PROTECTION & DEPROTECTION

Introduction

The usual way of reacting a less reactive group in the presence of a more reactive one is to use a protecting group.

This tertiary alcohol, for example, could be made from a keto-ester if we could get phenylmagnesium bromide to react with the ester rather than with the ketone.

Due to the reactivity of carbonyl compound is :

One way of making the alcohol we want is to protect the ketone as an acetal.

An acetal-protecting group (shown in black) is used.

Via Mechanism :

The first step puts the protecting group on to the (more electrophilic) ketone carbonyl, making it no longer reactive towards nucleophilic addition.

The Grignard then adds to the ester, and finally a ‘deprotection’ step, acid-catalysed hydrolysis of the acetal, gives us back the ketone.

Alkylation of an alkynyl anion with this compound is not possible, because the anion will just deprotonate the hydroxyl group.

Protect the hydroxyl group, and the group chosen here was a silyl ether.

Such ethers are made by reacting the alcohol with a trialkylsilyl chloride (here t-butyl dimethyl silyl chloride, or TBDMSCl) in the presence of a weak base, usually imidazole.

Silicon has a strong affinity for electronegative elements, particularly O, F, and Cl, so trialkylsilyl ethers are attacked by hydroxide ion, water, or fluoride ion but are more stable to carbon or nitrogen bases or nucleophiles.

They are usually removed with aqueous acid or fluoride salts, particularly Bu4N+F- which is soluble in organic solvents.

1) Protection of Amines :

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 electron pair, which can be protonated or reacted with electrophiles (R-X).

To render the lone pair less reactive, the amine can be converted into an amide via acylation.

Protection of the amino group in amino acids plays a crucial role in peptide synthesis.

1.1) Benzyl Protection :

N-Benzyl groups (N-Bn) are especially useful for replacing the N-H protons in primary and secondary amines when exposed to organometallic reagents or metal hydrides.

Depending on the reaction conditions, primary amines can form mono and or dibenzylated products.

Hydrogenolysis of benzylamines with Pd catalysts and H, in the presence of an acid regenerates the amine.'

Generally, benzylamines are not cleaved by Lewis acids.

The nonpyrophoric Pd(OH)2(Pearlmens catalyst) catalyzes the selective hydrogenolysis of benzylamines in the presence of benzyl ether.

1.2) Amides :

Acylation of primary and secondary amines with acetic anhydride or acid chlorides furnishes the corresponding amides in which the basicity of the nitrogen is reduced, making them less susceptible to attack by electrophilic reagents.

Benzamides (N-Bz) are formed by the reaction of amines with benzoyl chloride in pyridine or trimethylamine.

The group is stable to pH 1-14, nucleophiles, organometallics (except organolithium reagents), catalytic hydrogenation, and oxidation.

It is cleaved by strong acids (6N HCl, HBr) or diisobutylaluminum hydride.

2) Protection of Alcohols :

The most important protecting groups for alcohols are ethers and mixed acetals.

The proper choice of the protecting group is crucial if chemoselectivity is desired.

Reactivity of Alcohols: l° > 2° > 3° ROH

2.1) Methyl Ethers :

Methyl ethers are readily accessible via the Williamson ether synthesis, but harsh conditions are required to deprotect them.

For hindered alcohols, the methylation should be carried out in the presence of KOH/DMSO.

Reagents for cleaving methyl ethers include Me,SiI (or Me,SiCl +I+NaI) in CH2Cl2 BBr3 in CH2Cl2 BBr3 is especially effective for cleaving PhOCH3.

2.2) Tert-Butyl Ethers :

t-Butyl ethers are readily prepared and are stable to nucleophiles, hydrolysis under basic conditions, organometallic reagents, metal hydrides, and mild oxidations.

However, they are cleaved by dilute acids.

2.3) Benzyl Ethers :

Benzyl ethers are quite stable under both acidic and basic conditions and toward a wide variety of oxidizing and reducing reagents.

Hence, they are frequently used in organic syntheses as protecting groups.

It should be noted, however, that n-BuLi may deprotonate a benzylic hydrogen, especially in the presence of TMEDA (tetramethylethylenediamine) or HMPA (hexamethylphosphoramide).

2.4) p-Methoxybenzyl Ethers:

The PMB ether, also refelred to as an MPM ether [(4-methoxyphenyl)methyl], is less stable to acids than a benzyl ether.

Its utility as a protecting group stems from the fact that it can be removed oxidatively with DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) under conditions that do not affect protecting groups such as acetals, RO-Bn (or RO-BOM), RO-MOM, RO-MEM, RO-THP, RO-TBS, benzoyl, tosyl, or acetate groups, nor do they affect epoxides or ketones.

Alternatively, RO-PMB ethers can be cleaved with (NH4)2Ce(NO3)6.

2.5) Silyl Ethers :

The popularity of silicon protecting groups stems from the fact that they are readily introduced and removed under mild condition.

Moreover, a wide variety of silylating agents are available for tailor-made protection of ROH groups.

The chemoselectivity of silylating agents for alcohols and the stability of the resultant silyl ethers toward acid and base hydrolysis, organometallic reagents, and oxidizing and reducing agents increases with increased steric size of the groups attached to silicon.

Generally, the sterically least-hindered alcohol is the most readily silylated but is also the most labile to acid or base hydrolysis.

a) Triethylsilyl Ethers

b) t-Butyldirnethylsilyl Ethers

2.6) Methoxyrnethyl Ethers

a-Halo ethers are often used for the protection of alcohols.

The high reactivity of a-halo ethers in nucleophilic displacement reactions by alkoxides permits the protection of alcohols under mild conditions.

Moreover, as acetals the alkoxy-substituted rnethyl ethers are cleaved with a variety of reagents.

The reaction of chloromethyl methyl ether (MOM-CI, a carcinogen) with an alkoxide or with an alcohol in the presence of i-Pr2NEt (Hunig's base) furnishes the corresponding formaldehyde acetal.

Alkylation of 3°-alcohols requires the more reactive MOM-I derived from MOM-C1 and NaI in the presence of i-Pr2Net.

Cleavage of the MOM group with dilute acids or with PPTS in t-BuOH regenerates thealcohol.

2.7) 2-Methoxyethoxymethyl Ethers :

MEM ethers are excellent protecting groups for l°, 2°, and 3° alcohols and even 3° allylic alcohols.

They are stable toward strong bases, organometallic reagents, and many oxidizing ents and are more stable to acidic conditions than THP ethers.

3) Protection of Diols :

Acetalization of 1,2- and 1,3-diols plays an important role in manipulating the reactivity of cyclic and acyclic polyhydroxy compounds.

Acetals derived from 1,2- and 1,3-diols are readily accessible via their reactions with ketones or aldehydes in the presence of an acid catalyst.

Once they are formed, acetals are very stable to basic conditions but are labile toward acids.

Both cis- and trans-1,3-diols form cyclic acetals with aldehydes in the presence of an acid catalyst to furnish the corresponding benzylidene and ethylidene derivatives, respectively.

4) Protection of ketones & Aldehydes:

Acyclic and cyclic acetals are the most important carbonyl protecting groups of aldehydes and ketones, and also serve as efficient chiral auxiliaries for the synthesis of enantiomerically pure compounds.

The acetal protective group is introduced by treating the carbonyl compound with an alcohol, an orthoester, or a diol in the presence of a Lewis acid catalyst.

In recent years, several transition metal catalysts such as TiCl4 have been shown to offer major advantage over general Brgnsted acid catalysts.

Acyclic acetals are somewhat unstable it will cleave faster as compare to cyclic acetals.

Reactivity Order :

5) Protection of Acid & Amine Oxazolins:

1,3-Oxazolines protect both the carbonyl and hydroxyl group of a carboxyl group.

The starting material, 2-amino-2-methylpropanol, is readily available.

6) Protection of Double Bond :

There are few reported efficient methods available for protecting double bonds.

Both halogenation-dehalogenation and epoxidation-deoxygenation are procedures that have been used for protection-deprotection of double bonds.

However, these procedures are limited in their application, especially in the presence of other functional groups.

Selective protection of double bonds has been achieved using cyclopentadienyl iron dicarbonyl tetrafluoroborate as a protecting group.

7) Protection of Triple bond :

Masking the potentially acidic proton of l-alkynes (pK, 25) is readily achieved by their conversion to the corresponding 1 -silyl- 1 –alkyne.

Protection of an internal triple bond (or an internal triple bond in the presence of a double bond)'1° can be done by converting the former to the dicobaltoctacarbonyl complex.

The following alkene hydroboration-oxidation example illustrates this approach :