Chapter 6 Cycloadditions and Rearrangements 1. Diels-Alder Reactions 2. [2 + 2] Cycloadditions 3. 1,3-Dipolar Additions 4. Cheletropic Reactions 5.

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1 Chapter 6 Cycloadditions and earrangements 1. Diels-Alder eactions 2. [2 2] Cycloadditions 3. 1,3-Dipolar Additions 4. Cheletropic eactions 5. Sigmatropic earrangements 1

2 Diels Alder eactions s-cis 6e-intermediate 4π 2π 2π 4σ 1. eversible reactions: enthalpy decrease and entropy decrease 2. Concerted reactions: stereospecific FM interactions diene C C C C dienophile C C M ϕ 4 ϕ 3 ϕ 2 ϕ 1 LUM M LUM M ϕ 2 ϕ 1 supra LUM supra 2

3 Diels Alder eactions Dienes for Diels Alder eactions eactivity toward maleic anhydride: Me > > > > > Cl 1, s-trans not substrate s-trans not substrate 3

4 Diels Alder eactions Alkenes (Dienophiles) for Diels Alder eactions eactivity toward cyclopentadiene: S C Cl > > C 3 > Me = 6, C C C C C C > > > C C C C 4

5 Diels Alder eactions Alkenes (Dienophiles) for Diels Alder eactions eactivity toward cyclopentadiene: S C Cl > > C 3 > Me = 6, C C C C > > > C C C C C C eactive dienophiles Increased reactivity by electron-withdrawing group, and by releasing ring strains after Diels-Alder reactions 5

6 Diels Alder eactions egioselectivity: ortho and para C C ortho C C not meta C C C 2 Me para C 2 Me not meta C 2 Me 6

7 Diels Alder eactions Stereoselectivity: endo vs. exo 25 o C 100 o C endo exo kinetic thermodynamic Y Y Y Y electronic effect (secondary interactions) less steric effect 7

8 Diels Alder eactions Pyrones: Forward and etro Processes Me 2 C Diels-Alder rx. Me Me Me 2 C Me Me C 2 Me Me Me 2 C etro-diels-alder rx. 8

9 Diels Alder eactions egio- and Stereoselectivity Bn Me 110 o C syn Me Bn Me C endo selectivity 9

10 Diels Alder eactions Lewis Acid Catalysis: Enhanced Selectivity C 3, 120 o C, 25 o C, SnCl 4 para 71% 93% meta 29% 7% C 2 C 2 endo 0 o C, no catalyst 84 : 0 o C, AlCl 3 93 : exo 16 7 C 2 10

11 Diels Alder eactions Lewis Acid Catalysis B(Ac) 3 Me Me Me π-π stacking determines conformation B(Ac) 3 Me B chelation determines regioselectivity Me endo (97% de) 11

12 Diels Alder eactions Lewis Acid Catalysis -15 o C Cl Ti Cl 0 o C endo 90% (92%ee) exo 10% 12

13 Diels Alder eactions Acetylene Equivalents Cl Cl Cl Cl Cl Cl S 100 o C Cl Cl Cl Cl Cl Cl S Cl Cl Cl Cl Cl Cl S 2 S 2 S 2 S 2 a/g Me 13

14 Diels Alder eactions Danishefsky Diene Me Me 2 C Me C 2 Me C 2 Me Me 3 Si C 2 Me 3 Si Me 3 Si Me Me 2 C Me 3 Si Me C 2 Me C 2 Me 14

15 Diels Alder eactions Danishefsky Diene TMS t Bu ()-Eu(hfc) 3, 10 o C C 3 F 7 Eu 3 TMS t Bu TFA 58% ee hfc = 3-(heptafluoropropylhydroxymethylene)-()-camphorato 15

16 Diels Alder eactions etero Alkenes and Dienes TMS Me C 2 Me Me I 25 o C TMS I a Me Me 2 Me Me Me Bn Bn 250 o C, 10 h 13% 25 o C, 3 h, AlCl 3 63% Stepwise or concerted process? TBS TBS 92% TBS 16

17 Diels Alder eactions rtho Quinodimethane Equivalents Br Br Zn-Ag 74% heat 17

18 Diels Alder eactions Inter- vs. Intramolecular eactions Intermolecular reaction Me 2 C Me 2 C cis C 2 Me endo-selectivity Intramolecular reaction Me 2 C 180 o C C 2 Me trans C 2 Me E cis trans C 2 Me steric effect cis 18

19 Diels Alder eactions Intramolecular eactions Me 2 C 180 o C C 2 Me trans C 2 Me trans C 2 Me cis Me 2 C C 2 Me 150 o C trans 19

20 Vollhardt Annulation and Intramolecular Diel-Alder eaction 3 C C CpCo(C) 2 SiMe 3 CpCo(C) 2 Me 3 Si SiMe 3 Me 3 Si Me 3 Si Me 3 Si Me 3 Si Me 3 Si 20

21 [2 2] Cycloadditions: Thermal Process Ketenes [2 2] C C =, Me C C [2 2] = = Me 21

22 [2 2] Cycloadditions: Thermal Process Ketene and Analogs [2 2] C C 2 5 C C 2 5 [4 2] not observed C 2 5 Et Cl Et 3 Et C Et 22

23 Diels Alder eactions Ketene Equivalents Me Me Cl C 2 Me, 2 Me Cl C Me 25 o C TiCl 3, 4 Ac Me 2 Me Ar S Me S Ar Ac 2 Me SAr Ac Me 23

24 [2 2] Cycloadditions: Thermal Process Ketene Equivalents CF 3 S 3 (CF 3 S 2 ) 2 40 o C C keteniminium salt 2 88% yield 98% ee 24

25 otochemical eactions 1. Jablonksy diagram: absorption of light with suitable wavelength E = hν = (kcal/mol) λ (nm) 400-nm light is equivalent to 71.5 kcal/mol 2. Mercury vapor lamp (medium pressure): applied in immersion well 313 nm (50%), 365 nm (100%), 405 nm (42%), 436 nm (78%) Multilamp reactor (ayonet): 250 nm, 300 nm, 360 nm. 3. Light transimission of glasses: Quartz: 240 nm (90%), < 200 nm (50%) Pyrex: 360 nm (90%), 300 nm (50%), 290 nm (20%) 4. Cutoff filter solutions: < 250 nm (a 2 W 4 ); < 305 nm (SnCl 2 in Cl); < 450 nm (CoS 4 CuS 4 ) 25

26 [2 2] Cycloadditions: otochemical Process Enone: [2 2] Cycloaddition δ δ * hν δ δ ground state excited state head-to-tail head-to-head 72 : 28 hν 3 P=C 2 77% 77% 98% Isocomene 26

27 [2 2] Cycloadditions: otochemical Process C=C C= Bonds: Paterno-Büchi eaction Z-alkene hν [2 2] cis oxetane E-alkene hν [2 2] trans oxetane C 2 C 2 hν 63% The [2 2] cycloaddition occurs in a regioselective manner. 27

28 eactions of Metal Carbene Metathesis: Grubb Catalyst ucl 2 (P 3 ) 3 C 2 (c-c 6 11 ) 3 P Cl Cl PCy 3 u PCy 3 cat. u C u C u C 24 u 'C ' MP: ring opening metathesis polymerization 28

29 eactions of Metal Carbene Metathesis: ing Closing Bn F 3 C Me C i Pr Mo Me 2 i Pr Bn Bn cat. Bn (Mo C) Bn Mo C 2 C Mo C 2 C Mo Mo 2 C C 2 Mo C 29

30 1,3-Dipolar Cycloadditions 1,3-Dipoles Propargyl Allenyl Type Allyl Type itrile xides C C Diazoalkanes C C Azides itrones zone C C 30

31 1,3-Dipolar Cycloadditions 1,3-Dipole Alkene (Dipolarophile) C C 2π 2n 2π 4σ 2n Concerted cycloaddition: Predictable stereochemistry 1,3-dipole M supra supra dipolarophile LUM 31

32 1,3-Dipolar Cycloadditions Stereochemistry Z C cis C E trans Me 2 C C 2 Me Me 2 C Me C 2 Me 2 C C 2 Me endo exo 32

33 1,3-Dipolar Cycloadditions egiochemistry: Less Predictable C C Y C C C C Y Y 33

34 1,3-Dipolar Cycloadditions Azides 20 o C 100% Triazoline 150 o C - 2 Aziridine Click Chemistry ' cat. CuC 2 Triazole ' 34

35 1,3-Dipolar Cycloadditions Diazoalkanes Cyclopropanation Et 2 2 C 0 o C 2 C Pyrazoline 20 o C 2 C C 2 Et C 2 Et [] C 2 Et Pyrazole 35

36 1,3-Dipolar Cycloadditions itrile xides C 2 X a 2 C 2 2 Ar C ( 2 ) C C 2 C acl [] C C Cl Et 3 Et 2, 20 o C C 36

37 1,3-Dipolar Cycloadditions itrile xides i Bu 2 Al 2 C 2 C CC 3 2, aney i i Pr 2 Li ( = ) C 37

38 1,3-Dipolar Cycloadditions itrile xides: Intramolecular Cycloaddition I C 2 Et Ag 2 Et 2 ; 90% C 2 Et p-clc 6 4 C Et 3, C C 2 Et 2 MsCl, Et 3 C 2 Et 2 97% C 2 Et 0 o C; 100% C 2 Et 38

39 Cycloaddition eactions with Allyl Cations [4 3] Cycloaddition CF 3 C 2 Ag I [43] Br Br Fe 2 (C) 9 [4 3] 39

40 Cycloaddition eactions with Allyl Anions [3 2] Cycloaddition S 2 S 2 C C 2 S C C Me 2 C Me 2 C 40

41 Cycloaddition eactions with Tetramethylene [3 2] Cycloaddition Me 3 Si Ac ( 3 P) 4 Pd Me 3 Si Pd tetramethylene 41

42 Cheletropic eactions Sulfolenes Disrotatory ring closure and opening S 2 S 2 S 2 S 2 S 2 S 2 42

43 Cheletropic eactions Sulfolenes LiMDS S S Br Δ S 2 β-ocimene Ts S 2 1) K 2) 3 S o C 85% 43

44 eactions of Sulfur eagents Alkene Formation: amberg Backlünd earrangement Cl 2 S S 2 K, CCl 4 2 S S 2 Cl 2 S S 2 S 2 44

45 [3,3]-Sigmatropic earrangement Δ Cope earrangement xy-cope earrangement Δ 45

46 [3,3]-Sigmatropic earrangement Anionic xy-cope earrangement M Δ =, Me M k 1/2 at 66 o C Li no reaction MgBr no reaction a 1.2 h K 1.4 min MgBr K, TF TF 92% rt, 2 h 94% 46

47 [3,3]-Sigmatropic earrangement Aza-Cope earrangement Ar Ar C Ag 3 Et 23 o C 80% xy aza-cope rearrangement 47

48 [3,3]-Sigmatropic earrangement Claisen earrangement o C 96% (E,E)-vinyl allyl ether threo-4-enone o C 95% (E,Z)-vinyl allyl ether erythro-4-enone 48

49 [3,3]-Sigmatropic earrangement Claisen earrangement: Johnson Variation 3 C C(Et) o C, 1 h 92% C 2 Et Et ketene acetal Et Et 49

50 [3,3]-Sigmatropic earrangement Claisen earrangement: Eschenmoser Variation Me 2 C Me C 3 C Me 2 Me amide acetal xylene 150 o C 70% Me 2 C Me 2 Me 2 Me 2 C ketene,-acetal 50

51 [3,3]-Sigmatropic earrangement Claisen earrangement: Ireland Variation 1) LDA, TF 2) TBDMSCl 78 o C TBDMS (E)-Silyl acetal 1) 78 o 2) 2 25 o C 89% threo 1) LDA, TF 23% MPA 2) TBDMSCl 78 o C TBDMS (Z)-Silyl acetal 1) 78 o 2) 2 25 o C 86% erythro 51

52 [3,3]-Sigmatropic earrangement Tandem Cope Claisen earrangement Δ 77% 23% Claisen Claisen Cope or 52

53 [2,3]-Sigmatropic earrangement [2,3]-Wittig earrangement G G or G or endo G G exo G = alkenyl, alkynyl G = acyl 53

54 [2,3]-Sigmatropic earrangement S Tf S K t Bu S S [2,3] sigmatropic rearrangement S ArC 2 SmI 2, MPA S Sm Ar Br S Ar 54

55 Ene eactions X Z Y ene enophile endo Z Y X exo Z X Y X, Y = C C, C, C S,,,, Z = C 2, 55

56 Ene eactions Ac 2, BF 3 C 2 Cl 2 ; 84% Ac 2 Metallo-ene reaction Cl 1) Mg, TF, 60 o C 2) C 2 82% C 2 Mg C 2 Cl Mg Mg Cl ene rx. MgCl 56

57 Electrocyclization and the everse Process Woodward-offmann rule system 4n electrons 4n2 electrons heat (M) con dis hν (LUM) dis con Me Me heat conrotatory 4e system Me Me M Me Me Me Me hν disrotatory 4e system Me Me LUM Me Me Me Me hν conrotatory 6e system LUM Me Me Me Me 57

58 Cationic Cyclization F CF 3 C 2 F C SiMe % SiMe 3 F C 58

59 Cyclization via Metallocycles Et 2 C Et 2 C i(cd) 2 3 P, 60 o C Et 2 C Et 2 C i Et 2 C Et 2 C Et 2 C Et 2 C Pd( 3 P) 2 (Ac) 2 TF, 50 o C Et 2 C Et 2 C Pd Et 2 C Et 2 C Me Pd( 3 Sb) 4 Me C 3, Ac E E PdX E E E = S 2 Me PdX Me E E E E 59

60 Periplanone-B A germacrane-type sesquiterpene that contains 3 isoprene units. The numbering follows the conventional decalin system Sex attractant and excitant pheromone of the American cockroach, Periplaneta americana, with activity at a threshold lower than g 60

61 Periplanone-B Strategy for 10-membered ring formation xy-cope ing opening xy-cope X Me 2 C 6 S 3 6 ()-limonene 61

62 Periplanone-B 1 2, a, (1) Et, aney i (2) LiAl 4 6 (3) 3 C 2 C C 2 =CLi K 18-crown-6 (1) EtC=C 2, g 2 (2) LDA; MeC=CC (3) Me 3 SnLi; Me 3 SiCl (4) Me 2 CuLi (5) m-cpba 2 10 EE 4 EE: Et EE 5 6 EE 6 (1) Me 3 SiCl; m-cpba (2) Me 2 Bu t SiCl (3) aq. Ac (4) ArSeC, 3 ; 2 2 (5) Bu t, K 2 SiMe 2Bu t (1) Me 2 S=C 2 (2) Bu 4 F (3) Cr 3. 2 pyr Periplanone-B (racemic) Still, W. C. J. Am. Chem. Soc. 1979, 101,

63 C C C hν (2:1 mixture) 6-cis isomer Periplanone-B C 2 =CMgBr (2:1 mixture) (1) (Me 3 Si) 2 Li 175 o C 2 10 SS 2 C 3 1 (2) ai trans isomer hν 1 (3) 110 o C (4) Bu t, K 2 6 K 18-crown (4:1 mixture) (1) (Me 3 Si) 2 Li SeBr (2) 2 2 (3) Ac 2, aac Me 2 S=C (4) K 2 C 3 7 Periplanone-B (racemic) Schreiber, S. L. J. Am. Chem. Soc. 1984, 106,