Organic Synthesis

سنتز مواد آلی

به نام خدا

Dr Morteza MehrdadUniversity of Guilan, Department of Chemistry,

Rasht, Iranm-mehrdad@guilan.ac.ir

2

C 1-1

2

Francis A. Carey

Department of Chemistry

Francis A. Carey is a native of Pennsylvania, educated in the public schools ofPhiladelphia, at Drexel University (B.S. in chemistry, 1959), and at Penn State (Ph.D.1963).Following postdoctoral work at Harvard and military service, he was appointed to thechemistry faculty of the University of Virginia in 1966.Prior to retiring in 2000, he regularly taught the two-semester lecture courses ingeneral chemistry and organic chemistry.With his students, Professor Carey has published over forty research papers insynthetic and mechanistic organic chemistry. In addition to this text, he is coauthor(with Robert C. Atkins) of Organic Chemistry: A Brief Course and (with Richard J.Sundberg) of Advanced Organic Chemistry, a two-volume treatment designed forgraduate students and advanced undergraduates. He was a member of the Committeeof Examiners of The Graduate Record Examination in Chemistry from 1993-2000.

University of Virginia

Richard J. Sundberg

Department of Chemistry

University of Virginia

Professor Sundberg is primarily engaged in teaching and chemical education.B.S. State University of Iowa, 1959Ph.D. University of Minnesota, 1962NIH Postdoctoral Fellow Stanford University, 1971-72Along with Francis A. Carey he is the author of “Advanced Organic Chemistry,” atwo-part text, which was recently published in its fifth edition.Professor Sundberg is also interested in synthetic methodology in heterocyclicchemistry and is the author of “Indoles” in the Best Synthetic Methods Series(Academic Press, 1996).

The focus of Part B is on the closely interrelated topics of reactions and synthesis.

We want to be able to answer questions such as:

What transformation does a reaction achieve?

What is the mechanism of the reaction?

What reagents and reaction conditions are typically used?

What substances can catalyze the reaction?

How sensitive is the reaction to other functional groups and the steric environment?

What factors control the stereoselectivity of the reaction?

Under what conditions is the reaction enantioselective?

5

For example, in the course of learning about the reactions in Chapter 1 to 12, we will encounter a number of ways of making ketones, as outlined in the scheme that follows.

6

Part B emphasizes the most important reactions used in

organic synthesis. The material is organized by reaction

type.

Chapters 1 and 2 discuss the alkylation, conjugate

addition and carbonyl addition/condensation reactions of

enolates and other carbon nucleophiles.

7

8

Chapter 1. Alkylation of Enolates and Other Carbon Nucleophiles Introduction

1.1. Generation and Properties of Enolates and Other Stabilized Carbanions

1.1.1. Generation of Enolates by Deprotonation

1.1.2. Regioselectivity and Stereoselectivity in Enolate Formation from Ketone

and Esters

1.1.3. Other Means of Generating Enolates

1.1.4. Solvent Effects on Enolate Structure and Reactivity

1.2. Alkylation of Enolates

1.2.1. Alkylation of Highly Stabilized Enolates

1.2.2. Alkylation of Ketone Enolates

1.2.3. Alkylation of Aldehydes, Esters, Carboxylic Acids, Amides, and Nitriles

1.2.4. Generation and Alkylation of Dianions

1.2.5. Intramolecular Alkylation of Enolates

1.2.6. Control of Enantioselectivity in Alkylation Reactions

1.3. The Nitrogen Analogs of Enols and Enolates: Enamines and Imine Anions 9

Introduction

C-C bond formation is the basis for the construction of the molecular framework of organic molecules by synthesis.

One of the fundamental processes for C-Cbond formation is a reaction between a nucleophilic and an electrophilic carbon.

Reactions of C-nucleophile(enolates, imine anions, and enamines) with alkylating agents.

10

Crucial Factor for C-C bond formationby SN2 reaction

(1) the condition for generation of the carbonnucleophile

(2) the effect of the reaction conditions on thestructure and reactivity of the nucleophile

(3) the regio- and stereoselectivity of the alkylationreaction

11

Isomers

compounds with the same molecular

formula but not identical structures

12

Constitutional Isomersایزومرهای ساختمانی

Different order of connections gives different carbon backboneand/or different functional groups

13

Stereochemistry of ReactionsRegioselective Reactions واکنشهای جهت گزین - reaction in which two constitutional

isomers can be obtained as products, but more of one is obtained than the other –

regioselectivity selects for a particular constitutional isomer

Stereoselective Reactions واکنشهای فضاگزین - reaction in which two stereoisomers

can be obtained as products, but more of one is obtained than the other –

stereoselectivity selects for a particular stereoisomer

Stereospecific Reactions واکنشهای فضاویژه- reaction in which each reactant stereo-

isomer forms a different stereoisomeric product or a different set of stereoisomeric

products

All stereospecific reactions are

stereoselective, but stereo-

selective reactions are not

necessarily stereospecific. 14

CH3

H CH3

\ / H Br

C = C + Br2

/ \ H Br

CH3 H

CH3

trans-2-butene meso-2,3-dibromobutane

CH3 CH3

H H

\ / H Br Br H

C = C + Br2 +

/ \ Br H H Br

CH3 CH3

CH3 CH3

cis-2-butene (S,S)- & (R,R)-2,3-dibromobutane

15

16

Addition of non-symmetrical reagent to a non-symmetrical

alkene, then two isomeric products that are constitutional

isomers can be obtained.

For example,

the reaction of HCl with propene gives 1-chloropropane

and 2-chloropropane.

Normally, 2-chloropropane is the major product.

Since one product is favoured over the other, the reaction

is said to be regioselective.

If 2-chloropropane were the only product then the reaction

is said to be regiospecific

زاشیمیدانهاهورمونیادارویکسنتزبرایStereoselectiveفضاگزینواکنشهای Reactionsاستفاده

هکآورندبدستراایزومریفقطکهکنندمیخودازبیولوژیکیسیستمدرایزومرآن

.باشدداشتهStereospecificityفضاویژگیفعالیت

17

Stereospecific: A term indicating that only a

single stereoisomer is produced in a given

reaction rather than a mixture.

Bromonium Ion Mechanism

• Stereospecific anti addition

18

Orientation in Hydration via Hydroboration

• Stereospecific syn addition

The reaction can be applied to various carbonylcompounds, including ketones, esters, and amides.

In the retrosynthetic sense, the disconnection isbetween the -carbon and a potential alkylating agent.

amidesKetones esters

19

imine anion

The alkylated imines can be hydrolyzed to thecorresponding ketone

Either enolate or imine anions can be used to introduce alkyl -substituents to a carbonyl group.

imine

20

In the present chapter we relate the properties and

reactivity of carbanions stabilized by carbonyl and

other EWG substituents to their application as

nucleophiles in synthesis

there is a fundamental relationship between the

stabilizing functional group and the acidity of the

C−H groups, as illustrated by the pK data

21

1) pK data

the stability and reactivity of carbanions.

(The acidity of the reactant determines which bases can

be used for generation of the anion.)

2) distinction between

kinetic or thermodynamic control

of enolate formation by deprotonation

which determines the enolate composition.

22

Generation of an enolate or other stabilizedcarbanion by deprotonation

• under conditions in which the enolate is in

equilibrium with its conjugate acid or under

which the reactant is completely converted to its

conjugate base

(The key determinant is the amount and strength

of the base)

23

The base must be derived from a substantiallyweaker acid than the reactant.

Or the reagent must be a stronger base thanthe anion of the reactant.

Most current procedures for alkylation ofenolates and other carbanions involvecomplete conversion to the anion.

The solvent and other coordinating orchelating additives also have strong effects onthe structure and reactivity of carbanionsformed by deprotonation.

24

strongest acids

strongest bases

water and ROH are appropriate for hydroxylicsolvents.

25

Ability to stablize carbanion:

26

1960

sodium or potassium alkoxides

aprotic solvents

1- lithium di-isopropylamide (LDA)2- anions of hexaalkyldisilylamines, especially

hexamethyldisilazan (LiHMDS, NaHMDS, andKHMDS).

3- lithium tetra-methylpiperidide (LiTMP)

THF

27

4- amide anion − NH2

5- conjugate base of DMSO (“dimsyl” anion)

6- triphenylmethyl anion

7- Sodium and potassium hydride NaH and KH

28

-

For a carbon acid C−H and a base B−H,

29

By comparing the approximate pK values of the bases with those of the carbon acid of interest,

it is possibleto estimate the position of the acid-base equilibrium for a given

reactant-base combination

R= CH3

alkyl ketone

primary alkoxide ion

convert only a fraction of a ketone to its anion

pK= 20 pK= 16

tertiary alkoxide

more favorable equilibrium will be established

R= CH3 pK= 20 pK= 19

amide basesR = (CH3)2CH

complete formation of the enolate occurs

R= CH3 pK= 20 pK= 36

30

Deprotonation of carbonyl compound

unsymmetrical dialkyl ketone

two regioisomeric enolates

By adjusting the conditions of enolate formation, it is possible to establisheither kinetic or thermodynamic control.

31

Conditions for kinetic control of enolate formation are those in

which deprotonation is:

- rapid,

- quantitative,

- and irreversible

This requirement is met experimentally by using:

- a very strong base such as LDA or LiHMDS

- in an aprotic solvent

- in the absence of excess ketone.

32

Lithium is a better counterion than sodium or potassium forregioselective generation of the kinetic enolate,as it maintains a tighter coordination at oxygen and reduces therate of proton exchange.

Use of an aprotic solvent is essentialbecause protic solvents permit enolate equilibration by reversibleprotonation-deprotonation,which gives rise to the thermodynamically controlled enolatecomposition.

Excess ketone also catalyzes the equilibration by protonexchange.

33

Conditions of kinetic control usually favor formation of the less

substituted enolate, especially for methyl ketones.

The main reason for this result is that

removal of a less hindered hydrogen is faster, for steric reasons,

than removal of a more hindered hydrogen.

Steric factors in ketone deprotonation are accentuated by using

bulky bases

34

35

lithium di-isopropylamide

EZ

In general, the more highly substituted enolate is the preferred isomer, but if the alkyl

groups are sufficiently branched as to interfere with solvation, there can be exceptions.

This factor, along with CH3/CH3 steric repulsion, presumably accounts for the stability of

the less-substituted enolate from 3-methyl-2-butanone

36

The acidifying effect of an adjacent phenyl group outweighs steric effects in

the case of 1-phenyl-2-propanone, and as a result the conjugated enolate is

favored by both kinetic and thermodynamic conditions

37

For cyclic ketones conformational factors also come into play in determining enolate

composition. 2-Substituted cyclohexanones are kinetically deprotonated at the C(6)

methylene group, whereas the more-substituted C(2) enolate is slightly favored at

equilibrium38

A 3-methyl group has a significant effect on the regiochemistry of kinetic deprotonation

but very little effect on the thermodynamic stability of the isomeric enolates

39

C(1) deprotonation is favored under both conditions,

Deprotonation of 2-pentanonewas examined with LDA in THF,with and without

HMPA (hexamethylphosphoramide)

2-pentanone1

3

40

C(3) deprotonation

HMPA

but the Z:E ratio for C(3) deprotonation is sensitive to the presence of HMPA

whereas the open TS favorsthe Z-enolate

The effect of the HMPA is to solvate the Li+ ion,

reducing the importance of Li+ coordination with the carbonyl oxygen

More Z-enolate is formed when HMPA is present.

The cylic TS favors the E-enolate,

41

In contrast to LDA, LiHMDS (Li hexamethyldisilazane) favors the Z-enolateCertain other bases show a preference for formation of the Z-enolate

The Z-selectivity seems to be associated primarily with reduced basicity of the amide anion

2-methyl-3-pentanone

Z-stereoselectivity is the result of a looser TS,in which the steric effects of the chair TS are reduced.

42

Strong effects owing to the presence of

lithium halides

43

2:1:4:1 complex of• the enolate of methyl t-butyl ketone, • an HMDS anion, • Four lithium cations, • one bromide

HMDS (hexamethyldisilazane)

TMEDA (tetramethylethylenediamine )

enolate oxygens bridging between two lithium ions.

enolate of methyl t-butyl ketone

enolate of methyl t-butyl ketone

The amide base also bridges between lithium ions.

44

methyl t-butyl ketone

enolate

Very significant acceleration in the rate of deprotonation of 2-methylcyclohexanone

was observed when triethylamine was included in enolate-forming reactions in toluene.

Steric effects in the amine are crucial in selective stabilization of the TS and the extent

of acceleration that is observed.

2-methylcyclohexanone

TS containing LiHMDS dimer

and triethylamine

45

in Table 1.2, The switch from E to Z in the presence of HMPA (hexamethylphosphoramide)is particularly prominent for ester enolates

2-methyl-3-pentanone and ethyl propanoate, good selectivity is possible for both stereoisomers.

There are several important factors in determining regio- and stereoselectivity in enolate formation:- The strength of the base, - The identity of the cation, - The nature of the solvent and additives.

46

2,2-dimethyl-3-pentanone, the inherent stability difference between the enolates favors a single enolate, regardless of conditions

47

b. C. H. Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn, and J. Lampe, J. Org. Chem., 45, 1066 (1980).

%98 %2

66:3460:40

98:298:2

For example, the formation of the enolates from siloxyesters:

It has been suggested that this stereoselectivity might arise from a chelated TS in thecase of the less basic LiHMDS

(tert-Butyldimethylsilyl ethers)

Chelation affects the stereochemistry of enolate formation.

is Z for LiHMDS but E for LiTMP

LiTMP(lithium tetramethylpiperidide)

LiHMDS(lithium hexamethyldisilazan)

48

Kinetically controlled deprotonation of ,b-unsaturated ketones usually

occurs preferentially at the ’-carbon adjacent to the carbonyl group.

’

The polar effect of the carbonyl group is probably responsible for the faster

deprotonation at this position

49

Under conditions of thermodynamic control, however, it is the enolate corresponding to deprotonation of the g-carbon that is present in the greater amount.

These isomeric enolates differ in that 1 is fully conjugated, whereas the p system in 2 is cross-conjugated

In isomer 2, the delocalization of the negative charge is restricted to the oxygen and the ’-carbon, whereas in the conjugated system of 1 the negative charge is delocalized on oxygen and both the - and g-carbon

50

It is also possible to achieve enantioselective enolate formation by using chiral bases(chiral lithium amides)

Enantioselective deprotonation requires discrimination between two enantiotopic

hydrogens, such as in cis-2,6-dimethylcyclohexanone or 4-(t-butyl)cyclohexanone.

51

Enantioselective enolate formation can also be achieved by kinetic resolution throughpreferential reaction of one of the enantiomers of a racemic chiral ketone such as2-(t-butyl)cyclohexanone

52

2-(t-butyl)cyclohexanone

Such enantioselective deprotonations depend upon kinetic selection between

prochiral or enantiomeric hydrogens and the chiral base, resulting from

differences in diastereomeric TSs.

For example, transition structure E has been proposed for deprotonation of

4-substituted cyclohexanones by base D. This structure includes a chloride

generated from trimethylsilyl chloride.

Cl-

53

4-substituted cyclohexanones

potassium enolates equilibratemore highly substituted enolate is more reactive

When KO-t-Bu is used for the cleavage,

Regio isomer a Regio isomer b

54

(Dimethoxyethane)K

very strong Si−F bond(142 kcal/mol)

CH3

-CH3

-

T

55

K Control the corresponding trimethylsilyl enol ether can be obtained in high purity.

Trimethylsilyl trifluoromethanesulfonate (TMS-OTf), which is more reactive, gives primarily the less-substituted trimethylsilyl enolether

Under these conditions the kinetically preferred enolateis immediately trapped by reaction with trimethylsilyl chloride.

less-substituted silyl enol

More hinderedlithium amide fromt-octyl-t-butylamine (LOBA) 56

Lithium-ammonia reduction of ,b-unsaturated ketones provides a very useful method for generating specific enolates.

57

For acyclic enones, the TMS-Cl trapping of enolates generated by conjugate reduction gives a silyl enol ether having a composition that reflects the conformation of the enone.

trade name Selectrides®

58

Trimethylsilyl enol ethers can also be prepared by 1,4-reduction of enonesusing silanes as reductants

Pt complex of divinyltetramethyldisiloxane

This catalyst gives good yields of substituted silyl enol ethers59

Excellent yields of silyl enol have also been obtained from enones using B(C6F5)3 as a catalyst.

Another very important method for specific enolate generation is the conjugate addition of organometallic reagents to enones

60