Structure and Reactivity

Fall Semester 2008

Summary

Prof. Jérôme Waser BCH 4306 021 693 93 88 [email protected]

Assistant:

Davinia Fernandez-Gonzalez BCH 4409 021 693 94 49 [email protected]

Structure and Reactivity 2008, Summary page 1

Table of Content

1. Introduction and Literature

2. Conformational Analysis 2.1 Alkanes 2.2 : Allylic 2.3 Cyclohexane 2.4 Stereoelectronic Effects: HOMO-LUMO interactions

3. Alkenes 3.1 Synthesis of Alkenes 3.1.1 Elimination 3.1.2 From Acetylenes 3.1.3 (see inorganic chemistry lectures) 3.1.4 From carbonyls 3.1.4.1 Aldol Condensation 3.1.4.2 Wittig and Variations 3.1.4.3 Julia and Variations 3.1.4.4 Peterson Olefination 3.2 of Alkenes 3.2.1 Important Boron Reagents and General Mechanism 3.2.2 Control of Diastereoselectivity 3.3 Oxidation 3.3.1 Epoxidation 3.3.1.1 Directed Epoxidation with m-CPBA 3.3.1.2 Directed Epoxidation with metal catalysts 3.3.1.3 Opening and the Fürst-Plattner Rule 3.3.2 Dihydroxylation

4. Addition to Carbonyl 4.1 General Concepts and Models 4.2 Addition to Carbonyls not Following the Felkin Ahn Model 4.2.1 Chelate Control 4.2.2 Directed Reduction 4.2.3 Reagents Binding to Carbonyl during Addition 4.3 Allylation of Carbonyls

5. Enolate Generation and Reactivity 5.1 Selective Generation of Enolates 5.2 Chiral Auxiliary and Enolate Alkylation 5.2.1 General Concept 5.2.2 Evans Oxazolidinone Auxiliary 5.2.3 Other Auxiliaries

6. 6.1 Zimmermann-Traxler Transition State 6.2 Aldol Reactions using Evans' Auxiliary 6.3 (Paterson) Aldol

7. Reaction of Imines and Conjugated Systems 7.1 Chemistry of Imines 7.2 Chemistry of Enamine and Metalloenamine 7.3 Conjugate Addition and the Vinylogous Principle

8. Cross Coupling Reactions 8.1 Organometallic-RX Cross Coupling

Structure and Reactivity 2008, Summary page 2

8.2 Heck Coupling 8.3 C-Heteroatom Coupling

9. Cycloadditions 9.1 Diels-Alder Cycloaddition 9.1.1 General Aspects 9.1.2 Diastereoselective Diels-Alder with Evans' Auxiliary 9.1.3 Special Diels-Alder Reactions 9.2 [3+2] Cycloaddition Reactions (1,3-Dipolar Cycloadditions)

10. Rearrangements 10.1 Rearrangements via Reactive Intermediates 10.1.1 Cationic Intermediates 10.1.2 Carbene and Nitrene Intermediates 10.2 [3,3] Sigmatropic Rearrangements 10.2.1 General Mechanism 10.2.2 Overman's Aza-Cope Mannich approach towards Strychnine

Supplementary Material - Prerequired Knowledge (required for exam) - General Mechanism for Diels Alder Reaction (required for exam) - Polyketides and Drugs (not required for exam)

Structure and Reactivity 2008, Summary page 3

Structure and Reactivity: Summary

1. Introduction and Literature

Warning: This summary is meant as an help to check the note taken in the lecture and contains only the most important concepts and transition states, it cannot replace the blackboard notes!

Important Supporting Material

- Prerequired Knowledge Summary (necessary to solve exam problems!) repetition of easy concepts from bachelor

- Evans CHEM 206 (on the internet via google) probably the best lecture on the net on advanced organic chemistry, contains most of the topics of this lecture and much more

- Carey Sundberg: Advanced Organic Chemistry Part A and B Comprehensive books, focusing mostly on reactivity, but weaker on selectivity.

- March's: Advanced Organic Chemistry Book good for consultation, not for learning

- Kurti-Czako: Strategic Applications of Named Reactions in Organic Synthesis One of the best book for named reactions, very good to revise mechanism and scope of specific reactions 2. Conformational Analysis (Energy Values in Kcal/mol, M = Medium, L = Large) 2.1 Alkanes

H H Butane CH3 H3C H H

Sägebock Projection

H CH H CH3 3 H3C H 1.4 H CH3 H H H 3 H 0.9 H C H H C H H3C H 3 H3C H 3 1 H H H H Gauche Interaction Newman Projection 1.4 0.9 H H3C 3 H H CH H H H3C H 3 H3C H H3C CH3 H3C H CH3 H H H H H H H H 1 Relative Energy 0 3.8 0.9 5

staggered eclipsed staggered eclipsed antiperiplanar anticlinal synclinal synperiplanar gauche conformer

Structure and Reactivity 2008, Summary page 4

Structure and Reactivity 2008, Summary page 5

AValues

R 2 gauche interactions (also called 1,3-diaxial interactions) H R CH3 1.7 H R CH2CH3 1.7 Raxial R equatorial CH(CH3)2 2.1

C(CH3)3 4.7 Avalue(R)=- G (axial-equatorial) CN 0.2 !!! A value are exact only for monosubstituted cyclohexanes!!! H C6 5 2.8 Important number to remember:

Si(CH3)3 2.5 A Value CH3: 1.7 Kcal/mol OCH3 0.6 1.4 Kcal = 10:1 mixture 21 Kcal = thermal energy at room temperature Cl 0.6

2.4 Stereoelectronic Effects: HOMO-LUMO interactions

Important Rules for HOMO-LUMO interactions

1) The nearest the energy of HOMO and LUMO, the strongest the interaction.

2) The absolute energy of orbitals is correlated to the electronegativity of the atoms/bonds

3) Stereoelectronics: a geometrical overlap of orbitals is necessary for interaction

Important examples:

Structural Anomeric Effect Enolate Formation

R R1 H O n C-O O RO O C-H H H O O O A value: -0.6! R n H O O Axial is favored RO O RO *C=O R1 H R H C-H 1 C-H H C-O Hydrogen is acidic only to C=O! Microscopic Reversibility: nO Protonation from Enolate is to C=C!

Anomeric Effect: In the axial position, a better stabilization with the more electronegative C-O is possible.

Other examples seen in the lecture: Sn2 substitution, elimination, conformation of , stabilization of carbocations

Structure and Reactivity 2008, Summary page 6

3. Alkenes 3.1 Synthesis of Alkenes

3.1.1 Elimination

SCH3 X O S 150 °C 20 °C H O H Se Ph H OtBu

E2, trans elimination Chugaev syn elimination Selenoxide syn elimination

3.1.2 From Acetylenes

Pd/CaCO3 Lindlar cat. R1 R2 M R1 R2 R MH cross-coupling R2 R Li/NH3 M = B, Sn, Zr,... R1 Reduction Hydrometallation

3.1.3 Olefin Metathesis (see inorganic chemistry lectures)

3.1.4 From carbonyls

3.1.4.1 Aldol Condensation

3.1.4.2 Wittig and Variations

Original Wittig

O R1 cis for R = 1 or R PPh 1 R R trans for R = CO R' 3 R H R 2 phosphor ylide

Mechanism R R = alkyl R R= CO2Et CO2Et O H O H Ph H Ph H Ph Ph H P P H Ph Ph P 1 Ph Ph P 1 1 R 1 R Ph R Ph Ph R Ph H O H O Puckered PlanarPuckered Planar

R CO2Et Ph P Ph P 3 cis trans 3 O O R1 R1 Two transition state are possible: puckered and planar. For alkyl groups, the reaction is controlled by sterics and the puckered TS is favored (less interactions with bulky Ph group). For esters, the reaction is controlled by electronics and the planar TS is favored (better Dipoles orientation).

Structure and Reactivity 2008, Summary page 7

Schlosser Variation

O PhLi, LiBr R1 R PPh + trans for R = alkyl 3 R1 H then H R

Br Br Br R R R Li R Ph3P + Ph3P LiBr Ph3P PhLi Ph3P Ph3P H O Li R O trans 1 O O O 1 R 1 1 1 R Li R Li R Li R

General problem with Wittig: Strong base is needed! It cannot be used for base-sensitive substrates.

Milder Variations: Horner-Wadsworth-Emmons (HWE)

O O O O Base P 1 EtO OEt R OEt EtO R1 H

HWE is trans selective and weaker base can be used: very often used in total synthesis. Cis-selective variations: O O O O F CH CO P P 3 2 OEt PhO OEt F3CH2CO PhO

Still-Gennari Ando

3.1.4.3 Julia and Variations

Julia-Lythgoe O HO R1 1 1) BuLi, 1 AcO R R H Ac2O R SO2Ph 2) H O 2 R SO2Ph R SO2Ph

Na, Hg

1 R1 AcO R 1 Na, Hg AcO R

R R R Highly trans selective, but multi-steps Julia-Kocienski

S 1steponly R S N Highly trans selective, milder than many Wittig methods O O

Structure and Reactivity 2008, Summary page 8

3.1.4.4 Peterson Olefination 2 2 1 R 3Si O R 3Si O R

base R R1 R R1 R 2 O SiR 3 trans 2 1) R1 H R 3Si OH R MgBr 1 2) H2O R R OH2

+ 2 1 H ,H2O R 3Si R

1 R OH2 R R cis If high selectivity can be achieved in the first step, the Peterson protocol allows obtaining trans or cis olefins depending on the reaction conditions. 3.2 Hydroboration of Alkenes 3.2.1 Important Boron Reagents and General Mechanism

H Me O O BH B Me 3 B H B H borane O Me O Me 9-BBN catechol borane pinacol borane

1 1 H O ,NaOH R R 1 1 2 2 1 R R 2BH BR 2 B OH OBR R R O R 2

H2O2,NaOH cross-coupling OH R

Regioselectivity: H goes to more stabilized carbocation, because the mechanism is asynchronous:

Partial positive charge H BH2 + tertiary carbocation > secondary carbocation > primary carbocation

3.2.2 Control of Diastereoselectivity

Hydroboration with BH3: Minimize strongest Allylic strain, BH3 comes opposite from RL

H H2B H2BH OH R R R H L 3 BH M H R3 H2O2 R R 3 H H L 3 R H R2 RM H R R3 M R2 2 R R RL M 2 RL A1,3 Minimized

R H R3 R1 L R1 R R1 H O R R BH3 3 R BH2 2 2 R R L 3 R1 L L 3 H H R H H M H RM RM OH H RM HBH2 A1,2 Minimized

Structure and Reactivity 2008, Summary page 9

Hydroboration with bulky boron reagents: Minimize reagent-substrate interactions

H R1 HBR2 R1 BR H RM H R BR2 H O RL R3 2 3 R1 2 2 RL R3 R1 H RM H H R3 RM H R OH H RL M RL A1,2 not minimized RL R3 A minimized but R 1,2 1 H strong steric interaction with reagent! Reagent control is important! H RM HBR2 3.3 Alkene Oxidation

3.3.1 Epoxidation 3.3.1.1 Directed Epoxidation with m-CPBA

Cl m-CPBA Cl

OH directs m-CPBA O H O OH H O O H O O H H BH3 H O R1 H HO R1 H R2 R2 HO H R R2 1 H OH R2 H R1 A1,3 minimized

OH OH

Prediction easy for cyclic substrates: m-CPBA O

Directed reactions often allows for good selectivity in organic chemistry!

3.3.1.2 Directed Epoxidation with metal catalysts

General Mechanism

HO R O O Lm-1M R O ROOH O MLn O Often used MLn: VO(acac)2,Ti(OR)4 LmM R HO O O O ROH ROOH Lm-1M O

Structure and Reactivity 2008, Summary page 10

Catalytic Asymmetric Version: Sharpless Epoxidation

i t conditions: 5 mol% Ti(O Pr)4,5mol%DET, BuOOH, molecular sieves, CH2Cl2,-20°C

HO OH DET = diethyltartrate a cheap member of the chiral pool

EtO2C CO2Et

Substitution at R4 is not tolerated Allylic O binds to Ti: directed reaction

Important: - tBuOOH does not react until bound to Ti Catalysisispossible - Face of attack of the peroxide is determined by the chiral diester ligand, not the conformation of the substrate very good reagent control

The Sharpless epoxidation is very often used for the synthesis of complex organic molecules!

3.3.1.3 Epoxide Opening and the Fürst-Plattner Rule

R [O] R O 1 R R1 also for bromonium opening Nu Nu 1 1 R OH OH R R R R favored product OH R1 Nu Nu Nu thermodynamically more stable twist boat, high energy directly to chair

The thermodynamically more stable product is not observed, because an unvaforable twist-boat intermediate has to be formed.

Structure and Reactivity 2008, Summary page 11

3.3.2 Dihydroxylation

General Mechanism

VIII O O O VI O Os H O OsO Os 2 4 O O O O HO OH

Problem with first method: Stoichiometric use of very toxic and expensive OsO4 N Sharpless Catalytic Asymmetric Dihydroxylation: Ad-mix Et OMe 5mol%K OsO (OH) (catalyst) N 2 4 4 N N H O O K3Fe(CN)6 (stoichiometric oxidant) H sold as Ad-mix N cinchona-derived amines (chiral ligand) MeO Et Inorganic Base N (DHQ)2-PHAL example of chiral ligand

The Sharpless dihydroxylation is the most used method for the asymmetric synthesis of diols.

This reaction will be discussed in details in the couse catalytic asymmetric reactions in organic synthesis.

4. Addition to Carbonyl 4.1 General Concepts and Models Comparison with Olefins - Sterics is different: only lone pairs on O R1 R3 R1 + - O - C=O bond is polarized: no issue of regiochemistry 2 4 2 R R R LA - Further activation of carbonyls with Lewis Acis is easy and allow to Olefins Carbonyls modulate the reactivity

Felkin-Ahn Model Bürgi-Dunitz Trajectory Nu Nu R1 H RM Nu OH RM R1 OH O R1 O RM H RM R1 RL H R L RL RL

-RL is to C=O - Nu comes along the Bürgi-Dunitz trajectory (109 °C to C=O) - Minimize Nu-Substrate interaction Smallest Substituent on Bürgi-Dunitz trajectory (Here H)

n Polar Felkin-Ahn Rule Nu Nu *C-X H RM Electron-deficient groups behave as RL Favorable Interaction nNu to *C-X R1 O X X=OR,F,Cl,Br,I,...

Structure and Reactivity 2008, Summary page 12

4.2. Addition to Carbonyls not Following the Felkin Ahn Model

4.2.1. Chelate Control

1,2 Chelate control

R R1 O 1 H R R Nu OH R M Metal M M M RM R O R1 O R1 O M Nu M M O R1 RO H H H O OR R OR Nu R

- Metal forces two donors in plane through chelation - Nu comes towards smallest substituent (H)

1,3 Chelate control O Et OH O O B OH OH Et2BOMe R1 R Et R R1 NaBH4 R R H 1 BH "Aldol Product" 4 syn-diol R equatorial axial attack (see Fürst-Plattner rules) Factors favoring chelation - R group sterically not hindered:

good: R = Me, Bn, MeOCH2 (MOM), BnOCH2 (BOM) t t i bad: R = Bu, SiMe3,SiMe2 Bu (TBDMS or TBS), Si Pr3 (TIPS) - non-coordinating solvents:

Toluene, CH2Cl2 >> Et2O>THF>>DMF,EtOH,H2O - Strong Lewis Acid, with more than one coordination site available

+ + Bad: Na ,K (too weak Lewis Acid), BF3 (only 1 coordination site), LiX

Good: MgX2,ZnX2, LiX, TiCl4,SnCl4,SnCl2,LnX3,AlCl3,...

Importance of anion X: If X is not too tightly bond to the metal, it can dissociate generating a new free coordination site. F-,R- generally don't dissociate, Cl- and OAc- can dissociate and Br-,I-,OTf- often dissociate easily. For example BF3 is not a chelating agent, but BBu2OTf is a chelating agent.

4.2.2. Directed Reduction AcO OAc B H R R OH O O O O OH OH NaBH(OAc)3 OH H OAc R1 B R1 H R R1 R R1 H R R1 "Aldol Product" O OAc OH Anti diol - Chair transition state chelate conditions give syn! - All R groups equatorial Sodium trisacetoxy borohydride is a very weak reducing reagent Only intramolecular reduction is possible

Use of chelate conditions or directed reductions allow to acces both syn and anti diols from aldol synthons, and are also essential methods for the selective synthesis of polyols polyketide natural products.

Structure and Reactivity 2008, Summary page 13

4.2.3 Reagents Binding to Carbonyl during Addition

Borane Reduction H R HBR2 OH 1 BR BR2H RM H 2 H O RL R1 O 2 RL O R1 O R1 RM H RM H R RL M RL

-RL is to C=O -BR2 bind to O during reduction - Minimize BR2-Substrate interaction Smallest Substituent towards BR2 (H)

Other important examples where Felkin-Ahn models does not apply: Allylation, Aldol Reactions via Chair Transitions States

4.3 Allylation of Carbonyls

Allylation O O H OH RCHO B B O O O R R

Crotylation

H O OH O RCHO B O Me B Me O R O R Me

O OH O H RCHO B B O R O O R Me Me Me

- 6-membered, chair transition state - Substituent in equatorial position - Transfer from double bond geometry to stereochemistry ( E to anti, Z to cis)

Chiral Reagents For Allylation Reactions

Ester group in axial position further away i i CO2 Pr interaction less important CO2 Pr O OH O RCHO H i i B CO2 Pr B CO2 Pr O O O R R Roush Reagent

Minimize nO-nO repulsion and dipole interaction

Structure and Reactivity 2008, Summary page 14

Structure and Reactivity 2008, Summary page 15

Deprotonation of Imides with Bu2BOTf and NEt3 (soft enolization)

Bu Bu Bu OTf O B Bu B OTf O O O O Bu2BOTf H R O BBu2 N + - R R N O H - HNEt3 OTf R R 2 1 O N O N NEt3 H R H H H NEt3 Cis Enolate only NEt3

Very strong A1,3 with Imides! Deprotonation of Minimize R /R 1 TfO B B 9-BBN-BOTf TfO O i + - O i H R B R1 - HNEt Pr2 OTf NEt Pr2 R R1 O H R R1

H H Cis Enolate O i NEt Pr2 i R NEt Pr2 R1 Cy BCl R H Cy 2 Cy B O B + - 2 R1 O Cy R1 Cy - HNEt OTf O NEt3 3 B R H H Cl Cl Cy R1 * NEt3 H Minimize BCy2/R R

NEt3 Trans Enolate *The complete switch of selectivity is not well understood, some authors proposed an extra Cl-hydrogen interaction

5.2 Chiral Auxiliary and Enolate Alkylation

5.2.1 General Concept

O O X* R R The chiral auxiliary X* should be: Y Introduction *X - easy to introduce and remove Base - able to create an efficient asymmetric induction - cheap and recoverable E Disadvantage: multi-step protocol O O R Advantage: chiral auxiliary is bound covalently: good asymmetric * R Z Removal *X * induction and separation of diastereomers possible E E

5.2.2 Evans Oxazolidinone Auxiliary

Synthesis: easy from cheap natural amino acid

O O Me Me Me Me LiAlH4 EtO OEt O NH H N Oxazolidinone H3N CO2 2 OH L-Valine Me Me

Structure and Reactivity 2008, Summary page 16

Structure and Reactivity 2008, Summary page 17

6.2 Aldol Reactions using Evans' Auxiliary

Evans Syn Aldol: R R B O O O O OH O R BOTf Me 2 Me R1CHO N O N O R1 Rc NEt3 Me i i Pr Pr up to 500 : 1 O iPr H O O H iPr N N - Chair Transition State H O R - Minimized Dipoles H H - comes opposite from iPr O O B R R B O R H O 1 R Me R1 Me Newman view from the left Important: In order to activate the aldehyde for addition, B has to bind to the aldehyde. As B has only two free binding sites, the oxazolidinone carbonyl is now free and rotates to minimize dipole interactions.

Crimmins Syn Aldol Cl Cl Cl Ti Cl O O O O OH O TiCl Me 4 Me R1CHO N O N O R1 Rc base Me Bn iPr O O Bn H H - Chair Transition State O N H O - All Carbonyl bound to Ti H Bn Cl N - Aldehyde comes opposite from Bn Cl H O Ti R1 Cl Cl Ti O Cl H O Cl O R1 Me Me Newman view from the back

Anti aldol with external Lewis Acid R R B O O O O OH O R BOTf Me 2 Me R1CHO N O N O R1 Rc NEt3 Et2AlCl Me i i Pr Pr O i O Pr - Free transition state (no chair) O H H H N O - B chelates the auxiliary R H iPr N R - Minimized dipoles and steric: B H R O 1 B carbonyl antiperiplanar to enolate R O H R i O - Aldehyde comes opposite from Pr R1 O AlEt2Cl Me Me -R1 group away from auxiliary Newman view from the back

Structure and Reactivity 2008, Summary page 18

6.3 Ketone (Paterson) Aldol

Me BR Me O 2 R1 R O OH R CHO O 1 RL Me 1 H HO R O H RL B O R1 RM H R H R M RM RM Me H R H L RL Minimized steric

H BR H O 2 R1 R O OH R CHO O 1 RL 1 Me HO R O Me RL B O R1 RM Me H H H R H RM Me RM R R L M RL Minimized A1,3

- Chair transition state -R1 group of aldehyde equatorial - position of chiral group: minimize steric interaction with BR2 for cis enolate, aldehyde comes towards RM,notRL, 1,3 minimize A with Me of enolate for trans enolate, RM and not RL towards BR2, aldehyde comes towards H

7. Reaction of Imines and Conjugated Systems (Mannich and Michael Reactions)

7.1 Chemistry of Imines Comparison of Reactivity as Electrophile

Me Me Me Me N O N O < < < Me Me Me Me Me Me Me Me Imine Ketone Iminium Oxonium

+on C +0.33 +0.51 +0.54 +0.63

Imine are less reactive as electrophile then carbonyl compounds, but they are easy to activate as iminium

Reductive Amination

R1 R1 N R1 R1 O Na(BH3CN) N HNR1 2 R H R H H R H B CN CN deactivated BH H

Because of the electron-withdrawing CN group, Na(BH3CN) is not able to reduce carbonyls, but it is strong enough to reduce the more reactive iminium.

Structure and Reactivity 2008, Summary page 19

Mannich Reaction = Imine equivalent of aldol reaction

1 R1 X R X OM N O N 2 -amino ketone R R2 H R R

7.2 Chemistry of Enamine and Metalloenamine

Comparaison of Nucleophilicity

R1 H R1 M N OM N Enamine are easily formed from iminium, but less nucleophilic < < than enolate. Metalloenamine are very reactive. R2 R R2

Enders SAMP Chiral Auxiliary for Ketone

O O N N N N N + R H2N 1) LDA H OMe R OMe 2) RX H2O OMe

SAMP Hydrazone

H - A highly reactive Li enamine is formed H H - The Li metal is bound opposite to the enamine double N R' N bond to minimize steric interactions with the electrophile Transition State O Li R' - The electrophile comes opposite to the pyrrolidine ring Me RX

Proline Catalyzed Aldol: via enamine intermediates

H H O O N CO H N N CO H O OH O O 2 N O O 2 Me H OH H Me O H Me Me H Me Me H2O Me Me Me H2O Me H H Me 96% ee Me Me

7.3 Conjugate Addition and the Vinylogous Principle (Michael Addition)

Vinylogous Principle Regioselectivity 1 O 1,2 -Addition favored for hard nucleophile (Grignard) O 2 compared to 3 + R1 1,4 (Michael) Addition favored for soft nucleophile (Cuprate) + 1 R R 4 + R Electronic properties are "transmitted" by double bond = vinylogous principle

Structure and Reactivity 2008, Summary page 20

Structure and Reactivity 2008, Summary page 21

Recent efforts to accelerate oxidative addition (important to use cheaper Cl reagents)

Oxidative addition is faster for: Electron-rich ligands (more electrons) mono-coordinated Pd intermediates (more place)

Important recently introduced ligands: Cy Cy PCy2 P P MeO OMe MeO Pd (0) OMe

Tri-tert-butyl phosphine Biarylphosphine Fu, MIT Buchwald, MIT Steric bulk to promote mono-coordination Pd-Aryl interaction to promote mono-coordination

iPr iPr

N N N-Heterocyclic Carbenes (NHC) more electron-rich than phosphines iPr Cl Pd Cl iPr N here: commercially available PEPPSI ligand (Aldrich)

Cl

Special for Suzuki with alkyl-boronic acid derivatibes

PPh2 dppf (Di(bisphenylphosphino)ferrocene) Fe Bidentate ligand good to prevent -hydride elimination PPh2

Building blocks for the synthesis of all diene isomers via Suzuki coupling

O O H+ R B H B BOH2 R O R O H2O

1) Br2 I2 2) NaOMe 1) BuLi R R I R 2) B(OR)3 B(OH)2 Br 3) H+, H2O

Hydrozirconation-Transmetallation for the synthesis of Organozinc reagents:

ZnCl2 HZrCp Cl ZrCp2Cl ZnCl R 2 R R

Structure and Reactivity 2008, Summary page 22

8.2HeckCoupling R R1 base-H+X- RX Base-Mediated PdL Reduction 2 base L R L base Oxidative H R R Pd Addition Pd cat. 1 RX R Pd X L R1 R 1 X L R1 Ligand Exchange -H Elimination R R H R1 R1 Pd Pd X L X L Olefin Insertion

The -H elimination step is reversible, which can lead to isomerization of the double bond!

RX 8.3 C-Heteroatom Coupling PdL RNu 2 Oxidative Addition Pd cat. NuH RX RNu Base R L Reductive Nu = R1R2N, RO, RS Pd Elimination X L

R L NuH base Pd Nu L base-H+X-

Especially the amination (Buchwald-Hartwig Amination) is important for pharma

8.4 Future Progress and Current Topic of Research: Olefin and CH Functionalization

9. Cycloadditions 9.1 Diels-Alder Cycloaddition 9.1.1 General Aspects

Mechanism, endo and ortho rules: see supplementary material

Important Dienes OMe

Me3SiO cyclopentadiene Danishefsky diene

Structure and Reactivity 2008, Summary page 23

9.1.2 Diastereoselective Diels-Alder Reactions with Evans' Auxiliary

O O R Me AlCl H R N O 2 Bn H Bn N O O O 2 Different models depending of stoichiometry of Lewis Acid:

1Eq.Me2AlCl: no chelate 2Eq.Me2AlCl: chelate Me Me Me Al Me Cl Al Me Cl Cl H O O H H O Al Me R Bn R H X* R O R H H N O H N H O O O X* Bn low selectivity high selectivity

-Endotransitionstate - Minimize dipole with oxazolidinone -Endotransitionstate - L. A. binds O opposite to bulky Bn group - Abstraction of Cl by second L. A. allows chelation - Dienophile in s-trans conformation to prevent - Dienophile in s-cis conformation to prevent interaction with L. A. interaction with bulky Bn - Diene comes opposite to bulky Bn - Diene comes opposite to bulky Bn

In this case, different mechanisms lead to the same product, because two key structural elements are changing: chelation vs dipole control and s-cis vs s-trans conformation of dienophile

O O X* R X* s-trans R s-cis 9.1.3 Special Diels-Alder Reactions

Intramolecular Diels-Alder Reactions

Inverse Electron-Demand Diels-Alder Reactions

CO2R' CO2R' RO RO

HOMO LUMO

Structure and Reactivity 2008, Summary page 24

Structure and Reactivity 2008, Summary page 25

10. Rearrangements 10.1 Rearrangement via Reactive Intermediates 10.1.1 Cationic Intermediates

1,2-Alkyl Shift: Wagner-Meerwein Rearrangement

R R R R 3 R1 R3 R1 R1 R R The group which stabilizes the best the cation is R 4 R2 R4 R2 3 2 R4 migrating 2 electrons - 3 centres transition state

Pinacol Rearrangement

HO OH + H O O R H R3 -H+ 4 R1 R3 R1 R R3 R2 R4 -H2O 4 R R2 1 R2 Same Starting from:

O HO Br HO N2 Semi-Pinacol Rearrangements R1 R3 R1 R3 R1 R3 R2 R4 R2 R4 R2 R4

Prins-Pinacol:

Ph Me Me Me Ph Ph H O SnCl H Me 4 Prins Cl4Sn Cl4Sn Me Me O Me O Me O O O Me Me Me Me Pinacol Me O Ph Ph H Me Cl4Sn Me Me O O Me O Me Me Me 10.1.2 Carbene and Nitrene Intermediates

R R carbene R1 R R R1 important special case: O C R2 R3 R2 R3 O R3 R3 ketene Name Reactions: Fritsch-Buttenberg-Wiechell, Arndt-Einstert, Wolff.

R R R R R nitrene N 1 N R1 N important special case: O CN R2 R O 2 isocyanate Name Reactions: Curtius, Hofmann, Lossen, Schmidt

Structure and Reactivity 2008, Summary page 26

Structure and Reactivity 2008, Summary page 27