Hai Dao Baran Group Meeting Allenes 11/03/2012 Part 1. Introduction A brief history 1828: Synthesis of urea = the starting point of modern organic chemistry. 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. alkyne 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. alkene: 1680 cm-1, alkyne 2200 cm-1) δ− 1H NMR:δ = 4.9-4.4 ppm 13 R = alkyl, alkenyl, aryl, alkynyl C NMR: δCα, Cγ = 120-73 ppm; δCβ = 220-200 ppm. EWG = CO2R,CN, SO2R... The most simple allene vs. ethylene 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 alkynes. 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 pentane [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 . carbonylation 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 alkenes (eg: Diels-Alder reaction, coupling) Cl 1. nBuLi - allenes as enones, unsaturated esters...(eg. 1,4-addition inEWG substituted 1. nBuLi allenes) C6H13 THF Et O:Hexane 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-halogen 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 palladium catalyzed hydrogenation (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 carbene 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 toluene, 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 .