Dr. Pere Romea Department of Organic Chemistry. Rouen Cathedral Claude Monet, Oxidations. Organic Synthesis.

Transcription

1 Dr. Pere omea Department of rganic hemistry ouen athedral laude Monet, xidations rganic Synthesis Autumn

2 xidations 1ary Alcohol Aldehyde + arboxylic Acid ary Alcohol Ketone Ester + Epoxide ,2-Diol Alcohol Alkene + 2 arbonyls Pere omea,

3 xidations 1ary Alcohol Aldehyde + arboxylic Acid ary Alcohol Ketone Ester r(vi) eagents DMS/E + Mixtures ther oxidizing agents 3 Pere omea, 2014

4 arbonyls from Alcohols r(vi) eagents r(vi) r r + r r(iv) r(vi) r r + r r(iv) r(iv) r r(iii) veroxidation is a problem Aqueous media facilitate the oxidation of the resultant aldehyde hromium wastes are harmful Pere omea,

5 arbonyls from Alcohols r3/3 + : Jones reagent Aqueous media facilitate the oxidation of the resultant aldehyde 2 2 r3/2py: ollins reagent r Kinetics are rather slow and high loadings are usually required 2 2 These reagents are hygroscopic and can easily catch fire and burn during their preparation, so other commercially available reagents are usually employed Pere omea,

6 arbonyls from Alcohols Bn TBS 2 Me Jones 10 to rt 90% Bn 2 2 Me 2 t-bu 1) Jones 2) 96% 2 r 3 2py 2 l 2 95% TBS 1) TBAF, TF 2) r 3 2py, 2 l 2 81% 6 Pere omea, 2014

7 arbonyls from Alcohols [py] + [r3l] : pyridinium chlorochromate, P r l More reactive than the ollins reagent Somehow Lewis acid character 2 2 2[py] + [r27] 2 : pyridinium dichromate, PD 2 [r 2 7 ] 2 DMF 2 l Pere omea, 2014

8 arbonyls from Alcohols Me 2 P 2 l 2 85% Me 2 l TIPS P 2 l 2, 4 Å MS, rt 100% l TIPS PD 2 l 2 92% TBS PD DMF 91% TBS 2 8 Pere omea, 2014

9 arbonyls from Alcohols DMS/Electrophile mixtures The activation of DMS with an electrophile gives an alkoxysulfonium salt This proceeds through a acid/base and an ene reaction Activated sulfoxide Alkoxysulfonium salt Me S Me E E Me S Me 2 Me S 3 2 Me S 2 Me 2 S 2 There is a variety of electrophiles: D, (l)2, py-s3,... 9 Pere omea, 2014

10 arbonyls from Alcohols Me S Me Me S Me E Me X S Me Electrophile Activated sulfoxide eaction name Moffat Me S Me l l Me l S Me Swern S 3 S Me S Me Parikh-Doering 10 Pere omea, 2014

11 arbonyls from Alcohols Moffatt: D, cat + Me S Me Me S Me 2 Me S 2 2 It was the first oom temperature 2 Me DMS, D TFA-py 2 Me + 2 Me Si-Pr 80% Si-Pr 9 : 1 Si-Pr TBDPS TBDPS DMS, D, + cat Me Me 2 l 2 80% 11

12 arbonyls from Alcohols Swern: (l)2, Et3, 78 l l Me S Me l Me S Me l 2, l Me S Me l l 2 Me S 3 2 Me S 2 Me 2 S 2 Very mild conditions Me TBS DMS, (l) 2, Et 3 2 l 2, 78 > 90% Me TBS Me TBS Me TBS TBS Me TIPS Me DMS, (l) 2, Et 3 2 l 2, 78 80% TBS Me TIPS Me TIPS 12 TIPS

13 arbonyls from Alcohols Parikh-Doering: S3. py, 3 Mechanism? Temperature: 0, rt Easy work-up Br DMS, S 3 py, Et 3 2 l 2, rt 99% Br TBS TBS DMS, S 3 py, i--pr 2 Et 2 l 2, 15 Bn : 94% 13 Pere omea, 2014

14 arbonyls from Alcohols Iodine(V) based reagents Ac Dess-Martin Periodinane: DMP Ac I Ac Ac Ac I Ac I (V) 2 Ac 2 I Ac Ac Ac Ac 2 I I (III) This is a very mild oxidant that can safely be used in structurally complex and sensitive substrates a3 or pyridine are often added to moderate the acidity of the reaction mixture The addition of one equivalent of water usually enhances the kinetics 14 Pere omea, 2014

15 arbonyls from Alcohols i-pr TBS I DMP 2 l 2 89% i-pr TBS I Ac Ac I Ac DMP TBS 3 Si t-bu 2 Si TES TES TES Me TES TBS DMP, py 2 l 2 93% 3 Si t-bu 2 Si TES TES TES Me TES 15 Pere omea, 2014

16 arbonyls from Alcohols Iodine(V) based reagents 2-Iodoxybenzoic acid: IBX Pros and cons: I For a review, Kirsch, S. F. AIE 2011, 50, 1524 There are safely concerns regarding the potentially violent decomposition upon impact or at high T Low solubility in typical organic solvents. A mixture of Ph2, Ph()2, and IBX (22/29/49) has been developed DMS is the choice or polymer-supported IBX ot susceptible to hydrolysis emarkable chemoselectivity: exceptionally mild oxidant for the highly selective transformation of primary and secondary alcohols into carbonyl compounds, and 1,2-diols into hydroxycarbonyls atalytic amounts of IBX can be used in the presence of stoichiometric amounts of ozone 16 Pere omea, 2014

17 arbonyls from Alcohols MM TIPS IBX 1:1 DMS/TF MM TIPS Pinnik x see later MM TIPS 23 89% overall yield TBS 1) TBAF 2) IBX, EtAc, reflux Ph Me 70% Ph Me 17 Pere omea, 2014

18 arbonyls from Alcohols uthenium based reagents Tetra-n-propylammonium perruthenate: TPAP u Pr 4 Used as catalyst in the presence of stoichiometric amounts of a second oxidant (M, 2) TBS TPAP, M 2 l 2, ta 97% TBS Me M TPAP (10 mol%), 2 2 l 2, 4 Å MS, ta 85% 18 Pere omea, 2014

19 arbonyls from Alcohols adicals as oxidizing agents 2,2,6,6-Tetramethylpiperidinyloxy: TEMP xidation xidation TEMP is a very mild and chemoselective oxidant: only 1ary and 2ary alcohols are affected 1ary Alcohols are oxidized more easily than 2ary Alcohols : chemo- & siteselective TEMP is used under catalytic premises in the 2 + B presence of stoichiometric amounts of another B oxidizing agent as l, PhI(Ac)2, or u(i)/2 The mechanism depends on this second reagent ther mechanisms have been proposed 19

20 arbonyls from Alcohols Boc TEMP (20 mol%), al (1 eq) abr (1 eq), a 3 (3 eq) EtAc/toluè/ 2, 0 90% Boc TEMP (10 mol%), PhI(Ac) 2 (2 eq) 2 l 2, rt 65% Ac i-pr Ac i-pr TEMP (10 mol%) PhI(Ac) 2 (1 eq) 2 l 2, rt 76% overall al 2, a 2 P 4 t-bu/ 2, rt 20

21 arbonyls from Alcohols adicals as oxidizing agents 2-Azaadamantane -oxyl radicals: AZAD Iwabuchi, Y. JAS 2006, 128, 8412 TEMP AZAD 1-Me-AZAD 1,3-Me2-AZAD Four Me groups flanking the nearby catalytic center in TEMP prevent bulky substrates forming the key intermediates AZAD family, a structurally less hindered class of nitroxyl radicals, may overcome this problem 5 mol% AZAD al 2, p 4.6 TMS 2 Me Structurally hindered alcohol 67% overall 2 Sodium chlorite acts as the stoichiometric oxidant and transforms the resulting aldehyde into a carboxylic acid. See next slide 2 Me 21

22 arboxylic Acids from arbonyls Pinnik oxidation: sodium chlorite, al2: + l l Sodium chlorite is a cheap, mild, and chemoselective oxidizing reagent: only aldehydes are affected 2-Methyl-2-butene is usually added to remove the resultant sodium hypochlorite al 2, a 2 P 4, 2-methyl-2-butene TBS t-bu, 2 80% TBS 2 TBS F 3 2 Me 1) al 2, a 2 P 4, 2-methyl-2-butene t-bu, 2 2) F 3 2, 2,6-lutidine 95% TBS 2 Me 22 Pere omea, 2014

23 arboxylic Acids from arbonyls Pinnik oxidation is often the second step of an oxidizing sequence leading from primary alcohols to carboxylic acids 1) TPA, M, 2 l 2 2 2) al 2, a 2 P 4, 2-methyl-2-butene Bu 3 Sn TF, t-bu, 2 55% Bu 3 Sn Me PG Me PG 1) DMP, py, 2 l 2 2) al 2, a 2 P 4, 2-methyl-2-butene t-bu, 2 3) % PG Me PG Me 2 Me 23 Pere omea, 2014

24 Esters from Ketones Baeyer-Villiger oxidation: Peracids, 3: () > tertiary > secondary > benzyl phenyl > vinyl > primary > Me Although steric factors can come in to play, the propensity to migrate is enhanced by EDG groups Migration of 2 proceeds with retention of the configuration The oxidation is catalyzed by acids Electronically poor peracids and electronrich ketones give faster oxidations Peracids react with olefines very easily 24 Pere omea, 2014

25 Esters from Ketones A variety of peracids can be used 3 3 Boc 2 Me 1) F 3 3, 2 l 2 Boc 2 Me 2) a 2 P 4, 2 85% 58% but mpba is the most common one Et TBDPS m-pba Ac Et TBDPS 1) Me, K 2 3 2) TESl, base, TMSl 74% overall TES TMS Et TBDPS 2 Me Me m-pba 2 l 2 95% Me 1) a 2) I 2, KI 3) Ac 2, py Ac Me I n-bu 3 Sn benzene,rt 99% Ac Me 25 Pere omea, 2014

26 xidations 1ary Alcohol Aldehyde + arboxylic Acid ary Alcohol Ketone Ester + Epoxide ,2-Diol Alcohol Alkene + 2 arbonyls Pere omea,

27 xidations Epoxidation of alkenes Dihydroxylation of alkenes ther oxidations + Epoxide ,2-Diol Alcohol Alkene + 2 arbonyls 2 Pere omea, 2014

28 Epoxidation of Alkenes With peracids The third oxygen of peracids has a remarkable electrophilic character and the carboxylate is a good leaving group Me F 3 u u + l mpba electrophilic oxygen good leaving group Since alkenes have a nucleophilic character (remember electrophilic additions to =), they react with peracids and an oxygen is transferred in a syn concerted step syn Addition Pere omea, 2014

29 Epoxidation of Alkenes This epoxidation is sensitive to electronic effects. It proceeds faster with electronically poor peracids (F33 > mpba > 33) and electronically rich alkenes Me Me Me Me Me Me > Me Me >> Me Me > Me Me 2 Me F l 2, Δ 2 Me 84% mpba l 3,rt 72% mpba l 3,rt 86% 4 Pere omea, 2014

30 Epoxidation of Alkenes This epoxidation is also sensitive to steric effects. The peracids generally approach from the less hindered side of the olefin mpba + : 20 min, rt 99 1 : Me 24 h, rt < 10 > 90 2 mpba benzene/dioxane, 24 h, rt 2 80% unless other functional groups near the olefin can direct the orientation of the incoming reagent 5 Pere omea, 2014

31 Epoxidation of Alkenes This happens in allylic and homoallylic alcohols: hydroxyl group can direct the approach of the peracids overcoming the steric hindrance of the system this hydrogen bond determines the stereochemical outcome of the epoxidation 2 3 t-bu t-bu t-bu Ac 3 : Ac 3 : t-bu Ac Ac mpba 2 l 2 78% 6 Pere omea, 2014

32 Epoxidation of Alkenes With peroxides and bases: / Is it possible to transfer any nucleophilic oxygen? + B + B Me Me Me TBP 2 2 nucleophilic oxygen The geometry of the alkene does not control de configuration of the resulting epoxide because it is a stepwise process Pere omea, 2014

33 Epoxidation of Alkenes 2 2, a 85% bz Me TBP, BnMe 3 TF, 20 95% bz Me 8 Pere omea, 2014

34 Epoxidation of Alkenes With peroxides in a neutral medium: dioxiranes Dioxiranes are three membered rings peroxides They can be prepared by oxidation with xone. They can be isolated in solution or prepared in situ xone 3 KS 5, KS 4, K 2 S a 3, DMD 3 F 3 TFD Shi The epoxidations are carried out under very mild conditions The reduced system is a carbonylic compound: acetone in the case of DMD! syn Addition Dioxiranes show an strong electrophilic character: electronrich alekenes are easily oxidized They are no compatible with amines or sulfur-derived compounds 9

35 Epoxidation of Alkenes SiMe 3 l DMD acetone, 2 l 2 40, 3 h 100% SiMe 3 DMD acetone, Δ, 57 h 100% l 2 Me DMD acetone 2 Me 100% 3 F 3 Pere omea, 2014 Ph xone, a 3 3 / 2, 0, 1.25 h 99% Ph 10

36 Epoxidation of Alkenes S S DMD 97% Shi, xone 3, 2, p 10.5, 0 SA, toluene, 0 31% overall Pere omea,

37 Epoxidation of Alkenes Enantioselective epoxidation of allylic alcohols: Sharpless epoxidation 2 3 TBP 5-10 mol% Ti(i-Pr) TBP 5-10 mol% Ti(i-Pr) MS, 2 l 2, 20 MS, 2 l 2, 20 2 Et 6-12 mol% 2 Et Et 2 Et mol% (2S,3S)-Diethyl Tartrate D-( )-DET (2,3) Diethyl Tartrate L-(+)-DET (2,3) Diethyl Tartrate L-(+)-DET 2 3 Pere omea, 2014 (2S,3S)-Diethyl Tartrate D-( )-DET 12

38 Epoxidation of Alkenes Unless disubstituted Z alkenes, any other alkene can be submitted to Sharpless AE ot appropriate 5 mol % TiL 4 (+)-DIPT 0 2 h 90% ee 65% Ph mol % TiL 4 (+)-DIPT 20 3 h Ph > 98% ee 89% mol % TiL 4 (+)-DET h 86% ee 74% Pr Pere omea, mol % TiL 4 (+)-DET h 95% ee 88% Pr 13

39 Epoxidation of Alkenes - The asymmetric induction imparted by the TBP, TiL4, tartrate system is pretty high + mpba TBP, Ti(i-Pr) 4 TBP, Ti(i-Pr) 4, ( )-DIPT TBP, Ti(i-Pr) 4, (+)-DIPT 1 : : : : 1 : Ph 2 Ti(i-Pr) 4 (+)-DIPT, TBP 2 l 2, 20 PhS, a t-bu/ 2, Δ SPh > 95% ee 92% 71% Ti(i-Pr) 4 ( )-DET, TBP, MS 2 l 2, 20 Pere omea, 2014 > 98% ee 92% 14

40 xidations Epoxidation of alkenes Dihydroxylation of alkenes ther oxidations + Epoxide ,2-Diol Alcohol Alkene + 2 arbonyls 15 Pere omea, 2014

41 Dihydroxylation of Alkenes syn Diols with s4 Stoichiometric version: recall Mn4 s s(viii) s ydrolysis s(vi) s syn Addition atalytic version: s4 is costly and toxic, so it is advantageous to use it as catalyst with a cooxidant (M) s s(viii) s s(vi) M 2 xidation s(viii) s syn Addition 16 Pere omea, 2014

42 Dihydroxylation of Alkenes - s4 is costly, toxic, and volatile! The only interesting way to use it is under catalytic premises s 4 cat, M t-bu, 2 syn Addition Ph Ph s 4 cat, M t-bu, 2 Ph Ph + Ph Ph acemic mixture Is it possible to obtain a diol stereoselectively? Substrate controlled dihydroxylation s 4 cat, M t-bu, 2 84% 17 Pere omea, 2014

43 Dihydroxylation of Alkenes Sharpless enantioselective dihydroxylation Asymmetric Sharpless dihydroxylation uses osmium(viii) complexes containing chiral tertiary amines as ligands Iron(III) acts as oxidant The mechanism is complex s L quiral s(viii) s L s L 2 2, 2 4 s 6 2 s(vi) + L + hiral tertiary amines 2 [Fe() 6 ] 4, 2 2 Fe(II) 2 [Fe() 6 ] 3, 2 Fe(III) Et Et Et Et Me Me Me Me (DQD)2-PAL 18 (DQ)2-PAL

44 Dihydroxylation of Alkenes ommercially available mixtures of oxidants are ligands are commonly used AD-mix-α : K 2 [ 4 s 6 ], (DQ) 2 -PAL, K 3 [Fe() 6 ], K 2 3 AD-mix-β : K 2 [ 4 s 6 ], (DQD) 2 -PAL, K 3 [Fe() 6 ], K 2 3 The most suitable alkenes for the Sharpless AD are ot appropriate ot appropriate AD-mix-β (DQD) 2 -PAL S L M Pere omea, 2014 AD-mix-α (DQ) 2 -PAL 19

45 Dihydroxylation of Alkenes AD-mix-a AD-mix-b (DQ)2-PAL (DQD)2-PAL ee % ee % (S) 84 () Ph 97 (S) 97 () Ph 93 (S) 94 () Bu Bu 93 (S) 97 () Bu 95 (S) 98 () Ar 2 Et AD-mix-β t-bu, 2 98% ee 89% Ar 2 Et AD-mix-α t-bu, 2 99% ee 72% Ar 2 Et 20 Pere omea, 2014

46 Dihydroxylation of Alkenes AD-mix-β 93% ee 78% Et AD-mix-β 92% ee 78% Et Et AD-mix-β 95% ee 93% Et AD-mix-β 98% ee 70% Me anti Me s 4 M AD mix α AD mix β (1.9 : 1) 88% (54 : 1) 86% (1 : 35) 86% Pere omea, 2014 sin Me 21

47 xidations Epoxidation of alkenes Dihydroxylation of alkenes ther oxidations + Epoxide ,2-Diol Alcohol Alkene + 2 arbonyls Pere omea, 2014

48 arbonyls from Alkenes zonolysis 3 1,3-dipolar cycloaddition ED red molozonide This is a mild, reliable, and minimal side products or waste producing process XID ED: ab4, Zn/Ac. red: Me2S, Ph3P. XID: 22 TBS Me 1) 3, Me/ 2 l 2, 78 TBS Me 2) Me 2 S, then ab 4 TMS Ph 92% 1) 3, Me/ 2 l 2, 78 Me 2) Me 2 S, 78 to rt Me 92% 23

49 arbonyls from Alkenes Wacker Process Pdl 2 cat, u (II) cat 2, 2, l Methyl Ketone This Wacker process involves a series of redox steps with oxygen serving as the terminal oxidant 2 u(ii) u(i) Pd(II)L 4 riginally developed by Wacker hemie in the 50s and 60s Pd(0)L n Pd(II)L 3 L 2 Pd(II)L 3 Pd(II)L 2 Pd(II)L 3 β-ydride elimination 24

50 arbonyls from Alkenes 10 mol% Pdl 2, u(ac) 2, 2 7:1 AcMe 2 / 2 84% Smith, A. B, III. JAS 1999, 121, Me 2 Me 25 mol% Pdl 2, ul, 2 10:1 DMF/ 2, rt 79% Li, A. JAS 2012, 134, 920 ccasionally, highly regioselective Wacker oxidations of internal alkenes are possible... SPh SPh PMB TBS 15 mol% Pdl 2, ul, 2 DMF, 2 40% PMB TBS Forsyth,. J. L 2013, 15, 1178 For an interesting analysis, see: Grubbs,.. AIE 2014, 53,

51 xidation of Diols xidative cleavage with ai4 I I I PMB 8 15 ai 4, a Et, rt PMB % When using with s4, alkenes can be transformed into carbonyls PMB TBS s 4, ai 4, 2,6-lutidine Dioxane/ 2, rt 90% PMB TBS TE: u2/ai4 pair works in a similar manner 26

52 Allylic xidation xidation of allylic and benzylic alcohols with Mn2 A heterogeneous mixture of Mn2 under neutral conditions can selectively oxidize allylic, benzylic, and other activated alcohols to the corresponding aldehydes or ketones Bu 3 Sn Mn 2 Bu 3 Sn 2 l 2 89% Mn 2, acetone 75% Me Mn 2 Me Me acetone, rt Me Pere omea, % 27

53 Allylic xidation xidation of allylic positions with Se2 Allylic positions can be oxidized with stoichiometric Se2 or cat Se2/TBP Se Se Se Ene reaction [2,3]-Sigmatropic ydrolysis The oxidation usually affects the most substituted part of the double bond eactivity ranking: 2 > 3 > isk: overoxidations Se 2, TBP + Aldehyde (5%) 2 l 2 2 Me 50% 2 Me Se 2, TBP Pere omea, 2014 dioxane, rt 95% 28

54 α-xidation of Ketones xidation with mpba: ubottom oxidation 2 Si 3 2 mpba Si 3 2 Si Si 3 TES mpba, a 3 EtAc 70% xidation with Pd(II): Saegusa process SiMe 3 Pd(II) SiMe 3 Pd II PdII Pd II PMB PMB TMS Pere omea, 2014 TIPS 5 mol% Pd(dba) 2. l 3, diallyl carbonate 3 TIPS 90% 29