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Intramolecular Cyclopropanations.Pptx Nicholas Tappin Topic Review Renaud Group January 28th 2016 Universität Bern Intramolecular Cyclopropanaons Me CO2Me O cat. Cu(TBSA)2 CO Me O O 2 O H DCM, 70 °C, 8 h H N2 60% Cl Cl Me LiCl, CSA O NC DMF, 140 °C O H 71% NH (–)-hapalindole G Example of u1lity of intramolecular cyclopropan1ons: Fukuyama, T.; Chen, X. J. Am. Chem. Soc. 1994, 116, 3125–3126. 1 A quick note on bonding “RinG strain confers excep1onal reac1vity to the cyclopropane ring.” Chimia, 2009, 63, 162-167. And many publicaons from a synthe1c orGanic chemists concerninG the synthesis and reac1vity of cyclopropanes has a similar phrase! 2 How do you explain the following observation? OR E E ROH E R R R no ring strain Markovnikov E E depending on ring strain: substitution 27.5 kcal mol−1 R R pattern E ring strain: no reaction 26.5 kcal mol−1 R c.f. C–C bond dissociation energy is ∼83-85 kcal mol−1 RinG strain miGht provide a stronG thermodynamic drivinG force for reac1on but is doesn’t explain the reacvity. A suitable answer must therefore invoke bondinG. 3 Problem: tightest angle between any AOs is 90° (e.g. orthogonal p-orbitals) but in cyclopropane we have to accomodate a bond angle of 60° Pauling τ-bond treatment Hückel σ/π-bond treatment Ψ(E',a) Ψ(E',b) Ψ(A2') Ψ(E',c) Ψ(E',d) Ψ(A1') 22° and ~20% less effective overlap Coulson-Moffit orbitals: Walsh orbitals: 2 sp3-hybridized C AOs orbitals sp -hybridized C AOs N.B.: This model is generally accepted (as is Hückel's approach to bonding) but it is likely wrong as it may not represent the ground state: Specifically, relative energies of Ψ(A2') with Ψ(E',a) and Ψ(E',b) are switched when valence AOs are used as the basis set instead of methylene and choosing methylene as basis set removes C–H bonds from MO picture See [Wiberg, K. B. Acc. Chem. Res. 1996, 29, 229–234] and [reference 17 therein]. Walsh orbitals work in other cases outside of cyclopropane. "the overall distribu1on of electrons [...] is exactly the same" [in the two models]. – Ian FleminG At least theore1cally and mathemacally, and assuminG that the basis sets are valid (interconver1ble). An excellent resource for Walsh’s theory using methylene as basis set: http://www.bluffton.edu/~bergerd/chem/walsh/derive.html, and references therein for the full story. 4 Banana Bond X-ray diffraction of cis-1,2,3-tricyanocyclopropane: Hartman, A.; Hirshfeld, F. L. Acta Crystallographica 1966, 20 (1), 80–82. 5 Classifications in a Venn diagram Cyclopropanations Intramolecular Intermolecular Cyclopropanations Cyclopropanations S P S I P all C atoms in product come from substrate: 'substrate-based' cyclopropanation S1 + S2 I P S + S P C atoms in product come from two educts 1 2 (but reaction occurs via an intermediate, i.e. C atoms in product overall still intermolecular cyclopropanation come from two educts even if the cyclopropanation step is itself mechanistically intramolecular) 6 Classifications in a Venn diagram Cyclopropanations Intermolecular Intramolecular Cyclopropanations Cyclopropanations S P S I P all C atoms in product come from substrate: 'substrate-based' cyclopropanation S1 + S2 P1 P2 S1 + S2 I P S + S P C atoms in product come from two educts 1 2 (but reaction occurs via an intermediate, i.e. C atoms in product overall still intermolecular cyclopropanation come from two educts even if the cyclopropanation step is itself mechanistically intramolecular) 7 Examples from free carbene chemistry Intermolecular cyclopropanation example (no intermediate) S1 + S2 P Br Br BrBr Me t-BuOK Br Br + Me + Me CHBr3 Me singlet carbene Me Me Me 70% yield <1% trans Me 8 Examples from free carbene chemistry Intermolecular cyclopropanation example (via an intermediate) S + S I P 1 2 65% cis 35% trans N2 Me Me Me Me hν Me + Me + triplet carbene hν Me Me Me Me spin-flip spin-flip slow slow Me Me rds Me Me bond rotation fast triplet diradical intermediate 9 Examples from free carbene chemistry Intramolecular cyclopropanation example S P or S I P Li H H n-BuLi -elimination t-BuOK α CH C—H insertion RO RO Cl RO RO Cl Me Me Me Me Me Me H H H 10 Ambiguous examples from free carbene chemistry and another, unambiguous (?), example S1 + S2 I P O NMe4 1) t-BuCOCl (CO) Cr 5 (CO) Cr Ph 2) (CO)4Cr O 4 O O Ph Ph Ph OH unstable – CO for homoallylic alcohols S1 + S2 P1 P2 COCl O Ph Ph Bn O NMe Bn O H O H 4 O (CO) Cr O O Cr(CO) 5 Bn Cr(CO)4 Bn 4 H Ph DCM, –10 °C to r.t., 2 h, – CO partially stable Ph at –10 °C Intramolecular cyclopropanation example via an isolable first product arrived at from an intermolecular process S1 + S2 P1 P2 Cl R ATRA Cl Cl 1,3-dechlorination R Ph + Cl Ph R Ph 11 Intramolecular cyclopropanation: 1,3-cyclization cyclopropane cyclization occurs with formation of 1 C—C σ-bond elimination products X Y – MX and MY or zwitterionic break 2 R – XY synthon σ-bonds R break 1 π-bond and 1 σ-bond X Y X Y R or or – MY R R R diradical break 2 synthon π-bonds X Y X Y or none R R Kulinkovich, O. G. Cyclopropanes in organic synthesis. (Hoboken, New Jersey: Wiley, 2015), 57-58. 12 Intramolecular cyclopropanation: [2+1] and insertion reactions cyclopropane cyclization occurs with formation of 2 C—C σ-bonds (except insertion reactions) carbene CH HC CH 2 addn H carbene Chemoselectivity CH2 C—H insern issuses (e.g. solvent) H2C CH2 carbene c.f. cyclobutane H C CH 2 CH 3 C—C insern chemistry, 2 other types difficult 1,1-carbodianion and CH2 HC CH2 1,2-carbodication Mostly intermolecular 1,1-carbodication CH HC CH and 2 2 1,2-carbodianion or involving recombination of respective radical-ion species Kulinkovich, O. G. Cyclopropanes in organic synthesis. (Hoboken, New Jersey: Wiley, 2015), 65. 13 Cyclopropane formation from reactions to cyclopropene (without cyclopropane cyclization) cycloadditions additions E Nu will not be covered in this topic review For some informaon, however, on this topic see: Kulinkovich, O. G. Cyclopropanes in organic synthesis. (Hoboken, New Jersey: Wiley, 2015), 88-90. 14 1,3-cyclizations by breaking 2 σ-bonds cyclopropane cyclization occurs with formation of 1 C—C σ-bond elimination products X Y – MX and MY or zwitterionic break 2 R – XY synthon σ-bonds R break 1 π-bond and 1 σ-bond X Y X Y R or or – MY R R R diradical break 2 synthon π-bonds X Y X Y or none R R 15 1,3-dehalogenation: dissolving metal Br Na Often attributed as first Freund, A. J. Prakt. Chem., cyclopropane synthesis Br 1882, 26, 367–377. Br Br Unique p-character of 2 bonding in cyclopropanes Br H2O Cl Mg Cl2 Cl Cl 17% 34% Gragson, J. T.; Greenlee, K. W.; Derfer, J. M.; Boord, C. E. J. Am. Chem. Soc. 1953, 75, 3344–3347. Na/ NH3(l), t-BuOH Cl THF, 65 °C 43% multigram Salaun, J. R.; Champion, J.; Conia, J. M. Org. Synth. 1977, 57, 36. 16 1,3-dehalogenation: dissolving metal ruthenium-catalyzed Kharash ATRA/ 1,3-dehalogenation 1-pot sequence ATRA Cl X 1,3-halogenation X R R + III R' Ru R' R Mg R' Cl Mg RuII [Cp*RuCl (PPh )] 2 3 Cl Cl THF (1 mol%) CO2Et Cl CO2Et Ph + 0 C , 1 h neat, Mg, 60 °C, 6 h Ph CO2Et ° Ph 74% Cl d.r. = 1:3 Thommes, K.; Kiefer, G.; Scopelliti, R.; Severin, K. Angew. Chem. Int. Ed. 2009, 48, 8115–8119. [Cp*RuCl (PPh )] Br 2 3 Br Cl THF Ph Ph + (1 mol%) CF Cl CF3 neat, Mg, r.t., 2 h Ph CF3 –78 °C to r.t., 1 h 3 55% d.r. = 27:1 Br [Cp*RuCl (PPh )] 2 3 Br Cl THF n-oct n-oct + (2 mol%) Cl CF CF 3 neat, Mg, r.t., 15 h n-oct CF3 –78 °C to r.t., 1 h 3 46% d.r. = 1.1:1 Risse, J.; Fernández-Zúmel, M. A.; Cudré, Y. Org. Lett. 2012, 14, 3060–3063. 17 elimination of HX ONa O O H O/ H+ NaOH(aq), boiling 2 Cl work-up 77–83% ONa Cl O ONa E2 ONa Cl O O ONa Cannon, G. W.; Ellis, R. C.; Leal, J. R. Org. Synth. 1951, 31, 74. 18 Double Tsuji-Trost by palladium-catalyzed allylation and palladium-catalyzed cyclopropanation method A, CN AcO CN CO2Et Genet, J.-P.; Piau, F. J. Org. Chem. 1981, 46, 2414–2417. or CO Et H CO2Et + 2 method B H CN Method A: NaH only 0 °C then 65°C: d.r. = 1:1; Y = 75% Method B: NaH, 0 °C then Pd0 65°C : d.r. = 19:1; Y = 70% - Tsuji-Trost type mechanism for first allylation and then second, except when no palladium used. For origin of this discovery: Colobert, F.; Genet, J.- P. Tetrahedron Lett. 1985, 26, 2779–2782 and reference [6] therein. DBU (1.1eq) ArCOCl = CO2Me PhO2S CO2Me ArCOCl Cl Cl R' OAc SO2Ph OH then 2.5 mol% R' Cl Pd(dppe)2 OH O attack from above CO Me R' ∗ CO2Me NaH, 0 °C; R' CO Me T-T SN2' 2 2 R' ∗ SO Ar OCOAr SO2Ph 5–10 mol% SO2Ar 2 PdLn Pd(dppe)2 PdLn 19 ‘Regio-incorrect Tsuji-Trost’ leads to isolable palladocyclobutane L R MeO2C Pd L MeO C Cl MeO C 2 + Pd 2 2 isolated and characterized: R = H 70% Hoffmann, H.
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