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Hai Dao Baran Group Meeting 11/03/2012

Part 1. Introduction A brief history 1828: Synthesis of = the starting point of modern organic . O Me 1875: Prediction of the correct structure, Van't Hoff, La Chimie dans I'Espace, Bazendijk, P.M., Rotterdam 1875, 29. HO . 1887: First synthesis of an allene (glutinic acid), Burton and Pechmann, Chem. Ber. 1887, 145. Confirmation of the structure of "glutinic acid", Jones et al., J. Chem. Soc. 1954, 3208. 1924: Isolation and characterization of first natural allene, pyrethrolone, Staudinger and Ruzicka, Helv. Chim. Acta 1924, 177. 1928: First review on allenes, Bouis, Ann. Chim. (Paris) 1928, 402. Me 1935: Synthesis of first chiral allene, Maitland and Mills, Nature 1935, 994. pyrethrolone Last decade (2002-2012): Shengming Ma (148 publications); Norbert Krause (42 publications), Benito Alcaide and Pedro Almendros (33 publications). Scifinder, key word: allenes. Google gave 184000 (vs. 999000) (Nov 2012).

Structure and physical properties HOOC HOOCHC . CHCOOH COOH initial proposal (1887) revised structure (1954) Csp R "glutinic acid" R α β γ χ(Csp3) = 2.63 . χ(Csp2) = 2.86 Classification R 2 χ(Csp) = 2.96 Csp2 Csp R EWG EDG R δ− Met Brown, J. Chem. Phys. 1960, 1881. .. δ− .. + .. δ− .. IR: antisymetrical streching vibration 1950-1960 cm-1 δ (vs. : 1680 cm-1, alkyne 2200 cm-1) δ− 1H NMR:δ = 4.9-4.4 ppm 13 R = , alkenyl, aryl, alkynyl C NMR: δCα, Cγ = 120-73 ppm; δCβ = 220-200 ppm. EWG = CO2R,CN, SO2R... The most simple allene vs. EDG = OR, SR, NR2, Hal, ... Erel Met = Li, Mg, B, Si, Sn, Zn, In, Ti, Cu, Pd [kcal/mol] - allenes can react as both nucleophiles and electrophiles H H H H - changing the substitutes can alter the reactivity preferences . 22.3 H H H H Determination the configuration of chiral allenes dC−H (Å) 1.061 1.086 . dC−C (Å) 1.309 1.337 2.1 HO2C H HO2C H H CO2H H CO2H IP 10.07 eV 10.51 eV 0.0 . . 10.64 eV isomers of smallest allene and nBu Me nBu Me Me nBu Me nBu their relative energies R R S S many substituted allenes are thermodynamically more stable than mirror the corresponding . Hai Dao Baran Group Meeting Allenes 11/03/2012

Part 2. Synthesis of Allenes Sigmatropic Rearrangements [2,3] [3,3] Prototropic Rearrangements X Y Y ZH X Y Y X X Z . .

. SnBu H 3 OH n BuLi H O . . H 71%, 93%ee OMe OMe C4H9 C4H9 Me Me [2,3]-Wittig Rearr. OH KOH, K2CO3 OH Marshall et al., J. Org. Chem. 1989, 5854. N PhMe, reflux N N2 H 68% H R2 N N MeO C R1 CO Me Rh (S-DOSP) 2 OH Hoffmann et al., Helv. Chim. Acta 2000, 777 2 2 4 R1 Me 1mol% . + . Me OH Me [Rh] R2 Me R2 R1 Et N CO Me O 3 O HO 2 quant. Davies et al., J. Am. Chem. Soc. 2012, 15497. OEt Me OMOM OMOM OH EtC(OEt)3 Me tBu Marshall et al., J. Org. Chem. 1991, 6264. . CO2Et tBu EtCO H O 2 t Bu H H O E O O dr = 9:1, 68% ee t O KO Bu Heathcock et al., J. Org. Chem. 1988, 4736. O O O 84% O . H O H HO O COPh COPh Au(I)LOTf Ar . NaBH4 Ar . Newton et al., J. Chem. Soc., Perkin Trans 1, 1985, 1803. Ar R R R LDA then NH Cl Shi et al., Org. Lett. 2011, 2618. 4 Toste et al., J. Am. Chem. Soc. 2004 15978. kinetic cond. . 220 oC HO O O O O microwaves . 64% HO OH O O (−)-myltaylenol 98%, dr > 98% Winterfeldt et al., Chem. Eur. J. . 1998, 1480. Barriault et al., Org. Lett. 2002, 1371. Hai Dao Baran Group Meeting Allenes 11/03/2012

Nucleophilic Substitution H H 1 OH OH R1 anti S 2' R1 H R Nu N H O Cu species . . . Nu n OH + OH H LG OH OH Bu H H H nBu 1 syn R1 R R1 anti H X H X H RCuX.MgX.LiX syn: anti: nBu CuLi = 60:40; nBu CuLi.Me S = 6:94; nBu CuMgBr.Me S = 1:99 Cu 2 2 2 2 2 LG R LG R Cu LG (III) Cu-promoted racemization of allenes through SET Me2S stablizes Cu species H H Oehlschlager and Czyzewska , Tetrahedron Lett. 1983, 5587. back donation:

dCu to π∗C−C (III) X CuX R1 dCu to σ∗C LG Cu 1 coupling − R . 2 R 1 Pd(0) R XPd R pdt H . H X R2 H reduction mechanism of organocopper-mediated stereospecific substitution allylpalladium species OAc Me Me Me . Pd(PPh3)4 MsO 5 mol% H Ph Me n . MeMgBr (30 equiv) Me C6H13 nC H OAc LiBr (30 equiv) F3C PhZnCl, THF F3C 6 13 CuI (30 equiv) . Me 96% ee 77% yield, 96% ee THF, 0 oC, 3.5 h Me . Kono and Yamanaka et al., Chem. Lett. 2000, 1360. o Me 15 min 0 C AcO 85% Me Pd(PPh3)4 OAc . CO, ROH O AgNO3 Me O Me Me . 73% Fallis et al., Angew. Chem. Int. Ed. 2008,568. MsO 75% Br H H RO2C R H O H LiCuBr2 O H . H : PPh3, MeCN O kallolide B TMSO O TMSO H OSO Ar O H 2 H O isolaurallene precursor Marshall et al., J. Org. Chem. 1995, 796. Crimmins et al., J. Am. Chem. Soc. 2001,1533. O Hai Dao Baran Group Meeting Allenes 11/03/2012

1,2-Elimination Additions to Enynes Systems X R3 R3 EWG R1 R1 EWG 4 . R R2 R R2 . R . R4 Y H R R OM H OH H AlH3 1,2-elimination R1 R1 R1 . R2 CO Et H H anti H 2 CO Et 1. Me2CuLi.LiI Me . 2 R 2 R2 AH3 n t n 2. BuCO2H Olsson et al., J. Am. Chem. Soc. 1979, 7302. R R Me Me 1. PhCHO OH Me Tf2O R = tBu, n = 1, 90% (1,8 addition); R = Me, n = 2, 68% (1,10 addtion); Li H . 2. separation Ph R = Me, n = 3, 26% (1,12 addtion) Ph TASF H Krause, Liebigs Ann. Chem. 1996, 1487. SiMePhR* SiMePhR* 50% yield, 18% ee Bn N NBn2 nBuLi 2 McGarvey, Tetrahedron Lett. 1988, 1355. (−)-sparteine O SiMe R R2 O . O 3 t Me Si O 50-80 oC Ph O N MeOH N 1. BuLi 3 Li . R 2 Ph Br 1 2 R R 1 S R 2. R COR R H H O dr = 7:3 O R1

Oestreich and Hoppe, Tetrahedron Lett. 1999, 1881. Takeda, Synthesis 2006, 2577.

Wittig-type Reaction R3 O R 1 1 R (cat)B R Cp Ti(P(OEt) ) R R1 R4 Pd(0) 2 3 2 R4 R B(cat) Cl . PdL* 2 2 . . R R 2 3 (S)-MeO-MOP R TiCp2 R R Me H Cl O PdL* (cat)B BH H PhCHO Takeda, Org. Biomol. Chem., 2005, 2914. O Me R R1 COCl Ph CO2Et Fe cat. CO2Et R2 R1 CO2Et . OH N 2 PPh3 PPh3 Et N R2 up to 63% ee 3 Hayashi, J. Chem. Soc., Chem. Commun 1993, 1468. Dai et al., J. Am. Chem. Soc. 2007, 1494. Hai Dao Baran Group Meeting Allenes 11/03/2012

Other Methods Part 3. Reactions of Allenes NOT to be covered: allenyl and propargyl metal reagents - allenes as an (eg: Diels-Alder reaction, coupling) Cl 1. nBuLi - allenes as enones, unsaturated ...(eg. 1,4-addition inEWG substituted 1. nBuLi allenes) C6H13 THF Et O: H H 2 . . Allenylmetal Compounds 2.C6H13CH2I H H 2. Br(CH2)3Cl R1 R2 88% 98% E E, S 2 . Hooz et al., Tetrahedron. Lett. 1985, 271. [1,3] E R1 2 E H Arseniyadis et al., Tetrahedron 1979, 353 R2 R 1 . SnnBu R 3 Ti(IV)/(S)-binaphthol OH 2 10 mol% M M H R 2 . R1 + R CHO 2 E, S R E E2' 1 i E R PrSBEt2 ,DCM 1 R General rule (can be altered depend on R1, R2 and/or metals, electrophiles): - allenic isomer is more table than propagylic one titanium-phosphorus ylides - reaction in both SE2 (Li, Mg...) and SE2' (Sn, B, In, Zn...) manners - syntheses: metal- exchange/propargylic deprotonation (Li), Babier (iPrO) TiCl 2 2 O type oxidative addition (Mg, Zn, In...), transmetallation (Li, Mg to Cu, Sn, B, O (Me N) P=CH O n Si, Zn, Ti...), or catalyzed (B, Si) O 2 3 2 . n CHO - some allenic and propargylic metals can be isolated (M=B, Si, Sn) CHO NaNTMS 2 OPiv O n =2,4,6,8,10 40-50% OMs Pd(OAc)2.PPh3 OH H Me Finn et al., J. Am. Chem. Soc. 1997, 3429. Me + H Me PivO Et2Zn, THF approach NHBoc Pd(0) Me NHBoc MeLi PivO PivO 78%, d.r>95:5 CBr2 H H Br . . Me Me Br . [Pd] MsOZn Thies et al., J. Org. Chem. 1975, 585. transmetallation Marshall et al., Org. Lett. 2005, 1593. fragmentation InICl, AgP* NHCbz NHCbz NHCbz TMSO Me OTf 10 mol% TBAF HO Me . + Cy OMe . H , cpme Cy Cy 52% O . 75%, 88% ee 18%, 25% ee OTMS Bpin Lawrence et al., J. Am. Chem. Soc. 2012, 12970. Kobayashi and Schneider et al., Angew. Chem. Int. Ed. 2011, 11121. Hai Dao Baran Group Meeting Allenes 11/03/2012

Cycloadditions Free Radical Addition thermal [2+2] o R2 R 125 C R1 β R2 β a: 31.2% α R2 R1 1 . R H α . + H H R in general, it is thermodynamic control c: 6.3% . . m Me OCOC6H4 CF3 b: 62.5% Me conrotatory H 1. hν/55 oC iPr H H CHD/NMC Me iPr disrot. H disrot. . a b, c 2. CHD/ C6H5SH Me Me hν CHD: 1,4 cyclohexadiene biradical as intermediate Me 46% NMC: N-methylcarbazole photochemial [2+2] Mayers et al., J. Am. Chem. Soc. 1993, 7926. O O O O . . . δ− Ph hν (R) Br − O O δ O O 1. Bu SnH, Et B, O R 3 3 2 O R LUMO . OR SOMO(π*) 2. TMS3SiH, Et3B, O2 . Br O Br O O O O O O 73%, dr = 9:1 . hν . . δ+ Nauguier and Renaud et al., Tetrahedron asymmetry 2003, 3005. O δ− Palladium-catalyzed Addition to Allenes LUMO SOMO(π*) carbopalladation Becker et al., Chem. Commun. 1975, 277.

NAc NAc R − R2Pd(II)X − R H δ 1 Nu hν . R R1 Nu H H . R1 H PdX H O π complex O O δ− concave = major Weisner, Tetrahedron 1975, 1655. Hai Dao Baran Group Meeting Allenes 11/03/2012

RN . Carbophylic Activation by Solf Lewis Acids I Pd(OAc)2, PR3 + R N N K2CO3, PhMe Ts H 110 oC N Ts Grigg, Chem. Commun. 2001, 964.

. Pd(0) O I CO, K2CO3 O + PdX σ−interaction π−back donation PhMe O OH Me 2 most important orbital interaction in TM-alkyne 45 oC OH Ph HN Ph N CO Me Rayon and Frenking et al., J. Phy. Chem. A 2004, 3134. 2 CO2Me 60%, 1:1 Me calculated data (CuI, AgI, AuI): + Grigg, Tetrahedron Lett. 2000, 7129. - ethylene ligand is slightly stronger bonded to TM Ph - σ−interaction contributed to about 55-70%, π−back donation contributed Ph to about 20-33% of covalent bonds. . TsN TsN Pd(OAc)2, PR3 TsN "In" that means: PhI - reactions at the alkyne (allenes) vs. olefin sites are kinetic in origin (steric?) + In, DMF, 80 oC OH - TM interacted multiple bonds become more electrophilic O O Furstner and Davies, Angew. Chem. Int. Ed. 2007, 3410. 93% allenes vs. alkenes (and alkynes): Kang et al., J. Org. Chem. 2002, 4376. - alkynes and alkenes coodinate to TM in η2 mode, additions of arylboronic acid to allenes - allenes have η2 and several η1 modes [Au]+ [Au]+ + . PdX Ar [Au] [Au] [Au] 1 R1 + R R1 . . ArB(OH)2 Pd(0)/Pd(II) PdHX (Pt, Rh give terminal olefin adducts) η2 allylic cation carbene bend X-ray and NMR studies of first gold allenes complexes

OMe OH Me OMe Pd(II) 5mol% C1-C2: 1.340 Å OH (HO)2B Et3N Ph C2-C3: 1.311 Å . + Ph dioxane:H2O Au−C1: 2.191 Å Me 80 oC Me Au−C2: 2.306 Å 68% C1-C2-C3: 165.0 OMe OMe

Yoshida et al., Org. Lett. 2009, 1441. Hai Dao Baran Group Meeting Allenes 11/03/2012

R HO HO O O O P AgA* O − − H O . A* . + dppm(AuCl)2 [Au] Me conclusions: π−face exchange R Me Me Me i - gold tends to bind to less substituted C=C Me Me R = 2,4,6- PrC6H3 - fluxional behavior: π-face exchange via η1 intermediate chiral counterion 91%, 97%ee Widenhoefer et al., Organometalic 2010,4207. interaction Halminton and Toste et al., Science 2007, 496. [TM]+ R2 R2Pd(II)X Ph α γ . R1 . - α and γ attack vs. 1 OH β - β attack is rare R Ph Ph Ph OH PdX AuCl − AgOTf 3 Nu OH TM = "cationic" Au, Pt, Ag, Pd π complex HO [Ag] O . [Au] Ph Br Br Ph I III PEt3Au Cl . Au Cl3 O Br R H H R O PhMe, rt R PhMe, rt O Kim and Lee et al., Adv. Synth. Catal. 2008, 547. O

LAuCl H I Br . E [Au] AgSbF6 E + [Au] . E Br Br E E .. R H . E R1 2 H O R H H O R R E = COOMe L = P(2,3-tBu C H O) 99:1 (91%) H [Au]III O 2 6 3 3 O L = P(tBu (o-biphenyl)) 4:96 (89%) [Au]III 2 3

Gevorgyan et al., J. Am. Chem. Soc. 2008, 6940. alkyl migration H shift Me Me (PhO) PAuCl/AgOTf 3 H (5 mol%) LAu LAu LAu O O O 2π H H O O H [2π+4π] HO DCM, rt Me Me E E O E [3C+4C] . 4π E exo like TS E E 55% H H Widenhoefer et al., J. Am. Chem. Soc. 2006, 9066. Toste et al., J. Am. Chem. Soc. 2009, 6348. Montserrat et al., J. Am. Chem. Soc. 2009, 13020. Hai Dao Baran Group Meeting Allenes 11/03/2012

O O O Carbonylation and Pauson-Khand Reaction 1 O O R [[M] R2 R2 O carbonylation R1 O + NHTs 1 . Ru(CO)4 TsN N [M] R Me R N H N H R 2 CO R R R R CO

[M] = Au(I) [M] = PtCl2, CO (CO)3 Ru(CO) CO O O 4 O Ru Me O TsN H Ru(CO) TsN 3 R2 R2 TsN R2 . Me O O O R R [M] . R [M]− [M] N N N allenic Pauson-Khand reactions R H R 1 1 R1 R R 2 R 2 1 R1 R R R R3 R3 R1 Pt cat. favors carbenoid mechanism vs. Au cat. via carbocationic intermediate R3 . M O R2 exo General conclutions (noble metals catalyzed reactions of allenes, [M] + + alkynes): R1 R1 - "importance of charge in synthetic design: introduction of a charged R2 R2 3 3 O into a molecular skeleton undergoing bond reorganization usually lowers the R M R activation of energy of the process, which leads to milder reaction conditons and greater selectivities" - effect of noble metals on TS: play important roles in various points of the endo reaction ( not just as solf Lewis acids). general rules: topics in current chemistry, 302, p125-6. - Co2(CO)8 is not effective, causing polymerization - Mo(CO)6 favors exo-cyclized products -catalyzed - [Rh(CO)2Cl]2 favors endo-cyclized products - R3 = H: endo products are prefered O O H PPh3 (10 mol%) i PhMe, 110 oC Pr . + (-)-geniposide O OTBS O . DPS [Rh(CO) Cl] DPS EtO C O 2 2 2 63% 10 mol% EtO C H 2 OPiv i OTBS OPiv OTBS Pr PhMe, 80 oC O O Me O OTBS 65% Me OEt DPS: dimethylphenylsilyl OEt guanacasterpene A O PH R 2 3 PH R 2π Brummond and Gao et al., Org. Lett. 2003, 3491. 4π 2 3 OPiv Hai Dao Baran Group Meeting Allenes 11/03/2012 other important topics: oxidation (including epoxidation), electrophilic additions...

Part 4. Important References

1. Modern allene chemistry, vol. 1 and 2; edited by Krause and Hashmi, Wiley-VCH, 2004. 2. Computational mechanism of Au and Pt catalyzed reactions, topics in current chemistry, 302, Soriano and Marco-Cotelles, Springer, 2011. 3. Allenes in , Schuster and Coppola, Wiley, 1984. 4. Recent development in allene chemistry, tetrahedron, 1984, 2805. 5. Allenes in catalytic asymmetric synthesis and natural product synthesis, Ma et al., Angew. Chem. Int. Ed. 2012, 3074. 6. Gold-catalyzed nucleophilic cyclization of functionalized allenes: a powerful access to carbo-heterocycle, Krause et al., Chem Rev. 2011, 111. 7. Catalytic carbophilic activation: by platinum and gold p acids, Furstner and Davies, Angew. Chem. Int. Ed. 2007, 3410. 8. how easy are the synthesis of allenes?, Ma et al., Chem. Commun. 2011, 5384