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Chapter 10 Protective groups

Topics:

• The strategy

• Protection of alcohols, carboxylic acids, thiols, aldeh

ydes and ketones, 1,2 and 1,3-diols, amines.

• Some examples

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References:

1. Comprehensive Synthetic Organic Chemistry, 6, 631-701.

2. Protective Groups in Organic Synthesis 2nd ed. Greene, T.W.; Wuts, P.G.M

3. Synthetic Organic Chemistry Michael B. Smith, 629-672. A very smart discussion.

2.4. Advanced Organic Chemistry part B: Reactions and Synthesis 3rd ed. Carey, F.A.; Sundberg, R.J. pp. 677-92

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Some things to consider before you use protecting groups

•Know why and when do you need to protect a functional group.

•Don’t just protect a group because you have to go through x

number of steps.

•One must use protecting groups when the functionality (you

wish to preserve) and the reaction conditions necessary to

accomplish a desired transformation are incompatible (non-

orthogonal).

•If you can avoid protection of a group in a synthesis, you should

•It is much better to plan ahead and avoid protection

•Protecting groups add extra steps to your synthesis more steps

cost time and money.

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‘Good’ protecting groups . . .

Are small compared to the mass of what you are trying to make.

Can be applied and removed in great yield.

Allow the functionality to survive the reaction conditions necessary.

Do not introduce stereocenters. Uncontrolled stereo centers in the p

rotecting group complicate the manipulation and handling of the mater

ial because the amount of diastereomers increases.

Allow selective deprotection under mild conditions.

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Protection of alcohols

The simplest protection of the OH group is the methyl ether

Protects alcohols and phenols from a variety of chemical conditions

Difficult to remove, removal is not as difficult with phenols

Protection: Williamson Ether synthesis

NaH/THF/ROH/MeX

Deprotect: BBr3

Often this reagent is compatible with Lewis acid-sensitive functionality

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Protection of alcohols (Formation of benzyl ether (OBn))

Performs similarly to the methyl ether.

Protection: Williamson ether synthesis where the electrophile is something like Ph−CH2−Br.

Deprotection is much easier.

Deprotection is under hydrogenation conditions or Na/liq. NH3.

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Protection of alcohols (Formation of methoxymethyl ether (MOM))

• Installed by Williamson ether synthesis

• Deprotection

Can be hydrolyzed in aqueous acid

above example is from: Protective Groups in Organic Synthesis 2nd ed.

Greene, T.W.; Wuts, P.G.M p. 20.

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Protection of alcohols (Formation of silyl ethers)

Are not as difficult to cleave as the methyl ether and can p

erform similar function

Ease of cleavage is as follows Acidic condition

TMS > TES > TBDMS > TIPS > TBDPS

Basic condition

TMS > TES > TBDMS = TBDPS > TIPS

For example TMSO- can be deprotected in the presence of

tBuMe2Si-O

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Protection of alcohols (Formation of esters)

• Installed by treatment with the appropriate acyl chloride or

anhydride in the presence of base.

• Deprotection by hydrolysis in basic media or by reduction

with metal hydride.

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Protection of carboxylic acids

• Formation of esters– Methyl ester

– t-Butyl ester

– Ester of MOM, MEM, BOM, MTM and SEM

– Benzyl ester

– Allyl ester

– Silyl ester

• Formation of ortho esters

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Protection of aldehydes and ketones

Ketones and aldehydes have π* orbitals as the lowest unoccupied molecular orbi

tals.

Nucleophiles interact with this orbital by doing 1,2 addition

Bases interact with this orbital by deprotonation at the alpha position.

Two things can happen to: Addition and Deprotonation / polymerization. Both ar

e governed by π*.

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Protect the aldehyde selectively in the presence of ketones

1 MeOH, dry HCl, 2 min, reflux, 12 min

2 deprotection 2N H2SO4, MeOH, H2O, reflux

Reference: J. Chem. Soc. 1953, 3864.

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Ketalization is not the only thing that can happen.

Epimerization can also occur. Why?

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Protection of aldehydes and ketones: Cyclic acetals

• Formation of O,O-acetals

– Inert with metal hydride reduction, organolithium reagents, basic soluti

on of water or alcohol, catalytic hydrogenation(not including benzylide

ne), Li/NH3 reduction, oxidation in neutral or basic condition.

• Formation of S,S-acetals

• Formation of O,S-acetals

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Protection of aldehydes and ketones: O,O-acetals

Preparation: diol react with aldehydes or ketones in the presence of aci

d catalyst.

Acetal is prepared easier than ketal.

Cyclic is easier than acyclic.

Bulky carbonyl compound react slower.

Electron-withdrawing group of aromatic ring promotes the reaction.

Nomenclature

Deprotection by acidic hydrolysis, Lewis acids

1,3-dioxolane > 1,3-dioxane

1,3-dioxane of ketones > 1,3-dioxane of aldehyde

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Nomenclature 3-membered ring ether: oxirane, with two oxygen atoms: dioxirane

4 membered ring ether: oxetane, with two oxygen atoms: dioxetane

5 membered ring ether: oxolane or tetrahydrofuran, with two oxygen atoms: dioxolane

6 membered ring ether: oxane or tetrahydropyran, with two oxygen atoms dioxane

7 membered ring ether: oxepin, with two oxygen atoms: dioxepin

8 membered ring ether: oxocane, with two oxygen atoms dioxocane

1,4-dioxane 1,3-dioxane 1,4-dioxepin

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Protection of aldehydes and ketones: S,S-acetals

• Protection– RSH (R = Et, Pr, Ph), Me3SiCl, CHCl3, 20 °C, 1 h. > 80%yield

– B(SR)3 (R=Et, Bu, C5H11), reflux, 2 h

– PhSH, BF3•Et2O, CHCl3 0 °C, 10 min, ZnCl2, MgBr2

– RSH, TiCl4, CHCl3 0 °C.

– RSSR (R=Me, Ph, Bu), Bu3P, rt, reagent also reacts with epoxides.

• Deprotection– By transition metal salts

– By oxidation• AgClO4, H2O, C6H6,

• HgCl2, CdCO3, aq. acetone

• I2, NaHCO3, dioxane, H2O

• H2O2 , H2O , acetone

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Protection of 1,2- and 1,3-diols

Driving force is the

removal of water

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The scheme above tells you that the formation of the cyclic acetals depends heavily on ring strain.

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Protection of amines

• N-alkylation

– Not commonly used

• N-Acylation

– Converted to amide by acylation with acyl chloride or anhydride

• Formation of carbamates

– Most commonly used

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Summary

• Alcohols are most commonly protected as ethers, especially where the

ether function is in reality part of a (mixed) acetal or ketal; this enables

the protecting group to be removed under relatively mild acidic conditi

ons. Silyl ethers, especially where the silicon carries bulky substituents,

offer acid-stable alternatives, deprotection being effected by reaction

with fluoride ion. Alcohols may also be protected by esterification; re

moval of the protecting group then involves hydrolysis or reduction us

ing lithium aluminium hydride.

• Carboxylic acids are ususlly lprotected as esters or ortho esters, depro

tection again requiring hydrolysis,.

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• For aldehydes and ketones, protetion usually involves the formation of an acet

al or ketal, the five- and six-membered cyclic derivatives (1, 3-dioxolanes and

1,3-dioxanes, respectively) being particularly important. Deprotection involve

s acid hydrolysys. The formation of these cyclic acetals and ketals is also used

for the protection of 1,2- and 1,3-diols.

• Amines may be protected as N-alkyl (especially benzyl, trityl and allyl) or N-a

cyl derivatives (especially acetyl, trifluoroacetyl, benzoyl or phthaloyl) or as c

arbamates. Hydrolytic or reductive methods of deprotection are employed, acc

ording to the individual circumstances.