The alkynyl terminus canbe substituted with a hydrogen or and alkyl or an arylgroup. These mild reaction conditions are tolerant of pro-tecting groups like silyl ethers and pivolate esters. Chiral-ity transfer of enantioenriched propargyl vinyl etherprecursors is also observed (Scheme 18).

Scheme 17

4037

R

O

R1

OOHLHMDS TMSCl

O

R1

R = alkyl, H; R1 = alkyl, TMS

R1•

R

CO2HH

38

OLiLiO

R

OR

H

OTMS

OTMS

R1HO

39

Cbz

42

44a R = Me, 49% for 3 steps44b R = i-Pr, 48% for 3 steps

•R

41

O

ONH

Cbz

RTMS

LDA ZnCl2

COOHHN

TMS

TBAF

MeIKHCO3

•R

COOMeHN

TMS•

RCOOMe

HN

4344

CbzCbz

Scheme 15

R1 = Bn; R2 = H, Me; R3 = H, Me

45

O

OR1

HN

R2R3

OPh

PPh3 CCl4, Et3N

NO

Ph

O

R3

R2R1

•

NOMe

R3

R1 O

R2

1) MeOH, Et3N2) EtO3 BF4

10% HOAc

•

NO

R3

R1 O

R2

Ph

Ph

EtO

•

H2N OMe

R3

R1 O

R2

•

H2N OH

R3

R1 O

R2

46 47

484950

1.0 M NaOH/MeOH

Scheme 16

•

51

O

OR

NH

BzCO2Me

NH

RBz

1) Et3N, PPh3, CCl4 MeCN, r.t.

2) HCl, MeOH

52

OMe FR = S

NBoc

53 54

R •R2

O

R1R

R = aryl, alkyl R1 = H, alkylR2 = H, aryl, alkyl

[(Ph3PAu)3O]BF4 (1 mol%)CH2Cl2, r.t.

NaBH4, MeOH, r.t.

R1

R2

OH



Scheme 18

3.2 Allene Synthesis via Other [3,3]-Sigmatropic Rearrangements

In addition to the Claisen rearrangement, other [3,3]-sig-matropic rearrangements can be employed for the con-struction of allenes from propargyl substrates. Forexample, the stereoselective Saucy–Marbetrearrangement56,57 has been used to access substituted al-lenes from chiral ynamides and propargyl alcohols. Thisrearrangement is catalyzed by p-nitrobenzenesulfonicacid (PNSBA) and leads to homoallenyl amides in highyield and diastereoselectivity. As shown in Scheme 19and Scheme 20, either allene 59 or 60 can be obtained,depending upon whether (S)- or (R)-propargyl alcohol 58is used for the reaction.

Scheme 19

Scheme 20

The metal-catalyzed formal [3,3]-sigmatropic rearrange-ment is a powerful method for the construction of allenylesters. This transformation has been successfully carriedout with silver,58 gold,59,60 platinum,61 and copper62,63 cat-alysts. A recent example of this protocol64 is shown inScheme 21, where propargyl ester 61 undergoes a gold(I)-catalyzed [3,3]-rearrangement when reacted with 10mol% of gold(III) chloride. The proposed mechanism forthis rearrangement begins with activation of the carbon–carbon triple bond by the gold(I) catalyst, which promotesa [3,3]-sigmatropic rearrangement of the indole-3-acet-oxy group resulting in allene 64.

Castelhano and Krantz65 have demonstrated that the aza-Cope rearrangement can be used for the construction of g-allenic pyrrolidin-2-ones. As shown in Scheme 22, hy-droxy lactam 65 is converted into acyliminium ion 66when reacted with formic acid. A [3,3]-sigmatropic rear-rangement then occurs, producing the desired allene 68 in35% yield. It is worth noting that the yield of the rear-

rangement reaction appears to be sensitive to the amountof water present in the formic acid, and that switching to20% trifluoroacetic acid resulted in an increased yield(>80%) of the g-allenic pyrrolidin-2-one.

Scheme 22

Substituted allenes can also be obtained through a [3,3]-sigmatropic ring expansion of alkynyl cyclic thiocarbon-ates.66,67 As shown in Scheme 23, thionocarbonate 69 istransformed into the desired cyclic allene 70 in 63–93%yield, depending upon the substitution of the thionocar-bonate precursor. This methodology has also been appliedto the synthesis of nine- to eleven-membered rings. Thelarger ring systems, however, undergo the [3,3]-rear-rangement spontaneously at room temperature. Allenylcyclic thiocarbonates can function as pivotal compoundsin allene synthesis as the free alcohol functionality can beobtained via a samarium(II) iodide–hexamethylphos-phoramide reduction protocol (Scheme 24).

Scheme 23

Ph •

55 56

n-Bu

O

Ph

[(Ph3PAu)3O]BF4 (1 mol%)CH2Cl2, r.t.

NaBH4, MeOH, r.t.

H

n-Bu

OH

91%, 90% ee(95% ee)

O

N

n-Bu

O Ph

OH

Ph (S)(R)

PNBSA, toluene 100 °C, 12–18 h

N

(R)

O

• H

Ph

O

O(S)

(S)-58

57

(R)

Phn-Bu

80%, 96:459

(R)(S)

(R)-58

OH

Ph

PNBSA, toluene 100 °C, 12–18 h

N

(R)

O

• Ph

H

O

O

Phn-Bu

78%, 90:1060

O

N

n-Bu

O Ph

57

(R)(S)

Scheme 21

61

HN O

O

Ph

O

•

Ph

ONH

AuCl3 (10 mol%)

CH2Cl2, r.t. 10 min, 52%

HN O

O

PhHN O

O

Ph

Au

64

62 63

Au

65

N

OH

O

N

O

HCO2H

r.t., 3–5 d

N

O

•

H3ONH

O

•

66

6768

69

benzene reflux, 1.5 h

R = t-Bu, TMS; R1 = Me, Ph

O

O

R1

R

S

70

O

S

RR1

O

•



Scheme 24

Banert and co-workers68,69 have shown that flash vacuumpyrolysis can be used to access allenyl isothiocyanatesfrom propargyl thiocyanates (Scheme 25). This method-ology has been applied to the synthesis of allenyl thio-cyanates,70 azides,71 and isoselenocyanates.72 Thesefunctionalized allenes, however, are very reactive and un-dergo spontaneous exothermic polymerization at roomtemperature.

Scheme 25

3.3 Allene Synthesis via [2,3]-Sigmatropic Rear-rangements

[2,3]-Sigmatropic rearrangements, like [3,3]-rearrange-ments, can be used to convert propargyl substrates intotheir allenyl counterparts. Propargyl phosphorous esters,for example, undergo a [2,3]-sigmatropic rearrangementto give allenic phosphinates and phosphonates.73–75 Mostrecently, this protocol has been used by Echavarren andco-workers76 to convert propargyl alcohol 75 into phos-phinite ester 76 with chlorodiphenylphosphine (Ph2PCl)and triethylamine (Et3N). Subsequent rearrangementgives allenylphosphine oxide 77 in high yield(Scheme 26). This thermal isomerization reaction pro-ceeds through a six-electron, five-membered cyclic tran-sition state.

Denmark and co-workers77 have developed a one-pot pro-cedure to form phosphonamide allenes from a diamine,

propargyl alcohol, and phosphorous trichloride (PCl3)(Scheme 27). In this procedure, phosphite 81 is formed insitu by treating chlorophosphorous amide 79 with N-methylmorpholine (NMM) and propargyl alcohol 80. Re-active intermediate 81, once formed, undergoes a [2,3]-sigmatropic rearrangement to produce phosphonamide al-lene 82.

Scheme 27

Like phosphorous-containing allenes, sulfur-substitutedallenes can be obtained via a [2,3]-sigmatropic rearrange-ment protocol. For example, propargyl alcohol 83 is con-verted into sulfenic ester 84 with triethylamine andbenzenesulfenyl chloride (PhSCl). Subsequent rearrange-ment yields allenyl sulfoxide 85 (Scheme 28).75

Scheme 28

Allenyl sulfones are easily generated in the same manner.Braverman and co-workers,78 for example, used this pro-cess to transform propargyl sulfinate 87 into diallene 88 in81% yield (Scheme 29).

Recently, Christov and Ivanova79 showed that sulfonyl-functionalized allenecarboxylates can be synthesized viaa one-pot reaction sequence. As shown in Scheme 30, eth-yl propynoate 89 is first converted into lithium acetylide90 with lithium diisopropylamide and then reacted with

O

S

OTBS

O

SmI2, HMPA

r.t., 2 h, 78% •OTBS

71 72

• HO

73

SCN400 °C •

SCN97%

74

Scheme 26

76

77

MeOOH

MeO

TMS Ph2PCl Et3N

THF, 93%

MeOO

MeO

TMS

PPh2

•

MeO

TMSPPh2

OMe

O

75

78

NH

NHR

R

R = i-Pr, Bn; R1 = Me; R2 = Me, H

PCl3+Et3N

N

N

R

R

OP

•

R1 R2

N

N

R

R

ClP

OHR2

R1

NMM80

79

82 81

OR2

R1P

N

NR

R

CH2Cl2

63–86%

86 85

8483

TBDPSOOH

PhSCl, Et3N

THF, –78 °CTBDPSO

OS

Ph

10% HClMeOH, r.t., 85%

•

SO

PhTBDPSO

•

SO

PhOH



acetone to give intermediate 91. Subsequent treatmentwith trimethylsilyl chloride produces silyl ether 92 whichis then converted into ethoxycarbonyl-substituted propar-gyl sulfinate 93 with methanesulfinyl chloride. A [2,3]-sigmatropic rearrangement then occurs upon reflux toyield allene 94.

Scheme 30

The [2,3]-Wittig rearrangement,80 a base-induced [2,3]-sigmatropic rearrangement, has proven to be a usefulmethod of forming a-hydroxyallenes. Marshall and co-workers81–83 have employed this methodology extensivelyin the synthesis of allenylcarbinols from propargyl tribu-tylstannylmethyl ethers and ethers of glycolic acid. Asshown in Scheme 31 and Scheme 32, allenes 96 and 98are obtained in yields of 71% and 85%, respectively.

Scheme 31

Scheme 32

More recently this protocol has been used by Troisi84 andco-workers for the construction of various a-heterocycle-substituted hydroxyallenes (Table 3). Propargyl ether 99,when reacted with n-butyllithium, undergoes a [2,3]-Wit-tig rearrangement to yield the desired allene. It was found,however, that a competing [1,2]-Wittig rearrangement

can occur, resulting from generation of the carbanion atthe a¢-carbon as opposed to the a-carbon.Cazes and Julia85 have demonstrated that allenyl ketonescan be obtained in 54–61% yields by reacting propargylcyanoethers 101 with lithium diisopropylamide(Scheme 33). This transformation likely occurs through a[2,3]-Wittig rearrangement; however, it is also proposedthat allenyl ketone 103 is formed via a two-step dissocia-tion–recombination mechanism. It is worth noting that theallenyl precursor 101 can be prepared via an etherificationof the corresponding cyanohydrin with a propargyl bro-mide.

Scheme 33

3.4 Allenes via Carbene Rearrangement: The Doering–Moore–Skatteböl Reaction

Pioneering work conducted by Doering and LaFlamme86

in 1958 showed that allenes can be obtained in moderateyields by reacting 1,1-dibromocyclopropanes with activemetals such as sodium or magnesium. Subsequently andindependently, Moore87,88 and Skatteböl89,90 in 1960 and1961, respectively, demonstrated that reacting the samegeminal dibromocyclopropanes with alkyllithium re-agents such as methyl- and butyllithium produced the de-sired allenes in higher yields. Today this transformation iscommonly referred to as the Doering–Moore–Skatteböl(DMS) reaction, and is still used by organic chemists toconstruct allenes from dihalocyclopropane precursors.13

Even though gem-dichlorocyclopropanes can be convert-ed into allenes in moderate yields when treated with mag-nesium metal in the presence of ethyl bromide,91

Scheme 29

OOS SO O

Cl3C CCl3

••

S

S

O

O CCl3

Cl3C O

O

CHCl3, 60 °C, 3 h

81%

87 88

O

EtO

LDA THF –100 °C

O

EtOLi THF, –100 °C

(CH3)2C=O O

EtO LiO

TMSCl, THF–100 to –10 °C

O

EtO TMSO

MeS(O)Cl

THF–10 °C to r.t.

O

EtO OSO

toluene reflux

49%

89

•S

O

O

OOEt

90 91

93 9294

95

ROH

SnBu3n-BuLi, THF

–78 °C, 71% R•

HOH

96

97

HO

ROH

CO2HLDA, THF

–78 °C, 85%R

•H

CO2H

98

Table 3 Hydroxyallenes from Propargyl Ethers

Substrate Heterocycle R Yield (%)

99a Ph 55

99b Me 80

99c Me 66

100

Het OR

n-BuLi

THF•

99R

Het

OH

α α '

O

N

N

N

S

102 103101

RO LDA

THF, –78 °C

R = Me, Et

•R

On-Bu

•R

n-BuHO CN

n-BuCN 54–61%



dibromocyclopropane derivatives are more commonlyemployed for this transformation. For example, gem-dibromocyclopropane 104 is readily transformed intobromoallene 107 in 90% yield when treated with methyl-lithium at low temperature.92 As shown in Scheme 34, thefirst step in the reaction mechanism is a halogen–lithiumexchange resulting in the formation of 1-lithio-1-bromo-cyclopropane 105. This intermediate then undergoes a-elimination to give cyclopropylidene 106, which subse-quently rearranges to bromoallene 107.90

Scheme 34

This protocol has been used to access b-allenylsilanesfrom the corresponding gem-dibromocyclopropane pre-cursors (Scheme 35).93 b-Silyl dibromocyclopropane 108,for example, is converted into allene 109 in high yieldwhen reacted with methyllithium at low temperature. It isworth noting that the free hydroxyl group present in 108does not adversely affect the rearrangement reaction.

Scheme 35

In addition to the commonly employed alkyllithium re-agents, Grignard reagents such as ethyl- and isopropyl-magnesium bromide can be used for this reaction(Table 4).94 For example, gem-dibromocyclopropanes110a–e are converted into their allenyl counterparts whenreacted with ethylmagnesium bromide in tetrahydrofuranin high yield. It is proposed that the reaction mechanisminvolves an initial magnesium–bromine exchange result-ing in the formation of magnesium carbenoid 111. Subse-quent loss of magnesium bromide and rearrangement ofcyclopropylidene 112 gives allene 113.

Satoh and co-workers95 have demonstrated that 1-chloro-cyclopropyl phenyl sulfoxides of type 114 are excellentsubstrates for a DMS-type reaction (Scheme 36). Sulfox-ide 114 is rapidly converted into magnesium cyclopropyl-idene 115 when treated with phenylmagnesium chloridein tetrahydrofuran at 0 °C via a sulfoxide–magnesium ex-

change reaction. Magnesium cyclopropylidene 115 thenrearranges to cyclic allene 116 in 89% yield.

More recently, Satoh and Gouda96 extended this method-ology to the synthesis of substituted cyanoallenes from a-bromocyclopropyl p-tolyl sulfoxides (Scheme 37). First,sulfoxide 117 undergoes a sulfoxide–lithium exchange re-action with the lithium carbanion of isobutyronitrile. Sub-sequent rearrangement gives allene 118.

Scheme 37

3.5 Allenes via Ene Reactions

The ene reaction has proven to be a powerful syntheticstrategy for the construction of carbon–carbon bonds97–99

and has recently found application in allene synthesis. Gilland co-workers, for example, have demonstrated that thethermal ene reaction between 1-hexyne (119) and a highlyreactive enophile such as indane-1,2,3-trione (120) results

107

Br

Br

Br

MeLi

–40 °C, 2 h

•

Br

104Br

Br

Li

Br

105

106

90%

108

TMS

Br BrMeLi (2.5 equiv) •TMS

10970%OH Et2O, –78 °C

OH

Table 4 Allenes from gem-Dibromocyclopropanes

Substrate R R1 R2 Yield (%)

110a Me Ph H 96

110b Ph Ph H 96

110c Ph H H 92

110d H –(CH2)6– 93

110e H n-Hex H 91

110 111 112 113

R

R1R2

Br

Br

EtMgBr

THF, r.t.

R

R1R2

MgBr

Br

R

R1R2

R1 •

HR2

R

Scheme 36

116

115

PhMgCl

THF, 0 °C

114

10 min, 89%

O

O

ClS

Ph

O

H

O

O

ClMgCl

H

O

O

•

CN

S(O)TolBr

Me2C(Li)CN

THF, r.t., 96%

118

•

CN

117



in the formation of allenyl indane-1,3-dione 121 in 58%yield (Scheme 38).100 Subsequent cleavage of the result-ing 2-hydroxyindane-1,2-dione moiety can be carried outwith periodic acid to give the corresponding allenyl car-boxylic acid 122.

Scheme 38

Similarly, Burger and co-workers101 have shown thatmethyl trifluoropyruvate can function as the enophilecomponent in the carbonyl-yne reaction. For example, thethermal ene reaction between 1-hexyne and trifluoropyru-vate 123 gives allenylcarbinol 124 as a 1:1 mixture of dia-stereomers (Scheme 39). Alternatively, the Lewis acidcatalyzed yne reaction between compounds 119 and 123affords allenylcarbinol 124 in higher diastereoselectivity(Scheme 40). It is worth noting that alkyne 125 is ob-tained as a byproduct and is thought to form via insertionof pyruvate 123 into the C–H bond of 1-hexyne.

Scheme 39

Scheme 40

Buchwald102 has shown that a titanocene catalyst systemcan be employed to access allenes appended to a ring fromacyclic dienynes via a formal ene reaction (Scheme 41).The proposed catalytic cycle begins with initial loss of CO

from the titanocene catalyst, followed by reaction with di-enyne 126 to give titanacyclopentene 127. Subsequent b-hydride elimination of Ha gives vinyl titanocene hydride128, which undergoes reductive elimination to afford al-lene 129 in 54% yield.

Scheme 41

The ene reaction of 1,3-dienes 130a–e with singlet oxygengives allenyl alcohols in 51–67% yields (Table 5).103–106

The regioselectivity of this transformation is largely at-tributed to the twisted geometry of 130, where there is alarge s*–p orbital interaction with the vinyl C–H bondand the neighboring C=C double bond. This interactionactivates Ha towards abstraction by perepoxide intermedi-ate 131.

HO

O

O

O

O

O

+

HIO4

Pr•

CO2H

Et2O, 58%

122

119 120

n-Pr

O

O

O

O

O

70–110 °C

CHCl3, 58%

HIO4

n-Pr•

CO2H

121

•n-Pr

119 123

n-Pr•

80 °C

62%+

124

F3COMe

O

O

CO2MeHO

CF3

dr ~ 1:1n-Pr

119

n-Pr

123

+ F3COMe

O

OMgBr2·OEt2

CH2Cl2, –78 °C to r.t., 90%

n-Pr•

124

CO2MeHO

CF3

dr ~ 8:1

n-Pr

CF3

CO2MeOH

10%125

+

Table 5 Ene Reaction of 1,3-Dienes with Singlet Oxygen

Substrate R Yield of 132 (%) Yield of 133 (%)

130a Me 51 29

130b Et 52 15

130c CH2CH=CH2 63 32

130d Ph 67 24

130e C≡C 55 27

•

20 mol% Cp2Ti(CO)2

PhMe, 105 °C, 54%

TiCp2

Ha •

TiCp2Ha

126 129

127 128

EtO2C

EtO2C

EtO2C

EtO2C

EtO2C

EtO2C

EtO2C

EtO2C

132 133

131130

RTESO

Hb

HaR

OO O

1) 1O2

2) PPh3 or P(OEt)33) BTAF

•

OHR

OH

R

OHOH+

TES



4 Allene Synthesis via Direct Homologation Reactions

4.1 Wittig, Wittig–Horner, and Horner–Wadsworth–Emmons (HWE) Reactions

Allenyl esters,107–117 ketones,118 lactones,113 lactams,113

and other functionalized allenes119 can be quickly synthe-sized via a Wittig reaction between a phosphonium ylideand a ketene or an acid halide (ketene equivalent). Brum-mond and Chen,120 for example, have applied this meth-odology to the synthesis of allenyne 136. As shown inScheme 42, phosphonium salt 134 is first transformedinto ylide 135 with potassium hydroxide, then treated withtriethylamine and heptanonyl chloride to give the desiredallenyl ester 136.

Scheme 42

This methodology has been extended to the synthesis ofchiral allenes.121,122 Pinho e Melo and co-workers,123,124

for example, have shown that chiral allenes can be synthe-sized from a phosphonium ylide bearing a chiral auxiliary,triethylamine, and an acid chloride (Table 6). The high di-astereoselectivity of the Wittig reaction between ylide 137and acid chloride 138 is attributed to the chiral 10-(phe-nylsulfonyl)isoborneol group. The presence of a bulkysubstituent on the acid chloride (entries 138c–e, Table 6),however, does not affect the selectivity of the reaction.

More recently, Tang and co-workers125 developed a pseu-do-C2-symmetric chiral phosphorous ylide for the enan-tioselective synthesis of allenyl esters (Scheme 43).Phosphonium salt 140a is deprotonated with sodiumbis(trimethylsilyl)amide and reacted with ethyl phenyl

ketene 141 to afford chiral allene 142a with 81% enantio-meric excess in 80% yield. Interestingly, replacement ofthe R group of the phosphorous salt with a tert-butylgroup (140b) produces the corresponding allene 142b inan increased enantiomeric excess of 92% ee, but in loweryield. One benefit to employing this method is that phos-phonium salt 140a can be easily regenerated from chiralphosphine oxide 143 and reused for subsequent reactions.

Scheme 43

Similarly, allenes can be formed from a Wittig–Horner re-action between a phosphinoxy carbanion and an alde-hyde.126,127 Wang and co-workers128,129 have used thisprotocol for the synthesis of enyne-allene 149(Scheme 44). Carbanion 146, prepared from vinyl iodide145 and n-butyllithium, undergoes nucleophilic additionto aldehyde 147 giving intermediate 148. Spontaneouselimination of lithium diphenylphosphonate occurs uponwarming to room temperature, thereby producing allene149.

Scheme 44

Takahashi and co-workers130 recently employed thismethod for the construction of vinyl allenes from 1-lithio-1,3-dienyl phosphine oxides and aldehydes (Scheme 45).It was found that the incorporation of a strong co-base likepotassium tert-butoxide helps promote the elimination ofthe diphenylphosphinate moiety and facilitates the forma-tion of functionalized allene 153.

Table 6 Chiral Allenes Accessed by a Wittig Reaction

Substrate R [a]D25 Yield (%)

138a Me –150 60

138b Et –180 75

138c i-Pr –160 61

138d t-Bu –180 73

138e Bz –180 86

136135134

Ph3PO

OBr KOHCH2Cl2

Ph3PO

OC6H13COCl

Et3N, CH2Cl2 72%

•

C5H11

O O

137 139

138O

O

PPh3

SO2Ph

Cl

OR

Et3N, THFO

OSO2Ph• H

R

H

141

P

Ph

Ph

PhO

ROBr

1) NaHMDS, r.t., THF

ROOC•

O•Et

Ph2) –78 °C

Et

Ph

H

+ P

Ph

PhO

Ph

P

Ph

Ph

Ph

144

143

LiAlH4, MeIDME, 90%

BrCH2COOEt

Et2O, 95%

140a: R = Et140b: R = t-Bu

142a: R = Et; 80%, 81% ee142b: R = t-Bu; 51%, 92% ee

145

Ph2PO

Ph

Ph

I

n-BuLiTHF, –78 °C

Ph2PO

Ph

Ph

Li

O

TMS

O

TMS

–78 °C to r.t.

PPh2

O

Ph

Ph

Li

Ph2POLiO

–

74%

TMS

• Ph

Ph

147

146

149148



Scheme 45

Huang and Xiong131 have demonstrated that sulfur-substi-tuted allenes can be prepared by a three-component reac-tion of 1-alkynylphosphine oxide 154, lithiumalkylthiolate 155, and aldehyde 156 (Scheme 46). First, aMichael reaction occurs between lithium alkylthiolate155 and phosphine oxide 154, followed by addition of al-dehyde 156 giving b-phosphonoallyl alkoxide 157. Sub-sequent elimination of diphenylphosphonate gives sulfur-substituted allene 158. Selenium-substituted allenes132

can also be accessed using this protocol by replacing lith-ium alkylthiolate 155 with lithium alkylselenolate 159(Scheme 47). It is worth noting that using tetrahydrofuranas the solvent proved to be crucial for the formation ofheteroatom-substituted allenes 158 and 161 – use of dieth-yl ether or benzene gave b-hydroxy phosphine oxides. Re-placement of tetrahydrofuran with 1,4-dioxane, however,did produce the desired allenes, but in lower yield.

Scheme 46

Scheme 47

Alternatively, a Horner–Wadsworth–Emmons (HWE) re-action between a phosphate carbanion and a carbonylcompound can be used to access a variety of substitutedallenes,133,134 allenyl esters,135 amides,136,137 and sul-fones.137 Tomioka and co-workers,138 for example, havedesigned a one-pot procedure for the synthesis of func-tionalized allenes using two sequential HWE olefinationreactions (Scheme 48). The first HWE reaction occurs be-tween methylenebisphosphonate 162 and benzaldehyde togive alkenylphosphonate 163. Subsequent deprotonationwith lithium diisopropylamide generates a phosphonatecarbanion which adds to pivaldehyde, giving lithium

alkoxide 164. Activation of lithium alkoxide 164 for elim-ination with potassium tert-butoxide affords 1,3-disubsti-tuted allene 165 in high yield.

Correspondingly, Fuji and co-workers139 developed aone-pot procedure for the synthesis of allenyl esters by aHWE reaction between 2,6-di-tert-butyl-4-methylphenyl(BHT) esters and phosphonate carbanions (Scheme 49).Ketene 168, generated in situ from BHT ester 166 and n-butyllithium, is reacted with phosphonate carbanion 169in the presence of zinc chloride or tin(II) chloride to affordallene 170.

Scheme 49

The same authors140 have further developed this method-ology into a tandem Michael–HWE reaction in order toaccess d-branched allenyl esters (Scheme 50). A Michaelreaction of phenyllithium or n-butyllithium onto a,b-un-saturated BHT ester 171 in the presence of zinc chlorideor tin(II) chloride affords substituted ketene 173. Subse-quent addition of phosphonate carbanion 169 yields allene174. The addition of the zinc chloride or tin(II) chlorideadditive to the reaction proved to be crucial to the forma-tion of allenes 170 and 174. It is proposed that the pres-ence of the Zn2+ or Sn2+ countercation reduces thenucleophilicity of the enolate intermediate, preventing nu-cleophilic addition onto the ketene functionality.

PPh2O

I n-BuLiEt2O, –78 °C

O

–78 °C to r.t.•

R2

150 153151

R1

R1

R

PPh2O

Li

R1

R1

RR2

1)

2) t-BuOK (1 equiv)R1

R1

R152

R = alkyl, Ph; R1 = alkyl, Ph; R2 = alkyl, aryl

48–90%

154 155 156

R PPh2

O

+ R1SLiO

R2+

–25 °C to r.t.

61–87%

R1S • R2

H

158

R

R = alkyl, Ph; R1 = alkyl; R2 = Ar

R1S

RPPh2

OR2Li

O

157

THF

154 159 156

R PPh2

O+ R1SeLi

O

R2+

–25 °Cto r.t.

59–89%

R1Se • R2

H161

R

R = alkyl, Ph; R1 = alkyl; R2 = Ar

R1Se

RPPh2

OR2Li

O

160

THF

Scheme 48

162 163

164

P(OEt)2

P(OEt)2

O

O

1) NaH, THF 0 °C, 10 min

OPh2)

Ph

(EtO)2P O

3) LDA, –78 °C 10 min

Ot-Bu

4)

Ph

(EtO)2P O

t-BuOLi

5) t-BuOK r.t., 50 min

73%H • H

t-Bu

165

Ph

169 168

THF, –78 °C

166

R = Ph, Bn, β-naphthyl; R1 = alkyl, Ph

167

O

t-Bu

t-Bu

Me

R1

R

O

n-BuLi OBHT

R1

R

OLi

O•R

R1

1) ZnCl2 or SnCl2

2)(MeO)2P

OCO2Me

Li

R1 • CO2Me

H170

R

15–93%



Scheme 50

An asymmetric HWE reaction can be used to access non-racemic chiral allenes from optically active phosphonate(S)-177 and various unsymmetrical ketenes (Scheme 51).The transformation of BHT ester 175a into ketene 176could only be achieved with n-butyllithium, whileKHMDS proved to be essential to the formation of allene178a.141 Alternatively, when phenyl ester 175b was em-ployed, lithium diisopropylamide could be used for boththe generation of ketene 176 and the subsequent HWE re-action.142

Scheme 51

4.2 Peterson Allenation

Takeda and co-workers143 have developed a procedure forthe construction of allenes from carbonyl compounds andalkenylsilanes. As shown in Scheme 52, bromoalkenylsi-lane 179 is converted into vinyl carbanion 180 with tert-butyllithium via a halogen–metal exchange reaction. Sub-sequent addition of 181 gives lithium alkoxide 182, whichundergoes elimination at 50 °C to yield allene 184. It wasfound that the allenyl product was obtained in higheryields when diethyl ether was employed for the prepara-tion of alkoxide 182 rather than tetrahydrofuran.

Scheme 52

4.3 Crabbé Homologation Reaction

Since its development in 1979, the Crabbé reaction hasproven to be a useful method for the construction ofmonosubstituted allenes from terminal acetylenic precur-sors (Scheme 53).144–147 The reaction mechanism consistsof a copper-catalyzed addition of 185 onto iminum ion188, which is formed in situ from paraformaldehyde anddiisopropylamine. Complexation of the cuprous bromideto the acetylenic triple bond results in p-complex 189.Subsequent intramolecular hydrogen transfer from theamine moiety to the copper species occurs to afford hydri-docopper(I) complex 190. The hydride is then delivered tothe carbon–carbon triple bond in an SN2¢ fashion to yieldallene 192.146

Scheme 53

This homologation reaction is commonly used to accessa wide variety of functionalized monosubstituted al-lenes,22,37,148–159 such as allene-substituted alcohols,153,160–171

amides,120,172 carbamates,92,173,174 and lactams.175,176

Crews and co-workers,177 for example, recently appliedthis methodology to the synthesis of a-allenyl alcohol194. As shown in Scheme 54, propargyl alcohol 193 istransformed into the desired allene when treated withparaformaldehyde, diisopropylamine, and cuprous bro-mide in refluxing dioxane. Similarly, Trost andMcClory178 have employed cuprous iodide as the catalystcomponent for the synthesis of allenyl ester 196 from ter-minal alkyne 195 (Scheme 55).

172171

CO2BHTR

R1 THF, –78 °C

169

(MeO)2PO

CO2Me

Li

–78 °C to r.t. 46–77%

• CO2Me

H174

R

Nu

R1

R = R1 = alkyl, Ph, β-naphthyl NuLi = n-BuLi, PhLiadditive = ZnCl2 or SnCl2

R

R1 Nu

OLi

OBHT

173

O•R

R1

Nu

NuLi, additive

Me

O

O

Me

PO

OMe

O

176

THF, –78 °C

175a: R = BHT 175b: R = Ph

R1 = Ph, BnR2 = alkyl, Ph

OR

R2

R1

OO•

R1

R2

(S)-177, baseR2 • CO2Me

H

R1base, ZnCl2

–78 °C to r.t.

178a: R = BHT; 60–94%, 10–81% ee 178b: R = Ph; 21–71%, 23–89% ee

(S)-177

184

181

•R

R2

179

RBr

SiMe3

R = H, alkyl, PhR1 = H, alkylR2 = alkyl, alkenyl

–78 °Ct-BuLi, Et2O

180

RLi

SiMe3

O

R2R1

183 182

RSiMe3

OLi

R1

R2Me3Si O

RR2

R1

LiR1

46–90%

–78 to 0 °CEt2O

50 °C

DMF

187

188

192185

RO

H HNH

•

R

dioxane+

NR

H

NR

Cu BrH

N

CuBr

+CuBr

N

R

190

191

189

186

CuBr

reflux

+



Scheme 54

Scheme 55

5 Allene Synthesis via b-Elimination Reactions

5.1 b-Elimination of Enol Phosphates

b-Elimination of olefins represents another class of reac-tions used to access allenes. Brummond and others havedemonstrated that acyclic179–181 and macrocyclic179 al-lenes can be formed in high yields from enol phosphates.As shown in Scheme 56, 1-phenyl-4-octanone (197) isconverted into enol phosphates 198a and 198b as a mix-ture of E/Z isomers with lithium diisopropylamide anddiethyl chlorophosphate. Subsequent base-induced elimi-nation of the phosphate moiety with lithium diisopropyl-amide affords disubstituted allene 199. It was found thatreplacing lithium diisopropylamide with n-butyllithiumproduced the allenyl product in lower yield, whereas useof lithium bis(trimethylsilyl)amide led to no reaction.

Scheme 56

5.2 b-Elimination of Sulfoxide Derivatives

Satoh and co-workers182 have developed a procedure forthe construction of trisubstituted allenes from various b-ketosulfones. As shown in Scheme 57, sulfone 200 istreated with lithium diisopropylamide and phenyl triflim-ide to give enol triflate 201. A sulfoxide–metal exchangethen occurs with n-butyllithium at low temperature to af-ford reactive intermediate 202. Subsequent b-eliminationproduces cyclic allene 203 in good yield.

Scheme 57

Satoh183 has also shown that allenes can be obtained in asimilar fashion from vinyl sulfoxides bearing a b-acetoxyor b-mesylate functionality (Scheme 58). For example,treatment of 205a and 205b with n-butyllithium producesthe desired allene via a sulfoxide–metal exchange and b-elimination sequence. It was found that b-acetoxy deriva-tives such as intermediate 205a proved to be more stablethan the corresponding mesylate intermediates. Thismethodology has been extended to the synthesis of chiralallenes, as optically active alkenyl sulfoxides can be em-ployed as starting materials.

Scheme 58

1-Chlorovinyl p-tolyl sulfoxides such as 207 can be trans-formed into allenes via a one-pot procedure as illustratedin Scheme 59.184,185 First, vinyl sulfoxide 207 undergoes asulfoxide–magnesium exchange with a Grignard reagentto give magnesium alkylidene carbenoid 209. Subsequentaddition of lithium a-sulfonyl carbanion 210 to the elec-tron-deficient carbenoid carbon gives vinyl anion 212. b-Elimination of the sulfonyl group affords allenes of type213 in yields of 51–63%.

(CH2O)n CuBr, i-Pr2NH OTBDPS

PMBO

•HO

194

OTBDPSHO

PMBO

193

dioxane, reflux, 70%

(CH2O)n CuI, i-Pr2NH

196

•MeO2C

195

dioxane, reflux, 80%MeO2C

198aPh

OTHF, 1 h

LDA –78 °C

2)(EtO)2PCl

O

–78 °C to0 °C (45 min)

1.5:1, E/Z

LDA–78 °C 73%

197

Ph•

n-Pr

198b

199

n-Pr2

Ph

OPO(OEt)2n-Pr

2Ph

OPO(OEt)2n-Pr

2+

1)

1.5:1, E/Z

2

201200

OPh(O)S

LDA, PhNTf2

THF–HMPA–80 °C, 65%

OTfPh(O)S

n-BuLi–80 °C

OTfLi•

202203

206

SPh

O

R

R1

OHAc2O

or MsCl

SPh

O

R

R1

OX

205a, X = Ac205b, X = Ms

n-BuLi (4 equiv)

THF, –78 °C10 min, 76–89%

R = alkyl; R1 = (CH2)2Ph204

R•

R1

Scheme 59

208 209S(O)Tol

ClO

O

1) t-BuMgCl (0.5 equiv)

2) EtMgCl (3 equiv)

THF, –78 °C

Cl

MgClMgCl2

207

PhO2S R

Li210

212

H RSO2Ph

O

O

213

•R

H

R = alkenyl, alkynyl, Ph, naphthyl

(3 equiv)

PhSO2CHR

211



5.3 Allenes via Deoxystannylation

b-Elimination of b-stannyl alcohols occurs in an anti-periplanar fashion to afford functionalized allenes.186–189

For example, alcohol 214 is hydrostannylated to form in-termediate 215, which is then reacted with triethylamineand methanesulfonyl chloride to give allene 216(Scheme 60). Alternatively, tetra-n-butylammonium fluo-ride can also be employed for the elimination reaction,producing allene 219 in high enantioselectivity(Scheme 61).186

Scheme 60

Scheme 61

5.4 b-Elimination via Radical Intermediates

Malacria and co-workers190,191 have designed a synthesisof allenes based on the b-elimination of a sulfinyl radical.As shown in Scheme 62, allyl bromide 220 is treated withexcess amounts of tris(trimethylsilyl)silane (TTMS) and2,2¢-azobisisobutyronitrile (AIBN) to give conjugatedradical 221. This intermediate then rotates to give 222,which then undergoes the desired b-elimination reactionto afford allene 223. It was found that using tin hydride inplace of TTMS led to contamination of the allene with tinresidues.

5.5 Allenes from b-Chlorovinylsilanes

Early work by Chan and co-workers192,193 demonstratedthat terminal allenes could be obtained in moderate togood yields via elimination of b-chlorovinylsilanes. Morerecently, Tius and Pal194 have extended this methodologyto the synthesis of disubstituted allenes (Scheme 63).

Scheme 63

5.6 Transition-Metal-Catalyzed b-Elimination

Tanaka and co-workers151,195–199 have reported a proce-dure that employs a diethylzinc-mediated reductive syn-thesis of functionalized allenes in the presence of apalladium catalyst. As shown in Scheme 64, oxidativeaddition of allyl bromomesylate 226 to the palladium(0)catalyst gives p-allylpalladium complex 227. syn-1,2-Elimination of palladium(II) from intermediate 228 yieldsallene 230. The palladium(II) species 229 is then reducedby diethylzinc to regenerate the palladium(0) catalyst.

Scheme 64

6 Transition-Metal-Catalyzed Allene Synthesis

The synthesis of allenes using transition-metal-catalyzedreactions is becoming more common. This topic has re-cently been reviewed,200 so only a few examples are high-lighted in this work.

6.1 Palladium-Catalyzed SN2¢ Substitution of Dienes

The most common transition metal used for the prepara-tion of allenes is palladium, which allows for their forma-tion under relatively mild conditions. Hayashi and co-workers,201 for example, have reported a novel palladium-

215

OH

n-HexSnBu3

•n-Hex

MsCl Et3N

CH2Cl20 °C to r.t. 81% 216

OH

n-Hex

n-Bu3SnH AIBN

neat 90 °C

214

218 219217

MeH

OAc

n-HexSnBu3

F

MeH

OAc

n-HexSnBu3

TBAF42%

•n-Hex

H

Me

94% ee

Scheme 62

221

223

222

220

R1

R

SOAr•

R

R1TTMS, AIBN

53–80%

R = H, alkyl; R1 = alkyl, Ar

R1 HHR

SO

PhR1

R

SO

Ph

H

H

toluene, reflux

rotate 90°

(Me3Si)3Si

Br

ArSO

224 225

RSiEt3

•R

R = alkyl; R1 = Ar

R1ClTBAF

DMSO

R1

55–90%

230

227

BrOMs

NHMts

Pd(PPh3)4 (10 mol%)

Et2Zn (2 equiv) THF, 86%226

•

NHMts

PdIILn

Br

OMs

NHMts

PdIILnBr

OMsNH

Mts

BrPdIILnOMsPd0L4

228

Pd(II) Et2Zn Pd(0)

229

Mts = mesitylenesulfonyl



catalyzed substitution reaction of 2-bromo-1,3-butadienes(Scheme 65). This substitution reaction works well withsoft nucleophiles. Hard nucleophiles, however, tend togive 1,3-diene products. While Hayashi was not the firstto report this substitution reaction, he was the first to ex-amine the scope and limitations.

Scheme 65

A major advantage to this formal SN2¢ substitution reac-tion is the ready availability of the 1,3-dienyl precursors(Scheme 66). Dienes such as 231 can be quickly accessedvia a regio- and stereoselective palladium-catalyzed cou-pling reaction between a dibromoalkene (233) and a vinylzinc reagent (234).201

Scheme 66

The same protocol has been used to prepare allenes withhigh enantioselectivity.202 This enantioselective process isaccomplished by generating a chiral palladium catalyst insitu from Pd(dba)2 and (R)-BINAP. In all cases, the high-est enantioselectivities were obtained when cesium tert-butoxide was employed as a base and C(NHAc)(CO2Et)2was used a nucleophile (Scheme 67).

Scheme 67

Subsequently, 2-chloro-1,3-butadiene (chloroprene) wasfound to be reactive towards this palladium-catalyzed pro-cess. As shown in Scheme 68, terminal allenes can be ob-tained in good yields when chloroprene is reacted withsoft nucleophiles.203 Chloroprene is advantageous overthe corresponding 2-bromo-1,3-butadienes (Scheme 68)because of its availability and low cost.

Scheme 68

Recently, this methodology was extended to the prepara-tion of vinyl allenes from the corresponding 2-bromo-1,3,5-trienes.204 As shown in Scheme 69, 239 is convertedinto 240 in 80–96% yield (depending on the nucleophile)when R = tert-butyl. However, when R is a cyclohexyl orn-octyl group, the vinyl allene is contaminated with allene241, which is formed via a SN2¢ addition.

Scheme 69

Application of this palladium-catalyzed SN2¢ substitutionreaction has been extended to the asymmetric synthesis ofa methyl (R,E)-(–)-tetradeca-2,4,5-trienoate, a sex phero-mone of male dried bean beetle (Scheme 70).205

Scheme 70

6.2 Palladium-Catalyzed 1,4-Addition of Enynes

Palladium-catalyzed hydrosilation and hydroboration ofenynes produce the corresponding allenylsilanes and alle-nylboranes in good yields. For example, as shown inScheme 71, hydrosilation with trichlorosilanes affords the1,4-addition product exclusively.206 Moreover, if a chiralligand such as (S)-(R)-bisPPFOMe is employed, the cor-responding allenylsilane can be obtained in high enantio-meric excess (85%). A major limitation to thismethodology, however, is the lack of selectivity observedwhen anything other than a bulky group such as tert-butyl,mesityl, or tert-butyldimethylsilyl is present.

232

•Nu

R = H, alkyl, Bz, PhR1 = R2 = H, alkyl, alkenyl, PhNu = NaCMe(CO2Me)2, NaCH(CO2Me)2, NaOPh, KN(Boc)2, LiPPh2

231

RBr

R1

R2+ M-Nu

[PdCl(η-C3H5)]2

THF, 62–95%

dppb

R2

R1R

234233 231

RBr

Br ZnCl

R1

R2

Pd(PPh3)4(1.5 mol%)

THF+ R

Br

R1

R2

63–90%

236

•

R = alkyl, Ph, ferrocenylNu = C(NHAc)(CO2Et)2, CMe(CO2Me)2base = NaH, CsOt-Bu, KOt-Bu

235

RBr

+ NuH34–98%, 42–89% ee

Pd(dba)2(R)-BINAP, base

R

Nu

238

•Nu

base = NaH, NaOMe

237

Cl+ NuH

Pd2(dba)3·CHCl3

THF, 57–94%

DPEphos, base

OPPh2 PPh2

DPEphos

240

•

R = t-Bu, Cy, n-C8H17Nu = N(Boc)2, C(NHAc)(CO2Et)2, CMe(CO2Me)2base = NaH, KH

239

RBr

+ NuHTHF, 73–98%

R

Nu

+ •R

Nu

241

[Pd], dpbpbase

245

•

242

n-octylBr

Pd(dba)2

n-octyl 244CsOt-Bu, THF 71%, 77% ee

CH2(CO2Me)2

+

CO2Me

CO2Me(R)-segphos

•n-octyl

CO2Me

PPh2

PPh2

O

O

O

O (R)-segphos

243

243



Scheme 71

Similarly, the reaction of catechol borane 249 with 1,3-enyne 248 gives allenylborane 250 (Scheme 72).207 Com-peting hydroborations of the alkyne moiety can be mini-mized by varying the phosphine ligands and the molarratios of phosphine to palladium.

Scheme 72

6.3 Palladium-Catalyzed Hydrogen Transfer Reactions of Propargyl Amines

Palladium-catalyzed hydrogen transfer reactions havebeen used to convert propargyl amines into allenes.208 Thepropargyl amine functionality can be regarded as an alle-nyl anion equivalent, and can be accessed via a Sonogash-ira coupling (Scheme 73) or by deprotonation of aterminal alkyne and addition to a carbonyl compound(Scheme 74). Subsequent treatment of the functionalizedpropargyl amine with palladium-catalyzed hydrogentransfer protocol affords the corresponding allene. It waslater shown that in some cases, the dicyclohexylaminegave the allene product in the highest yields.209

Scheme 73

In addition, heterocycle-substituted allenes can be ob-tained in high yields using this methodology.210 As shownin Scheme 75, functionalized propargyl amines are firstaccessed through a Sonogashira coupling and then con-verted into their allenyl counterparts using a palladium-catalyzed transfer protocol.

Scheme 75

Finally, a one-pot transformation of substituted propargylamine 262 into allene 263 has been accomplished using anelectron-deficient phosphine ligand such as 1,2-bis(diphe-nylphosphino)carborane (Scheme 76).211

Scheme 76

6.4 Palladium-Catalyzed Carbonylation Reac-tions of Propargyl Substrates

Palladium-catalyzed carbonylation reactions to form al-lenes have been reviewed by Tsuji and Mandai212 andhave been shown to be quite general. A typical reactioncan be seen in Scheme 77, where the terminal triple bondreacts to give very high yields of the corresponding allene265 at 15 atmospheres of CO.213

Scheme 77

Fe OMe(S)-(R)-bisPPFOMe

Fe

PPhMeO

t-Bu + HSiCl3

[PdCl(π-C3H5)]2(S)-(R)-bisPPFOMe

59%, 85% ee247

•t-Bu

Cl3Si246

249 •Me3Si

248

Me3Si

OHB

O

Pd2(dba)3·CHCl3PPh2(C6F5)CHCl3, 46%

BO

O

250

254

Pd2(dba)3·CHCl3

253

N+

Pd(PPh3)4 CuI, Et3N

MeCN, 86%

I N

P(C6F5)3dioxane, ∆,

•

NR2 •

H

251 252

99%

Scheme 74

255

Pd2(dba)3·CHCl3P(C6F5)3

HO N

dioxane, 80 °C, 86%

•HO

256

257

Pd2(dba)3·CHCl3

259

N+

Pd(PPh3)4 CuI, Et3N

MeCN

NR ligand

•

R258

R-Br

260

N

•

99%

N

N

•

89%

N

N

•

91%

OMe

MeO

N

•

95%

MeO2C

N

•

86%N

•

51%

S

•

87%N

•

Boc 88%

Pd2(dba)3·CHCl3

261

NCy2+

262 263

•

PPh2Ph2P

= BH

I

CuI, Et3N, 99%AcHN AcHN

265

Pd(OAc)2, PPh3•

264

OCO2Me MeOH, 50 °C 15 atm CO, 96%

CO2Me



Alper and co-workers214 have shown that alkynyl ep-oxides such as 266 can be converted into allenyl esterslike 267 via a palladium-catalyzed carbonylation reaction(Scheme 78). The reaction conditions are relatively mildand have allowed for the formation of a variety of func-tionalized allenes.

Scheme 78

6.5 Palladium-Catalyzed Cross-Coupling of Pro-pargyl Derivatives

Molander and co-workers215 have shown that propargylcarbonates like 268 can be coupled with alkenyl trifluo-roborates such as 269 to afford allenes in good yield(Scheme 79). The reaction conditions are tolerant of awide range of functionality (nitrile, alcohol, silyl ether,amine, thioether, and sulfone). Moreover, if the propargylderivative is non-racemic, the corresponding enantioen-riched allene can be obtained.

Scheme 79

Recently, it was shown that triorganoindium reagents 271also react with propargyl esters and carbonates under pal-ladium catalysis to give allenes (Scheme 80). This reac-tion occurs via an SN2¢ addition and is highlyregioselective.216

Scheme 80

Allenyl indium reagents have been generated in situ frompropargyl bromides and coupled with a variety of electro-philes to give the corresponding substituted allenes.217

The reaction conditions of the cross-coupling reaction aremild and appear to be very general. A few representativeexamples are shown in Scheme 81.

Scheme 81

6.6 Indium-Mediated Allene Formation

Chan and Isaac218 have reported a regioselective additionof various propargyl indium reagents to aldehydes. Inmost cases, the allenyl alcohol was obtained selectivelyover the corresponding homopropargyl alcohol. A repre-sentative example is shown in Scheme 82.

Scheme 82

This protocol has been used by Hammond and co-workers219,220 to prepare difluoroallenes (Scheme 83),with the ultimate goal being their incorporation into annu-lation and cycloaddition strategies.

Scheme 83

Iwasawa and co-workers221 have found that indium re-agents prepared from propargyl bromides react with cy-cloalkenones in the presence of tert-butyldimethylsilyltriflate (TBSOTf) and dimethyl sulfide to give the 1,4-ad-dition product which is then trapped as the silyl enol ether(Scheme 84). All examples in this work possess a methylgroup at the C2 position and only cyclopentenones andcyclohexenones were investigated.

6.7 Chromium-Catalyzed Allene Formation

Molander and Sommers222 have utilized chromium(III)complexes to convert propargyl silyl ethers into the corre-sponding allene in high yield and with high enantioselec-

266

•

267

MeOH, 20 atm CO 90%

MeO2CO

(MePh2P)4Pd

HO

270

MeO2CO

Ph

KF3BPh

269Pd(PPh3)4 Cs2CO3

•

268

THF–H2O (10:1)reflux, 41%

Ph

Ph

272271

InR3X

R1

R2Pd(DPEphos)Cl2

THF, r.t.

273

•R1R

R2

R = Me, alkenyl, alkynyl, ArR1 = R2 = alkyl, PhX = OAc, OBz, OCO2Me

25–96%

R

278

277•R-X + Br

In

BrIn

or

Pd(0)/LiCl

DMF

•R

275274

276

•

90%

•Ph 91%

•N

Ph

OMe

86%

O

•

90%

•

OH 90%

N

N

•

92%

282279 281

n-C8H17CHO

BrPh

H2O, 89%In

280

•

PhHO

Ph

HO+ +

95 5:

n-C8H17 n-C8H17

BrTIPS

1) In, H2O–THF

284

•TIPS

OH

FF 2) O

HH

59%

F

F

283



tivity (Scheme 85). The reaction protocol at present haslimited utility because it is not tolerant of a wide array offunctionality and is sensitive to steric effects.

Scheme 85

A chromium-mediated one-carbon homologation proce-dure for the preparation of allenes from terminal alkeneshas been reported by Takai and co-workers(Scheme 86).223 The reaction is thought to proceedthrough a dicarbenoid of chromium which is formed byreduction of two chlorine atoms from carbon tetrachlo-ride. Substrates processing coordinating functionalitiessuch as a free hydroxyl group are not suitable for this re-action. This method is complimentary to the Crabbé pro-tocol (Section 4.3) which works best in the presence ofcoordinating groups.

Scheme 86

6.8 Ruthenium-Catalyzed Allene Formation

Grubbs’ first-generation catalyst (5 mol%) has been usedby Barrett and co-workers224 to catalyze a cross-metathe-sis reaction between monosubstituted allenes such as 291(Scheme 87). The yield of the 1,3-disubstituted allenylproducts obtained were found to be substrate-dependent.In certain cases, large amounts of a polymeric byproductwere obtained.

Scheme 87

6.9 Rhodium-Catalyzed Allene Formation

Roy and Banerjee225 have shown that propargyl bromidescan be added to aldehydes regioselectively to give allenylalcohols when treated with [Rh(COD)Cl]2 and b-SnO.However, the propargyl bromide must be functionalizedwith an aryl group if the allene is to be selectively ob-tained over the corresponding homopropargyl alcohol(Scheme 88).

Scheme 88

A rhodium(I) catalyst has been used to catalyze the 1,6-addition of aryltitanate reagents ArTi(Oi-Pr)4Li to alk-3-ynyl-2-en-1-ones.226 The reaction proceeds with highenantioselectivity when performed in the presence of achiral ligand such as (R)-segphos 243 (Scheme 89).

Scheme 89

6.10 A Zinc Carbenoid–Vinyl Copper Coupling to Form Allenes

A one-pot procedure to prepare allenes from alkynyl sul-fones or sulfoxides, organocopper reagents, and bis(io-domethyl)zinc iodide [Zn(CH2I)2] has been reported byMarek and co-workers.227 This method is useful whenalkyl or aryl allenes are desired (Scheme 90).

Scheme 90

6.11 Titanium-Catalyzed Allene Formation

Allenes have been accessed via titanium vinylidenes.228

As shown in Scheme 91, titanium cyclobutane 304 reactswith 3-methylbuta-1,2-diene to produce unsaturated met-allocycle 305. Upon liberation of ethylene gas, intermedi-ate 306 is produced which reacts with a ketone oraldehyde to give the corresponding allene. This protocolwas useful in the preparation of di-, tri-, and tetrasubstitut-ed allenes.

Scheme 84

285

O 1) Me2S, TBSOTf

2)

In, THF –78 °C to r.t., 86%

OTBS

•

286

CH2Br

CrCl2

288287

TBSO

3

TBSO

N

Me3Al, CH2Cl2

•

TBSO3

83%, 86% ee

290Ph

CrCl2, CCl4

THF, 60%•Ph

289

291

•

n-Hex

RuCl

Cl

Ph

PCy3

PCy3

CH2Cl2, 72%

•

n-Hex

n-Hex

292

BrPh+

[Rh(COD)Cl]2β-SnO

THF–H2O (9:1)∆, 81% Ph

•CH3(CH2)4

OH

CH3(CH2)4CHO

294 295293

297

298296

O

n-Bu

+

TMSCl

[RhCl(C2H4)2]2(R)-segphos 243

THF, 99%, 90% ee •

OTMS

Ar

n-Bu

ArTi(Oi-Pr)4Li

300299

+THF, 85%

CuEtO2C S(O)TolHexZn(CH2I)2 •

Hex

EtO2C301



Scheme 91

Petasis and Hu229 subsequently demonstrated a titanium-mediated carbonyl allenation process that is suitable forthe synthesis of more functionalized allenes. An examplethat demonstrates the high functional group tolerance ofthis protocol is shown in Scheme 92.

Scheme 92

An interesting three-component coupling reaction hasbeen reported between an enyne and two electrophilessuch as an aldehyde, ketone, or imine.230 As shown inScheme 93, enyne 313 is first treated with (h2-pro-pene)Ti(Oi-Pr)2 to generate enyne–titanium complex 315,which then undergoes addition to imine 316 and acetoneto afford functionalized allene 317.

Scheme 93

6.12 Copper-Catalyzed Coupling of Allenyl Halides with Amide Derivatives

Trost and Stiles231 have developed a protocol for the syn-thesis of N-substituted allenes via a copper-catalyzed cou-pling reaction of amide derivatives with allenyl iodidesand bromides. A representative example is shown inScheme 94, where oxazolidinone 318 is converted into al-lenamide 321 when reacted with allenyl iodide 319 andpotassium phosphate in the presence of copper(I)thiophenecarboxylate (CuTc) and amine ligand 320(trans-N,N¢-dimethylcyclohexyldiamine) at elevated tem-perature.

Scheme 94

Hsung and co-workers232 have extended this methodologyto the synthesis of optically enriched allenamides(Scheme 95). For example, chiral allene 322 and amide323 are transformed into optically active allenamide 324in good yield when reacted with copper(I) cyanide andN,N-dimethylethylenediamine (DMEDA) at room tem-perature.

Scheme 95

7 Conclusion

In conclusion, a snapshot of the wide array of diverselyfunctionalized allenes that can be prepared using synthet-ically straightforward methods is provided within. Whilethis review is organized according to reaction type, inmany cases there is commonality between the starting ma-terials and reaction types. Thus, when planning the instal-lation of an allene into a synthetic sequence, it is useful tothink about the conditions and the functional group re-quired. This review is meant to provide a tool for this pro-cess.

The most common manner for accessing an allene is froman appropriately functionalized alkyne; examples includean SN2¢ addition of a nucleophile to a propargylic electro-phile, sigmatropic rearrangement of propargyl alcoholderivatives, and one-carbon homologation reactions ofterminal alkynes. All represent very powerful methods for

303302

+

309

•

OCp2Ti •

benzene55%

Cp2Ti

Cp2Ti

– C2H4

Cp2Ti • O

RR

Cp2TiO

RR

304

305

306 307

308

Cp2Ti=O

311

312

Cp2Ti •H

H

OMeMeO

O

MeO O

81%

OMeMeO

MeO O

•

310

314

316

315313

317

TMS

n-Hex

Ti(Oi-Pr)2

Et2O Me3Si n-Hex

TiOi-Pri-PrO

N

Et

Ph

•TMS

1)

2) Me2C=O

OHn-Hex

HN

Et

Ph

45%, dr 93:7

Et2O–THF

321

O NH

O

Ph

I•

K3PO4

318

319

CuTc,

toluene, 85 °C, 99%

O

O

Ph

N •

MeHN NHMe320

NH

O•Me

H

322, 75% ee

CuCN, DMEDA

CsCO3, toluene, 71% O

I

N•

Me

H+

323 324, 75% ee



obtaining allenes and have stood the test of time. More-over, the literature is rife with examples that demonstratetheir synthetic robustness, utility and limitations.

Allenes are also commonly obtained from alkenes; theDoering–Moore–Skattebol protocol is just one exampleof a reaction that has been modernized to accommodateprecursors with more functionality. In addition, elimina-tion reactions of alkenes substituted with leaving groupsgive allenes.

Carbonyl groups can be converted into allenes usingHorner–Wadsworth–Emmons, Wittig or Peterson proto-cols. More recently, allenes have been prepared from al-lenes via transition-metal-catalyzed couplings or olefin-metathesis reactions. These reactions are in their infancyand therefore the synthetic scope is still somewhat limitedat this time.

Acknowledgment

We gratefully acknowledge the financial support provided by theNational Institutes of Health (GM54161).

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