Pericyclic Reactions 6 Lectures Year 3 Handout 2 Michaelmas 2017

Transcription

1 Pericyclic eactions 6 Lectures Year 3 andout 2 Michaelmas 27 π6 a σ2 s Prof Martin Smith CL 3.87 martin.smith@chem.ox.ac.uk

2 Cycloadditions: oxyallyl cation P46 ω s σ2 s odd disrotatory LUM ω M sigma disrotatory π4 s π2 s odd M diene LUM allyl cation

3 Cycloadditions: allyl cation & allyl anion P47 Allyl cation-diene AgBF 4 π4 s π 2 s Br Allyl anion-alkene and reverse process LDA,%45% C π2 s odd LUM alkene M allyl anion π4 s

4 Cycloadditions: allyl cation & allyl anion P48 Allyl anion-alkene (reverse process) BuLi + C 2 ω2 s 3 M ω σ2 s ψ 3 3 odd LUM butadiene LUM σ +σ σ2 s It can be easier to analyse the reverse reaction. M carboxylate LUM alkene

5 ,3-dipolar cycloadditions P49 sp 2 -hybridized central atom X Y Z π4 s π 2 s X Y Z X Y Z X Y Z,3-dipole azomethine ylid azomethine imine carbonyl oxide carbonyl ylid nitrone ozone sp-hybridized central atom Y X Z π4 s π 2 s X Y Z X Y Z X Y Z,3-dipole nitrile ylids nitrile oxides diazoalkanes nitrile imines alkyl azides nitrous oxide

6 ,3-dipolar cycloadditions: ozonolysis P5 ω2 s σ 2 s σ 2 s π2 s M alkene M carbonyl LUM carbonyl C C π4 s LUM ozone LUM carbonyl ylid M carbonyl ylid odd ψ 2 M allyl anion

7 ,3-dipolar cycloadditions: azomethine ylids P5 Et 2 C C 2 Et C 2 Et C 2 Et C 2 Et C 2 Et [ π 2 s π 4 s ] Et 2 C C 2 Et Et 2 C ω2 a C 2 Et Et 2 C M ω C 2 Et ψ 3 σ2 s odd conrotatory LUM σ conrotatory ψ 2 ψ

8 itrone cycloadditions in synthesis P52 itrones are readily formed between aldehydes and substituted hydroxylamines + ' ' ' ' istrionicotoxin 2 C C C C C C istrionicotoxin; J. Am. Chem. Soc. 26, 28, C C C C heat 8 C C C

9 Azomethine ylids in synthesis P53 Total synthesis of ominine (J. Am. Chem. Soc. 26, 28, 8734). X C C C C C C C 3.6 C

10 Azomethine ylids in synthesis II P54 C i)#ab 4 ii)#s 2 C i)#bu 3 Sn,# AIB C i)#dibal ii)# 3 P=C 2 +,$ 2 a,$ 3, $ipr,"

11 Cheletropic reactions P55 A sub-class of cycloaddition/cycloreversion reactions in which the two σ bonds are made or broken to the same atom (compare with ketenes as vinyl cations) + C odd ω s π2 a Addition of singlet carbenes (stereospecific) is most important: side on approach necessary: M carbene LUM carbene ω a ω2 s π2 s 2 3 odd LUM alkene M alkene

12 Cheletropic reactions: sulfur dioxide and polyenes P56 S heat and pressure S S 2 S 2 heat and pressure ω2 s (4q + 2) S s = π4 s odd The addition of sulfur dioxide to polyenes is a reversible process S S S M S 2 S LUM S 2 S M lone pair LUM diene M diene LUM

13 Cheletropic reactions: sulfur dioxide and polyenes P57 With trienes the extrusion process dominates but considering the reverse process, the reaction must be antarafacial with respect to the triene component. S 2 heat %&S 2 S 2 heat %&S 2 π6 a S S LUM triene M triene S ω2 s odd S LUM M lone pair S M S 2 S LUM S 2 S too strained; ca. 4 times less reactive than S 2

14 Cheletropic reactions: sulfur dioxide and polyenes P58 The cheletropic extrusion of S 2 is often used in synthesis to unmask a diene, as a prelude to a Diels-Alder or other cycloaddition Application in the synthesis of a steroid core S 2 exo Application in the synthesis of columbiasin endo S 2

15 Electrocyclic reactions P59 Thermal electrocyclic processes will be conrotatory if the total number of electrons is 4n and disrotatory if the total number of electrons is (4n +2). This is reversed for photochemical reactions. 4 C, 5 h 4 C, 5 h π6 s π6 s odd disrotatory odd disrotatory X π2 a σ2 s odd conrotatory Symmetry but geometrically constrained Does not occur

16 Electrocyclic reactions P6 hν SM diene LUM σ conrotatory π4 s σ2 a even conrotatory Cyclopropyl cation / allyl cation interconversion ψ 3 ψ 2 ψ σ2 s ω s odd disrotatory Lewis acid, low temperature

17 Electrocyclic reactions P6 The ionisation of cyclopropyl halides and tosylates is a concerted process to give allyl cations (i.e. discrete cyclopropyl cations are not formed). The reaction can be viewed as an internal substitution in which the electrons in a σ-bond (M) feed into the C-X σ* (LUM). The reaction is disrotatory and the sense of rotation (torquoselectivity) is specified this dictates the geometry of the allyl cation and can have a large influence on reaction rate. M σ disrotatory disrotatory LUM σ disrotatory Influence on rates solvolysis in acetic acid Ts Ts Ts Ts Ts Ts

18 Electrocyclic reactions: azarov cyclization P62 3 Si Fe 3 3 Si Fe 3 3 Si Fe 3 4π electrocyclic ring closure relative configuration set by pericyclic reaction π4 a odd conrotatory M allyl cation LUM alkene conrotatory The analogous anionic pentadienyl anion cyclization is also electrocyclic Li 6π electrocyclic ring closure π6 s odd disrotatory

19 Pericyclic reactions & natural products: the endiandric acids P63 C 2 C 2 C 2 C 2 endiandric acid A methyl ester endiandric acid B methyl ester endiandric acid C methyl ester endiandric acid D methyl ester Diels Alder Diels Alder Diels Alder 6π electrocyclic endiandric acid E methyl ester C 2 6π electrocyclic endiandric acid F methyl ester C 2 6π electrocyclic endiandric acid G methyl ester C 2 C 2 8π electrocyclic C 2 8π electrocyclic C 2 C 2 C 2 Biosynthesis: Black J. Chem. Soc., Chem. Commun. 98, 92. Synthesis: icolaou, J. Am. Chem. Soc. 982, 4, 5558.

20 Pericyclic reactions & natural products: the endiandric acids P64 2 Lindlar π8 a C 2 C 2 C 2 heat C C 2 exo-diels Alder reaction C 2 endiandric acid E methyl ester C 2 C 2 ' π6 s 6π electrocyclic disrotatory C 2 6π electrocyclic disrotatory 8π electrocyclic conrotatory C 2 ' π6 s endiandric acid A methyl ester endiandric acid D methyl ester

21 Pericyclic reactions & natural products: the endiandric acids P65 2 Lindlar π8 a endiandric acid F methyl ester heat, C endiandric acid B methyl ester exo-diels Alder reaction C 2 C 2 C 2 endiandric acid C methyl ester C 2 endo-diels Alder reaction C 2 6π electrocyclic disrotatory ' π6 s endiandric acid G methyl ester 6π electrocyclic disrotatory C 2 C 2 C 2 8π electrocyclic conrotatory ' π6 s

22 Sigmatropic rearrangements P66 Synthetically the most important sigmatropic rearrangements are the Cope and aisen rearrangements and variants thereof. The aisen/cope rearrangements can proceed via chair-like or boat-like transition states the chairlike transition state is strongly favoured unless there are steric constraints that force a boat-like transition state. Where possible, substituents generally adopt equatorial sites in the chair-like transition state. [3,3]-sigmatropic rearrangement ' =, tautomerism ' [3,3]-sigmatropic rearrangement tautomerism ' '

23 aisen rearrangements P67 heat + major minor π2 s σ2 s π2 s 3 3 odd diequatorial trans, trans - major diaxial cis, cis - minor heat cis, trans

24 aisen and Cope variants P68 Johnson-aisen rearrangement - synthesis of γ,δ-unsaturated esters. Et Et Et cat. heat Et Et Et Et Eschenmoser-aisen rearrangement Carroll rearrangement then%heat Ireland-aisen rearrangement LDA then 3 Si Si 3 [3,3] Si 3 3 +

25 Cope and xy-cope rearrangement P69 Cope rearrangement: high temperatures usually required (>2 C) Bullvalene - valence isomers interconvert by degenerate Cope rearrangements. heat c d c b a b b a a a a b a c b c c d The anionic oxy-cope can be conducted at low temperature ( C). k k 2 K oxy-cope k 2 /k 7 anionic oxy-cope A useful method for the synthesis of cis-decalins

26 ,n-hydride shifts P7 A suprafacial,n-hydride shift involves the hydrogen moving from one end of the conjugated system to the other across one face of the conjugated system [, 5] An antarafacial,n-hydride shift involves the hydrogen moving from one end of the conjugated system to the other and moving from one face of the conjugated system to the opposite face [, 7] σ2 s π4 s σ2 a π4 a π6 a odd odd σ2 s odd

27 ,n-hydride shifts P7,5-ydride shifts occur readily when the two ends of the diene are held close. C In acyclic systems,,5-hydride shifts can be much slower. tbu tbu T tbu D allylic strain T D T D T D Chiral acetic acid T D tbu T D tbu 2 C [,5] T D tbu disfavoured conformation

28 ,2-shifts P72,2-Shifts of alkyl groups can also be pericyclic. σ2 s ω s odd Allowed, concerted,2-shifts of carbanions are geometrically impossible. X σ2 s ω2 s 2 2 even forbidden,2-shifts of carbanions occur by a radical mechanism,2-wittig &,2-Stevens rearrangements BuLi X

29 ,3 &,4-shifts P73 Thermal [,3]-alkyl shifts occur with inversion of configuration in the migrating group. Ac,3-alkyl shift D D Ac Ac D Ac D odd π2 s Ac σ2 a D Thermal,3-shift of hydrogen is only geometrically reasonable in a suprafacial (thermally dis). antarafacial shift but geometrically unreasonable σ2 s 2 π2 s 3 2 even forbidden M σ LUM π In the following [,4]-shift, migration occurs with inversion of configuration with D always on the concave face of the bicyclic structure. 2 D 3 4 D odd D D π2 s σ2 a

30 ,n-shifts P74,5-Alkyl shift with retention of configuration in the migrating group. heat [,5] [,5] odd π4 s σ2 s [2,3]-Wittig rearrangement most likely proceeds via an envelope transition state; large groups at the allylic position will tend to occupy a pseudo-equatorial position. Ar Ar BuLi Ar [2,3] Ar σ2 s ω2 s π2 s 3 3 odd Sommelet-auser rearrangement. [2,3] 2 2 tautomerism

31 2,3-rearrangements P75 isenheimer earrangement. earrangement of allyl sulfoxides, sulfinimines and sulfonium ylids. [2,3] 2 X S [2,3] X S X =, Ts, C 2 A [9,9]-sigmatropic shift [9,9] 2 2 odd π8 s σ2 s 2 2 π8 s

32 Group transfer reactions P76 Group transfer appear to be a mix of a sigmatropic rearrangement and a cycloaddition. They are bimolecular and so are not sigmatropic rearrangements, and no ring is formed so they are not cycloadditions. 23 C Al 3 σ2 s π2 s π2 s 3 3 odd LUM π M σ + π Conia-ene reaction. 35$ C ene C 3 tautomerise

33 Group transfer reactions P77 Carbonyl-ene reaction - frequently catalysed by Lewis acids. C 2 C 2 8 C, 48 h Sn 4, C Thermal carbonyl ene reaction: sterics are important C 2 C 2 2 C C In the Lewis acid-catalysed reaction significant positive charge develops in the eneophile. C 2 C 2 C 2 C 2 Sn 4 C 2 C 2 2 C C2 etro-ene and retro group transfer reactions are common. S S heat retro-ene + S S X heat + X retro group transfer: X = S, Se, or (Cope elimination)

34 Summary of pericyclic reactions P78 Four classes: Cycloadditions (chelotropic reactions); Electrocyclic reactions; Sigmatropic rearrangements; Group transfer. A ground state pericyclic reaction is symmetry when the total number of (4q + 2) s and (4r) a components is odd (q and r must be integers). A pericyclic change in the first electronically excited state (i.e. a photochemical reaction) is symmetry when the total number of (4q + 2) s and (4r) a components is even. For thermal cycloadditions and group transfers:. If the total number of electrons is (4n + 2), both components can be used in a suprafacial manner. 2. If the total number of electrons is (4n), one of the components is suprafacial and the other antarafacial. For electrocyclic reactions: 3. Thermal electrocyclic processes will be conrotatory if the total number of electrons is 4n and disrotatory if the total number of electrons is (4n +2).