Chapter 10
Protective groups
Topics:
• The strategy
• Protection of alcohols, carboxylic acids, thiols,
aldehydes 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 (nonorthogonal).
•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
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cost time and money.
‘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
protecting group complicate the manipulation and handling of the
material 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
perform 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 * orbitals as the lowest unoccupied molecular
orbitals.
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
are governed by *.
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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
solution of water or alcohol, catalytic hydrogenation(not including
benzylidene), 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 acid
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
conditions. 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; removal of the protecting group then involves hydrolysis
or reduction using lithium aluminium hydride.
•
Carboxylic acids are ususlly lprotected as esters or ortho esters,
deprotection again requiring hydrolysis,.
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•
For aldehydes and ketones, protetion usually involves the formation of an
acetal or ketal, the five- and six-membered cyclic derivatives (1, 3-dioxolanes
and 1,3-dioxanes, respectively) being particularly important. Deprotection
involves 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-
acyl derivatives (especially acetyl, trifluoroacetyl, benzoyl or phthaloyl) or as
carbamates. Hydrolytic or reductive methods of deprotection are employed,
according to the individual circumstances.
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