Tapio Nevalainen Drug synthesis II 2012 A Summa ry of UefulUseful Reactions

Reactions of alkenes

Electrophilic Addition E Nu Nu

H3C CH2 E H3C

H Br Br

H3C CH2 H H3C

OH H+ + H2O H3C CH2 H H3C Halogenation Br Br+ - Br Br2 Br

1 Reactions of alkenes

Epoxidation and ring opening

Hydroxylation

Ozonolysis R O R'' + R' O H

Reactions of alkenes Hydroboration

Mechanism

Hydrogenation

2 Formation of alkenes

Dissolving Metal Reduction

Wittig reaction

Formation of alkenes

H3C Ph Ph LG CH3 E2 H H3C D CH3 D B:

B: H H3C LG H2C CH3 CH3 + E1 H CCH 3 3 CH3 - CH3

LG = Leaving group: - - - CF3SO2O>Ts>CH3SO2O>H2O, I >Br >Cl O R'SO Cl O R' = Me (mesylate) OH 2 R S R' = CF (triftlate) R R' 3 O R' = pCH3Ph (tosylate, Ts) poor LG good LG

O OH O O- OH - R R' -OH R R' R R' H aldol -unsaturated or B: = enone

3 Alkynes

Aromatics

NO2

Br

Nucleophilic Substitution Reactions

Nu:-

Nu CH3 H3C S 2 primary and secondary H3C N LG - LG CH3 alkyl halides and sulfonates

Nu:- Nu H3C LG H3C H3C CH3 S 1 tertiary alkyl halides + CH3 N and sulfonates H3CCH3 -LG H3C CH3

Alkyl halides and sulfonates are formed from the corresponding alcohols

SOCl or O 2 R'SO2Cl O X OH R S R R R' PBr3 O

4 Chemistry of the Carbonyl Group Oxidation and reduction

PCD = Pyridinium dichromate [C5H6N]2 [Cr2O7] Jones (CrO H SO acetone) 3, 2 4, PCD

OH OH PCC R R R'

PCC = Pyridinium NaBH4 or LiAlH4 chlorochromate NaBH4 or LiAlH4 Nucleophilic Addition

OH R OH C R C H R'' R' R'

Overview of Organometallic Reactions

via salt

5 Chemistry of the Carbonyl Group

- O +MgBr O OH O PhMgBr PhMgBr C R' R C O C R C Ph R O R Ph Ph R' Ph

O PhMgBr C R OH

α,β-Unsaturated Carbonyl Compounds

Chemistry of the Carbonyl Group

2 R'' OH Lewis acid Lewis acid OH + • Acetals or H+ OH or H O

R R'

H2O, Lewis H2O, Lewis acid or H+ acid or H+ • Carboxylic Acid Derivatives

O O O O O O R R Cl R O R R O R NR2 R OH

Most electrophilic Least electrophilic

6 Chemistry of the Carbonyl Group

Enolate reactions

O C R' C:- O :B R R C H X2 R' C R -Halogenation R O- C R'' X R' C R R enolate O Alkylation of Enolates C O R R C R''

Aldol reaction

Nucleophilic conjugate addition

Carbonyl Condensation Reactions • The aldol reaction –the carbon of one carbonyl component becomes bonded to the carbonyl carbon of the other component.

‒ Under the basic reaction conditions, the aldol product loses H2Oto form an ‐unsaturated carbonyl compound

8.2.2012 14

7 Carbonyl Condensation Reactions •Crossed Aldol Reactions – Crossed aldols are synthetically useful in two different situations: 1. When oyonly oeone car bony l com pone nt has  hyyogesdrogens—such cases often lead to the formation of only one product.

8.2.2012 15

Chemistry of the Carbonyl Group: Regioselective formation of enolates from • When an unsymmetrical carbonyl compound like 2-methylcyclohexanone is treated with base, two enolates are possible.

• Path 1 occurs faster because it results in removal of the less hindered 2° H. Path 2 results in formation of the more stable enolate. This enolate predominates at equilibrium.

16

8 Carbonyl Condensation Reactions: Crossed Aldol Reactions

•2. When one carbonyl component has especially acidic  hydrogens, these hydrogens are more readily removed than the other  H atoms. As a result, the ‐dicarbonyl compound always becomes the enolate component of the aldol reaction.

8.2.2012 17

Carbonyl Condensation Reactions: Crossed Aldol Reactions

•Entacapone, a catechol‐O‐methyl transferase (COMT) inhibitor for the tttreatmen t of PkiParkinson ’s disease, is prepared by crossed aldol reaction (Knoevenagel condensation).

O O HO CHO O Piperidine, HO HO OH 1. SOCl2,80°C N + HO OH CN CN CH3COOH, HO 2. diethyl HO NO CN EtOH, 80 °C 2 NO cyanoacetic 2 NO2 acid entacapone

8.2.2012 18

9 Carbonyl Condensation Reactions: Intramolecular Aldol Reactions

•2,5‐hexadienone forms a five‐membered ring.

•Six‐membered rings can be formed from the intramolecular aldol reaction of 151,5‐dicarbonyl compounds

8.2.2012 19

Carbonyl Condensation Reactions: The Claisen Reaction

•A Claisen reaction is a nucleophilic substitution in which an enolate is the nucllhileophile

8.2.2012 20

10 Carbonyl Condensation Reactions: The Crossed Claisen and Related Reactions

•A Claisen reaction between two different esters when only one has  hydrogens, one product is usually formed.

•A Claisen reaction between a ketone and an ester—the enolate is formed from the ketone and the ester has no  hydrogens

8.2.2012 21

Carbonyl Condensation Reactions: The Crossed Claisen and Related Reactions •‐Dicarbonyl compounds are also prepared by reacting an enolate with ethyl chloroformate or diethyl carbonate

22 8.2.2012 22

11 Chemistry of the Carbonyl Group: Regioselective formation of enolates from ketones • A kinetic enolate is favored by a strong nonnucleophilic base like LDA, polar aprotic solvent and low temperature (‐78°C) .

• A thermodynamic enolate is favored by a strong base (NaOEt, t- BuOK) in a protic solvent (EtOH) and toom temperature (25°C).

8.2.2012 23

Carbonyl Condensation Reactions: The Crossed Claisen and Related Reactions •An intramolecular Claisen reaction is called a Dieckmann reaction. Two types of diesters give good yields of cyclic products.

8.2.2012 24

12 Carbonyl Condensation Reactions: The Michael Reaction

•The Michael reaction involves the conjugate addition (1,4‐addition) of a enolate to the ‐carbon of the ,‐unsaturated carbonyl compound.

8.2.2012 25

Carbonyl Condensation Reactions: The Michael Reaction

•Michael reaction that was a key step in the synthesis of estrone, a female sex hormone

8.2.2012 26

13 Carbonyl Condensation Reactions: Nucleophilic Conjugate Addition Reactions

• -Unsaturated carbonyl compounds can potentially react with nucleophiles

(, thiols , alcohols , cyanide ions , organocopper reagents R 2CuLi, and enolates) at the end of the conjugated system:

8.2.2012 27

Carbonyl Condensation Reactions: The Robinson Annulation

•TheRobinson annulation is a ring-forming reaction that combines a Michael reaction with an intramolecular aldol reaction.

8.2.2012 28

14 Chemistry of the Carbonyl Group: Regioselective formation of enolates from ketones

• An unsymmetrical ketone can be regioselectively alkylated to yield one major prodtduct. •Treatmentof2‐methylcyclohexanone with LDA in THF solution at –78°C gives the less substituted kinetic enolate, which then reacts

with CH3ItoformA.

8.2.2012 29

Chemistry of the Carbonyl Group: Regioselective formation of enolates from ketones

•Treatment of 2‐methylcyclohexanone with NaOCH2CH3 in CH3CH2OH solltiution at room tttemperature forms the more substituted thermodynamic enolate, which then reacts with CH3I to form B.

8.2.2012 30

15 Common bases for preparing enolates

- - - + - OH CH3CH2O (CH3)3O Na H Hydroxide Ethoxide t-Butoxide Sodium hydride pKa (HB+) 15.7 pKa (HB+)16 pKa (HB+)18 pKa (HB+)35

H3C CH3 Li Li H3C CH H3C CH H C N N 3 N 3 3 Li H C H C Si Si 3 CH3 3 CH CH CH 3 CH3 3 3 lithium lithium lithium diisopropylamide tetramethylpiperidine hexamethyldisilazide LDA LTMP LHMDS pKa (HB+)36 pKa (HB+)37 pKa (HB+)30

Some important pKa values of carbonylcarbonyl--containingcontaining moleculesmolecules,, nitro compounds and nitriles

8.2.2012 32

16 equivalents : lithium enolates • In the presence of a very strong base such as lithium diisopropyl amide (LDA), stable enolates can be formed

. The lithium enolateis stable at low temperature (–(–7878 °°C)C) but reactive enough to be useful. . Lithium enolates are the most commonly used stable enolate equivalents in chemistry

O OH OLi O RCHO E+ E R E=alkyl halides, Aldol , esters, etc. reaction RX O Alkylation R

Enol equivalents:silyl enol ethers

. Silyl enol ethers are more stable, but less reactive, than lithium enolatesenolates.. . They are made by treating an enolate with a silicon electrophile..electrophile

34

17 Enol equivalents •The problem of self‐condensation of carbonyl compounds can be avoided by using specific enol equivalents (lithium enolates, enamines, silyl enol ethers, aza‐enolates ). BuLi R2 R2 or R2 R R LDA R 1 OH 1 O 1 O Li enol HN Li-enolate + R3 H+ H H2N R2 R2 R2 base R R R R R 1 N 1 N 3 1 N 3 imine enamine aza-enolate • Use of enamines as enol equivalents (Stork enamine alkylation)

Enol equivalents: aza‐enolates

•The aza‐enolates can be alkylated

•Mono‐protected dialdehydes can be made using aza‐enolates

8.2.2012 36

18 Reactions of Enolates—Malonic Ester Synthesis

•The malonic ester synthesis converts diethyl malonate to a carboxylic acid in three steps.

37

Reactions of Enolates—Acetoacetic Ester Synthesis

•The acetoacetic ester synthesis is a stepwise method for converting ethy l acettttoacetate itinto a ktketone hhiaving one or two alky l groups on the  carbon. Because the starting material is a ‐ketoester, the final product is a ketone, not a carboxylic acid

8.2.2012 38

19 Reactions of Enolates—Acetoacetic Ester Synthesis

•The steps in acetoacetic ester synthesis are exactly the same as those in the malonic ester synthesis.

8.2.2012 39

Nitriles and nitroalkanes are enolizable

•Nitriles and nitroalkanes can be alkylated and can undergo aldol‐ like condensations

8.2.2012 40

20 Nitriles and nitroalkanes are enolizable

•Nitroalkanes are enolized to nitronates and react well with aldehydes and ketones.

8.2.2012 41

The •Amino alkylation of an acidic proton with formaldehyde and amine. The product is known as a Mannich base

21 The Mannich reaction

• Electron-rich heterocycles such like indoles and pyrroles form Mannich bases H CH3 CH3 C N+ N Me2NH, CH2=O H CH3 CH3 + N HOAc, H2O N -H H H N H

•The Mannich products can be converted to enones (vinyl ketones) by alkylation with MeI and then treat the ammonium salt with base.

The Mannich reaction

•In the original synthetic route of fluoxetine (4) starts with Mannich reaction of acetophenone (7) to yield the aminoketone 8.

8.2.2012 44

22