ADVANCED ORGANIC CHEMISTRY
(20CY209)
Unit II: Protection and Deprotection Techniques
Syllabus:
Protection and Deprotection Techniques : Protecting Groups for
Alcohols: ester, ether, TBDMS, Protection of 1,2 and 1,3–diols:
Cyclic Acetal, Protecting Groups of Aldehydes and Ketones,
Protecting Group of Carboxylic Acid, Protecting Groups of Amino
Groups: Boc, CBz, etc. Use of protecting groups in multi-step
synthesis: Different protection and deprotection methods
• The Concept of Protecting Functional Groups
When a chemical reaction is to be carried out selectively at one reactive site in a
multifunctional compound, other reactive sites must be temporarily blocked.
• A protecting group must fulfill a
number ofrequirements:
• The protecting group reagent must react selectively
(kinetic chemoselectivity) in good yield to give a
protected substrate that is stable to the projected
reactions.
• The protecting group must be selectively removed in
good yield by readily available reagents.
• The protecting group should not have additional
functionality that might provide additional sites of
reaction.
• Protecting of NH groups
Primary and secondary amines are prone to oxidation, and N-H
bonds undergo metallation on exposure to organolithium and
Grignard reagents. Moreover, the amino group possesses a lone
pair electrons, which can be protonated or reacted with electrophiles.
To render the lone pair electrons less reactive, the amine can be
converted into an amide via acylation.
N-Benzylamine
Useful for exposure to organometallic reagents or metal hydrides
Benzylamines are not cleaved by Lewis acid
Pearlman’s catalyst
• Amides
Basicity of nitrogen is reduced, making them
less susceptible to attack by electrophilic reagent
The group is stable to pH 1-14, nucleophiles, organometallics (except
organolithium reagents), catalytic hydrogenation, and oxidation.
Cleaved by strong acid (6N HCl,
HBr) or diisobutylaluminum hydride
(DIBAL-H)
• Carbamates
Behave like a amides, hence no longer act as nucleophile
Stable to oxidizing agents and aqueous bases but may
react with reducing agents.
Iodotrimethylsilane is often the reagent for removal of this
protecting group
t-butoxycarbonyl group(Boc) is inert to hydrogenolysis and resistant to
bases and nucleophilic reagent. Cleaved by strong acid CF3CO2H or AlCl3
With
• Protection of OH groups of Alcohols
All ethers are stable to basic reaction conditions. Hence, ether or
mixed acetal protecting groups specifically tolerates
RMgX and RLi reagents
Nucleophilic reducing reagents such as LiAlH4 and NaBH4
Oxidizing agents such as CrO3•2Pyridine, PCC
Wittig reagents
Strong bases such as LDA
• Alkylethers
Prepared by Williamson ether synthesis
Harsh conditions are required to deprotect them.
or BBr3 in CH2Cl2
Especially good for PhOCH3
Sec-alcohol in sugars
• t-Butyl ethers
Stable to nucleophiles, hydrolysis under basic conditions,
organometallic reagents, metal hydrides, and mild oxidations
Cleaved by diluted acids (SN1 reaction)
• Benzyl ethers
Stable under both acidic and basic conditions and
toward a wide variety of oxidizing and reducing reagents.
Catalytic hydrogenolysis
• Acid-catalyzed Benzylation
Benzyl trichloroacetimidates, Cl3CC(=NH)OBn
Good for base-sensitive substrates such as hydroxy esters, lactones.
Readily hydrolyzed
• Trityl ethers: triphenylmethyl ethers
Selective protection
• Silyl Ethers
They are readily introduced and removed under mild conditions.
Generally, the sterically least-hindered alcohol is the most readily silylated
but is also the most labile to acid or base hydrolysis.
Silicon is a strong affinity for fluoride ion (bond energy, kcal/mol
Si-F, 143; Si-O, 111).
N-Bu4N+F- is soluble in organic solvent such as THF and CH2Cl2.
Unfortunately, TMS ethers are very susceptible to solvolysis in protic
media, either in the presence of acids or bases.
Cleavage occurs on treatment with citric acid in CH3OH at 20oC (10 min).
Used as protective groups in Grignard additions, Swern and Dess-Martin
oxidations, Wittig reactions, metallations with R2NLi.
• RO-TBDMS
TBDMS (t-Butyldimethylsilyl chloride) is the most widely used as silicon
protecting groups.
The rate of silylation of alcohol with TBSCl follows the trend: 1o ROH>
2o ROH > 3o ROH. This suited for the selective protection of the
-CH2OH group in methyl glycosides.
• Selective Deprotection
• Acetals
Tetrahydropyranyl Ethers
It is readily introduced by reaction of the enol ether dihyrdopyran with an
alcohol in the presence of an acid catalyst such as TsOH, BF3, POCl3.
THP group is readily hydrolyzed under aqueous acidic conditions with
AcOH-THF, TsOH, Dowex-H (cation exchange resin)
Diasteromers are possible.
MOM = Methoxymethyl
•
MEM = 2-Methoxyethoxymethyl
• Esters
The use of carboxylic acid esters as protective groups for alcohol is
limited since they undergo acyl susbtitution, hydrolysis or reduction.
Deprotection of esters is usually done under basic conditions.
Resistant to nucleophilc attack
including hydrolysis under mild
basic conditions. It can be cleaved
using metal hydride reagents.
• Selective
esterification
• Protection of Diols as Acetals
Acetalization of 1,2- and 1,3-diols plays an important role in manipulating
the reactivity of cyclic and acyclic polyhydroxy compounds.
Once they are formed, acetals are very stable to basic conditions but
are labile toward acids.
1,2-Diols
• Diols react with aldehydes and ketones in
the presence of an acid catalyst to yield
acetals in a reversible reaction.
• Acetal formation allows the selective
blocking of pairs of OH groups in
polyhydroxy compounds.
• Five- and six membered rings are formed
preferentially.
Method for removing H2O
a) Azeotropic distillation, b) Addition of
molecular Sieves, c) Transacetalization
Glucopyranose
Glucofuranose
Strong tendency for acetalization
of cis-1,2-diols: thermodynamic product
Kinetic acetalization (product)
without rearrangement
5-membered 1,3-dioxolane ring is favored even if one of the OH groups
is tertiary.
Preferential blocking of the two terminal 1,2-diol moieties
Cis- and trans-1,3-diols react with aldehyde to furnish the corresponding
benzylidene and ethylidene derivatives, respectively.
• Protection of carbonyl groups in aldehyde and ketones
The acetal protective group is introduced by treating the carbonyl compounds
with an alcohol, an orthoester, or a diol in the presence of a Lewis acid catalyst.
Several transition metal catalysts such as TiCl4 have been shown to offer
Major advantage over general Broensted acid catalysts.
1) General order of reactivity of various carbonyl group (probably due to
the steric effect)
2) 1,3-dioxanes(six-membered ring) hydrolyze faster than the corresponding
1,3-dioxolanes (five-membered ring acetal)
3) Acetals are stable to
strong aqueous bases, nucleophilic reducing agents, organometallic
reagents, oxidation under nonacidic conditions, Na or Li/NH3 reductions.
4) Acetals are cleaved by
acid-catalyzed hydrolysis
• Acetalization with Alcohols
• Acetalization with trialkyl orthoformates
• Acetalization with Diols
The formation of acetal with diols provides an entropic advantage
over the use of two equivalents of an alcohol. The water is removed
by azeotropic distillation.
Acid-catalyzed acetalization of a,b-unsaturated ketone may result
in double bond migration.
• Mechanism
R. Noyri developed a procedure that avoids migration of the double bond
during acetalization of a,b-unsaturated ketones.
• Chemoselectivity of Acetalization
Steric hindrance
Double bond increases the electron density at the carbonyl carbon
in a,b-unsaturated ketone.
• Chemoselective acetalization of the keto group
• Via S,S-Acetals
Since thioacetals are quite stable toward hydrolysis, there is no special
need to remove the H2O formed during the reaction. Since it is more
difficult to equilibrate thioacetals than acetal via protonation, double bond
migration in thioacetalization of enones is not usually observed.
An O,O-acetal moiety can be selectively deprotected in the presence of a
thioacetal protecting group.
• Deoxygenation of aldehyde and ketones
• Clemmensen Reduction
• Wolff-Kishner Reduction
• Protection of the Carboxyl Group
Protecting groups for carboxylic acids are used to avoid reaction of the
acidic COOH hydrogen with bases and nucleophiles or to prevent
nucleophilic additions at the carbonyl carbon.
• Alkyl esters
Classical method
A mild method for the specific preparation of methyl esters
Methanol with two equivalents of Me3SiCl
DCC = N,N′-dicyclohexylcarbodiimide
• Mitsunobu esterification under neutral conditions
• t-Butyl esters
t-BuO group provides steric shielding of the carbonyl carbon, thereby
lowering its susceptibility to attack by nucleophilic reagents. It is
cleaved by CF3CO2H or HCO2H in refluxing benzene.
• Benzyl ester: easily deprotected by hydogenolysis
• Aryl esters
BHT and BHA provide steric suppresion of the carboxylicreactivity
so they do not react with RMgX or RLi reagents.
Oxidative cleavage because of resisting toward hydrolysis
• Silyl Esters: resistant to attack of RMgX or RLi, and acid-induced
hydrolysis. Therefore, HF•pyridine is required for deprotection.
• Oxazolines: protect both the carbonyl and hydroxyl group of a carboxyl
group protecting group toward RMgX and LAH, not for RLi because the
protons at Ca may be deprotonated.
2-amino-2-metyhyl
propanol
• Orthoesters
Orthoesters are stable toward base but are readily hydrolyzed on exposure
to mild acids.
• Protection of Double Bond
Few report about protecting double bond: halogenation-dehalogenation
and epoxidation-deoxygenation. But limited use
• Protection of Triple bond
Masking the potentially acidic proton of 1-alkyne (pKa 25) is readily
achieved by their conversion to the corresponding 1-silyl-1-alkynes.
It can be removed under various conditions.
MeONa in MeOH, n-Bu4NF in THF, AgNO3 in EtOH
• Protection of an internal triple bond
D i c o b a l t o c t a c a rb o n y l c o m p l e x
Deprotection is achieved by oxidation of Fe(NO3)3
