Reduction of Carbonyls and others

1. Reduction of Carbonyls and others Hydrogenation (???) leaching: problem or activation 1) Catalytic hydrogenation : heterogeneous JACS, 2001, 123, 10139 -- Pd > Rh > Pt > Ni > Ru -- • Rxn depends on the surface structure – case by case • reversible – double bond migration, dehydrogenation • reacts from the less hindered face • more substituted olefins, slower the reaction • alkynes react faster than olefins • most common ones : Pd/C, PtO2/C • selective reduction of alkyne to alkene : Lindlar Catalyst Pd(BaSO4)/C Cis major

2. Specially prepared catalyst!!! Strategy & Tactics Vol.I, p155 Endiandric acid A

3. Hydrogenation 2) Catalytic hydrogenation : homogeneous – reliable, selectivity a. Wilkinson’s catalyst : (Ph3P)3RhCl No olefin isomerization b. [R3PIr(COD)py]PF4 [Rh(NBD)dppp]PF4 Stereoselective reduction through –OH coord. c. Enantioselective reduction

4. Hydrogenation 3) hydrogenolysis Benzylamines and allyl ehters react the same way • polar solvents are better for hydrogenolysis • Pd(OH)2 is the best for hydrogenolysis 4) Other reducible functionalities To amine alkane aldehyde

5. Diimide Reduction Reduces olefins only low reactivity – selective reduction : more substituted less reactive Through Generation of diimide JACS, 2005, 127, 14544

6. Reduction of carbonyls : Hydride reduction Primary hydride sources : LiAlH4 -- strong, very reactive NaBH4 -- mild, less reactive AlH3 -- true hydride source i) LiAlH4 • Solvent : THF or Ether • Can reduce 4 eq. of carbonyls faster slower • Reactivity : LiAlH4 > LiAl(OR)H3 > LiAl(OR)2H2 > LiAl(OR)3H Increase solubility -- better temp. control More selective reagent

7. i) LiAlH4 • Reactivity : LiAlH4 > NaAlH4 > KAlH4 less lewis acidic!! reagents NaAlH4 : less reactive but reduces most carbonyls NaAlH4 (OC2H4OMe)2H2 : Red-Al – strong reducing agent recdues epoxides, halides, sulfonates Biggest due to aggregation LiAlH(OMe)3 LiAlH(OEt)3 LiAlH(Ot-Bu)3 Selective due to the size

8. ii) NaBH4 Mild reducing agent, slowly reacts with protic solvent Solvent : MeOH, EtOH , rxn. very slow in other solvents reagents LiBH4 : more reactive, non-protic solvent O.K. Me4NBH4 : no reactivity alone, can use non-polar solvent ZnBH4 : strongly coordinating, stereoselective reduction NaBH4 -CeCl3: 1,2-reduction, enolizable carbonyls -- Luche reduction reactive and selective LiBHEt3 -- Super hydride : strongest reducing agent, reduces most functionalities

9. ii) NaBH4 reagents NaBCNH3 : much less reactive, even stable in aqueous soln. only used in reductive amination NaBH4 -AcOH: reduces aldehydes or b-hydroxyketones reductive amination real reagents : NaBH(OAc)3, Me4NBH(OAc)3

10. iii) AlH3 preparation : LiAlH4 + AlCl3 very lewis acidic reduces ketals DIBAL-H very reactive true hydridie source – does not reduce halides could form stable intermediates

11. iv) BH3 exists as dimer(BH3 )2, BH3 .THF BH3 .SMe 2 better knonwn for hydroboration of olefins needs Lewis acid to reduce carbonyls – selective reduction v) “CuH” DIBAL- CuX, LAH- CuX not a real “CuH” limited applicability [Ph3PCuH]6 true “CuH” TL, 39, 9229 (1998) Easy preparation :TL, 46, 2037 (2005)

12. vi) Hydride transfer reaction Meervwein-Pondorff-Verley reduction JACS, 115, 5821 (1993)

13. vii) Dissolving Metal reduction works through electron transfer Metals : Li, Na, K, Ca, etc Too reactive Less reactive reduces : carbonyls, conjugate carbonyls, aromatic reings

14. vii) Dissolving Metal reduction Birch Reduction substitution effect Alkynes

15. Stereoselective Reduction of Carbonyls 1. Diasteroselective reduction • Conformational effect • Chelation effect 2. enantioselective reduction • Conformational effect of transition state • Chiral ligands on hydride sources

25. JACS, 1986, 108, 1598

35. Electronic effect. TL, 1995, 36, 9155

38. Homework Chapter 5 : 1, 2, 4, 9, 11, 13, 15 Due :