Chem 35: Protecting Groups Handout

Most of the time a compound has more than one functional group that will react to a
given reagent. If the desired reaction only needs one functional group to react with the
reagent you need to protect the other functional group.

A protecting group (PG) is a group that protects a functional

group from a synthetic operation that it would not otherwise
survive.

In using PGs you add additional steps to carry out

your desired reactions.
o The first step is to convert the functional
group to another group that does not
interfere with the reaction by protecting or
the adding of a PG.
o The second step is to carry out the desired
reaction.
o The third and final step is deprotection or
the removal of a PG.

Fig. 2. Protection of Alcohol group with TBDMS ether

Deprotection: silyl ethers are usually removed with a

fluoride salt, usually tert-butylammonium fluoride.

Fig. 3. Deprotection of the Alcohol group with tert-butylammonium fluoride

Ethers
Methyl Ether (ROMe) Note that there are many ways to form ROMe with OH
but we will only give 3

Protection:
o Me2SO4, NaOH, Bu4NI, organic solvent, 6090% yield. This is an excellent and general method that
can easily be scaled up

MeI or Me2SO4, NaH or KH, THF. This is the

standard method for introducing methyl ether
onto hindered and unhindered alcohols.
o Me2SO4, DMSO, DMF, Ba(OH)2, BaO, rt,
18h, 88% yield.
Deprotection:
o Me3SiI, CHCl3, 25C, 6h, 95% yield. This
o

Fig. 1. General strategy in using protecting groups

IMPORTANT: The reaction in removing the PG must

not affect the other groups in the molecule.

reagent also cleaves many other ether type protective groups,

but selectivity can be maintained by control of the reaction
conditions and inherent rate differences between functional
groups.

Note that protecting groups can also be used to react less reactive
functional groups in a molecule by protecting the more reactive functional
group and carrying out the reaction.

PGs must only be used if necessary since the

addition of two more steps reduces the overall yield.

the most commonly used method for the cleavage of methyl

ethers because it generally gives excellent yields with a
variety of structural types. The solid complex BBr3Me2S that
is more easily handled can also be used. BBr3 will cleave
ketals.

Note: there are varying literatures about protecting groups and the list
provided below are a compilation of these various literature

Hydroxyl (-OH) Protecting Groups

o

-OH functional groups can be protected by using ethers, silyl

ethers, esters, acetals etc.

Protection: The PG will react with the molecule to

form a new O-X bond, wherein X is a group in the PG,
in place of the O-H bond of the alcohol.
o An example would be tertbutyldimethylsilyl ether (TBDMS ether).
The functional group is protected by reacting
the alcohol with TBDMS chloride and an
amine base, usually imidazole, as seen in
Fig. 2. Formed via SN2 rxn

BBr3, CH2Cl2, high yields. This method is probably

t-BuCOCl or AcCl, NaI, CH3CN, 37h, rt, 84%

yield. In this case the methyl ether is replaced by a pivalate
or acetate group that can be hydrolyzed with base.

Substituted Methyl Ethers

Methoxymethyl Ether (MOM Ether)

Protection:
o CH3OCH2Cl, i-Pr2Net, 0C, 1h25C, 8h,
86% yield. Most commonly employed procedure for MOM
introduction, choloromethyl methyl ether is carcinogenic, its
byproduct: dicholoromethyl methyl ether is even more toxic. A
procedure that does not produce both has been reported.

CH3OCH2Cl, NaH, THF, 80%

MOMCl, NaI, DIPEA, DME, reflux, 12h, 88%
yield. NaI increases the reactivity of MOMCl
Deprotection:
o
o

o
o

Trace conc. HCl, MeOH, 62C, 15 min.

Ac2O, BF3Et2O, 4C, 89% yield. This
reagent combination converts MOM ethers
to the AcOCH2OR ether which is cleavable
with base.
1,3-dithiane, BF3Et2O, 84% yield.

ethoxyethyl ether is more readily cleaved by acidic hydrolysis

than THP ether, but it is more stable than 1-methoxyethyl
ether. TBDMS ether are not affected by these conditions.

3 N HCl,
100C; 3 N NaOH, 100C; H2, 1200 psi; O3, MeOH, -78C; RaNi, 100C; LiAlH4;
Jones reagent and pyridinium chlorochromate (PCC).

Fig. 4. Example of protection via 1,3-dithiane

Methylthiomethyl Ether (MTM Ether)

Protection:
o NaH, DME, CH3SCH2Cl, NaI, 0C, 1h to
25C, 1.5h, >86% yield.
o CH3SCH2I, DMSO, Ac2O, 20C, 12h, 8090% yield.
o DMSO, Ac2O, AcOH, 20C, 1-2 days, 80%
Deprotection:
o HgCl2, CH3CN, H2O, 25C, 1-2h, 88-95%
yield. If water 2-methoxyethanol MTM becomes MEM, if

water methanol, MTM becomes MOM. If MTM ether has

adjacent hydroxyl, it is possible to form the formylidene acetal
as a by-product.

HgCl2, CaCO3, MeCN, H2O. The CaCO3, is

used as an acid scavenger for acid sensitive
substrates.

Methoxyethoxymethyl Ether (MEM Ether)

Protection:
o NaH or KH, MEMCl, THF or DME, 0C. 1060 min, >95% yield.
o MEMN+Et3Cl-, CH3CN, reflux, 30 min, >90%
yield.
o MEMCl, CHCl3, DIPEA, 0C
Deprotection:
o ZnBr2, CH2Cl2, 25C, 2-10h, 90% yield.
o TiCl4, CH2Cl2, 0C, 20 min, 95% yield.
o Me2BBr, CH2Cl2, -78C; NaHCO3, H2O, 8795% yield. This method also cleaves MTM and MOM
ethers and ketals.

others making it and its variants one of the most used pgs, but it can participate in
unwanted side rxns.

Protection:
o BnCl, powdered KOH, 130-140C, 86%
yield.
o BnX (X=Cl, Br), Ag2O, DMF, 25C, good
yields. This method is very effective for
monobenzylation of diols.
o BnOH, BiBr3, CCl4, rt, 76-95% yield.
Deprotection:
o H2/PdC, EtOH, 95% yield. (Reductively:
Hydrogenolysis)
o Na/NH3, or EtOH (Reductively: Single
Electron)
o Me3SiI, CH2Cl2, 25C, 15 min, 100% yield.
(Lewis Acid-Based) This reagent also cleaves most
other ethers and esters, selectivity can be achieved with
proper choice of conditions.

Methoxy-Substituted Benzyl Ethers More readily cleaved oxidatively

than the unsubstituted benzyl ethers

p-Methoxybenzyl ether (MPM/MPB Ether)

Protection:
o NaH, p-MeOC6H4CH2Cl, THF, 81% yield.
Most commonly used method for simple alcohol.

Ethoxyethyl Ether (EE Ether)

Protection:
o Ethyl vinyl ether, HCl (anhydrous)
o Ethyl vinyl ether, TsOH, 25C, 1h
o Ethyl vinyl ether, pyridinium tosylate (PPTS),
CH2Cl2, rt, 0.5h
Deprotection:
o 5% AcOH, 20C, 2h, 100% yield

Protection:
o From an alcohol: MeOC6H4I, CuI, Cs2CO3,
1,10-phenanthroline, 18-24h, 110C, 6493% yield.
o From a tosylate: p-MeOC6H4OH, DMF, NaH,
60C, 14h.
Deprotection:
o Ceric ammonium nitrate, CH3CN, H2O (4:1),
0C, 10 min, 80-85% yield or CAN, Pyr,
CH3CN, H2O, 0C, 0.5h, 96% yield.
o Treatment of PMP ether with Na/NH3 results
in the formation of an enol ether which can
be hydrolyzed to release the alcohol.

Benzyl Ether (Bn Ether) one of the most robust pgs, orthogonal to a host of

Substituted Ethyl Ethers

PPTS, n-PrOH, 80-85% yield. Acetonide was

not affected by these conditions

p-Methoxyphenyl Ether (PMP Ether) This group is stable to

0.5 N HCl, THF, 0C, 100% yield. The

p-MeOC6H4CH2Br (freshly distilled), THF,

TEA, KHMDS, -78C, 1h then rt 2h. The method
was used to protect a secondary neopentyl alcohol.

n-BuLi, Ph2PCl; p-MeOC6H4CH2OH,

fluoranil, CH2Cl2, rt, 3h, 30-94% yield. This
method works for a variety of ethers.

Deprotection:

Electrolytic oxidation: Ar3N, CH3CN, LiClO4,

20C, 1.4-1.7V, 80-90% yield. Benzyl ethers are

not affected by these conditions.

o
o

Dichlorodicyanoquinone (DDQ), CH2Cl2,

H2O, 40 min, rt, 84-93% yield.
SnCl4, PhSH, CH2Cl2, -78C to 50C, 5 min
to 1h, 88-93% yield. Benzyl, allyl, TBDMS ether are
stable along with various esters.

Silyl Ethers most frequently used hydroxyl protecting group

Trimethylsilyl Ether (TMS Ether)

Protection:
o Me3SiCl, Et3N, THF, 25C, 8h, 90% yield.
o Me3SiCl, Li2S, CH3CN, 25C, 12h, 75-95%
yield. Silylation occurs under neutral conditions with this
combination

Me3SiCl, Mg, DMF, rt, 70-99% yield. Tertiary

alcohols are readily silylated,

Deprotection: TMS are quite susceptible to acid hydrolysis, but acid

stability is quite dependent on the local steric environment.

o
o
o

Bu4NF, THF, aprotic conditions

BF3Et2O
K2CO3, anhydrous MeOH, 0C, 45 min,
100% yield.

Bu4NCl, KFH2O, CH3CN, 25C, 4 h, 95%

yield. Generates in situ TBAF, suitable for rxns that
normally requires anhydrous conditions.

Carbonyl Protecting Groups

In a synthetic sequence a carbonyl group may have to be protected against attack by
various reagents (e.g. Nu including organometallic reagents, reducing agents).
Because of the order of reactivity of the carbonyl group (aldehydes>acyclic ketones,
cyclohexanones> cyclopentatnone> , -unsaturated ketone, ,-disubstituted
ketones>> aromatic ketones) it may be possible to protect a reactive carbonyl group
selectively in the presence of a less reactive one.

In the protection of a carbonyl group, it reacts with diols to form

five or six-membered ring ketals or acetals.
Protection: The mechanism for the protection of the carbonyl
group is the same as that of the acetal formation, except that
instead of interacting with two separate molecules of alcohol,
the carbonyl group reacts with the two alcohol group of a
single molecule diol.
Deprotection: The PGs can be removed via Raney Ni and
Na/NH3 or via acid-catalyzed hydrolysis.

Triethylsilyl Ether (TES Ether)

Protection:
o Triethylsilyl triflate, pyridine or 2,6-lutidine,
CH2Cl2 or CH3CN
o Triethylsilane, catalytic B(C6H5)3, hexane or
CH2Cl2, 86-95% yield. Primary alcohols can be
reduced, alcohols and phenols: readily silylated, under
suitable condition can reduce some alcohol and ether

Fig. 5. Example of protection and deprotection of a carbonyl group.

Acyclic Acetals and Ketals

Dimethyl Acetals and Ketals: R2C(OCH3)2

o N-Methyl-N-triethylsilyltrifluoroacetamide
Deprotection: ~10-100 x more stable than TMS, shows much greater
stability to many reagents, methods used to cleave TBDMS can be used
to cleave TES

o
o
o

H2SiF6, IPA, -40C, 88% yield. Primary TES

group was removed in the presence of TBS
and TIPS
DDQ, CH3CN or THF, H2O, 86-100% yield.
TBDMS not usually cleaved
Ph3PHBr, MeOH, CH2Cl2, 0C, 80% yield.

ketals of diaryl ketones.

Protection:
o TBDMSCl, imidazole, DMF, 25C, 10h, high
yields. Most common method for TBDMS introduction on
alcohol with low steric demands, also silylates phenols

o
o

TBDMSCl, Li2S, CH3CN, 25C, 5-8h, 7595% yield. Rxn occurs under nearly neutral conditions
TBDMSCl, DMAP, Et3N, DMF, 25C, 12h.
Used to selectively silylate primary over secondary alcohol.

Deprotection:
o Bu4NF, THF, 25C, 1h, >90% yield. F ion is very
basic to moderate the basicity acetic acid can be added to the
soln

TBAF, NH4F, THF, rt, 30 min, 63% yield,

Ammonium fluoride was used to buffer the basic TBAF

LiBF4, ROH, (MeO)3CH, reflux, 72-100%

yield. Aromatic ketones and aldehydes react more slowly
but are efficiently derivatized

t-Butyldimethylsilyl Ether (TBS/TBDMS Ether)

Protection:
o MeOH, dry HCl, 2min.
o CH(OMe)3, MeNO2, CF3COOH, reflux, 4 h,
81-93% yield. Particularly effective for preparation of

Deprotection:
o TsOH, acetone
o Oxalic acid, THF, H2O, rt, 12 min, 72% yield.
o HCO2H, pentane, 1 h, 20C. Under these
conditions --double bond does not migrate into conjugation

Diisopropyl Acetal (i-PrO)2CHR

Protection: CH(Oi-Pr)3, CSA, IPA, removal of i-PrOH

by distillation, 68-92% yield.
Deprotection: Formic Acid, THF, H2O, 20C, 100%
yield.

Cyclic Acetals and Ketals

Protection: HOCH2C(CH3)2CH2OH > HO(CH2)2OH >

HO(CH2)3OH
Deprotection: acid-catalyzed hydrolysis

1,3 Dioxanes

Protection:

HO(CH2)3OH,
TsOH,
benzene, reflux
o HOCH2C(CH3)2CH2OH,
Sc(NTf2)3,
toluene, 0C,
3h, 87-92% yield.
Deprotection:
o For the most part, some form of aqueous
acid will cleave this ketals and acetals.
o TMSCl, SmCl3, THF, 71-99% yield. Ketals
are cleaved faster than acetals.
o

1,3-Dioxolanes
Protection of carbonyls containing other acid-sensitive
functionality use acids of low acidity or pyridinium
salts.
A molecule containing two similar ketones can be
selectively protected at the less hindered carbonyl.

Protection:
o HO(CH2)2OH, C5H5NTsOH, C6H6, reflux, 13h, 90-95% yield. This is a commonly used mild and
general method for dioxolane formation.

HO(CH2)2OH, Tetrabutylammonium
tribromide, triethylorthoformate, 21-97%
yield. This method produces HBr in situ and can be used to

carbamate is cleved preferentially

Ex: 2,2,2-Trichloroethyl Carbamate (Troc-NR2)

HO(CH2)2OH, Me3SiCl, MeOH or CH2Cl2. HCl

Deprotection: can be cleaved via acid-catalyzed exchange

dioxolanation, acid-catalyzed hydrolysis or oxidation

o
o
o

PPTS, acetone, H2O, heat, 100% yield.

Microwaves have been used to accelerate cleavage.
5% HCl, THF, 25C, 20h.
80% AcOH, 65C, 5min, 85% yield

Amino Protecting Groups

One of the many ways an amino group can be protected is by
being converted into an amide. The acetyl group can then be
subsequently removed via acid-catalyzed hydrolysis.

Protection:
o Cl3CCH2OCOCl, Pyr or aq. NaOH, 25C,
12h
o Silylate with Me3SiN=C(OSiMe3)CH3 then
treat with Cl3CCH2OCOCl
Deprotection:
o Zn, THF, H2O, pH 4.2, 30 min, 86% yield
o Cd-Pb, AcOH, 89-94% yield

Allyl Carbamates (Alloc-NR2 or Aloc-NR2): CH2=CHCH2OC(O)NR2

is produced insitu.

Protection:
o CH2=CHCH2OCOCl, Pyr
o (CH2=CHCH2OCO)2O, dioxane, H2O, reflux
or CH2Cl2, 1h, rt, 67-96% yield.
Deprotection:
o I2, CH3CN, H2O, 60C, 8-16h, 83-93% yield
o
Pd(Ph3P)4, Me2NTMS, 89-100% yield as the
TMS carbamate that is easily hydrolyzed. This
method was developed to suppress allylamine formation

Amides
Acetamide the simplest method for acetamide preparation is to react amine w/

acetic anhydride or acetyl chloride w/ or w/o added base. This method is quite reactive
thus are not usually selective. Below are some that tends to be more selective.

Protection:
o
C6F5OAc, DMF, 25C, 1-12h, 78-91% yield.

o
Fig. 6. Example of protection and deprotection of an amino group.

Carbamates
Protection:
o CH3OCOCl, K2CO3, reflux 12 h. Methyl

chloroformate is the most common reagent used for the

introduction of a methyl carbamate. Pyridine and TEA are the
most frequently used bases.

These conditions allow selective acylation of amines in the

presence of alcohols. If triethylamine is used instead of DMF
alcohols are also acylated.
CH3SO2NHAc, heat, 90% yield. This method can
also be used to transfer other acyl groups and is selective for
primary amines in the presence of secondary amines.

Deprotection: acetamides as well as other alkyl and aryl amides are

difficult to hydrolyze so you often need forcing conditions to achieve it

o
o

Methyl and Ethyl Carbamate (CH3OC(O)NR2)

KOH, H2O, ethylene glycol, 100C, 12h,

88% yield.
HBr, AcOH, 25C, 18h

Substituted Ethyl Carbamates

prepare both cyclic and acylic acetals.

Deprotection:
o Me3SiI, 50C, 70% yield. The most electron rich
o

If one carbonyl is conjugated with a double bond, the

unconjugated carbonyl is selectively protected.
Aldehydes are generally protected over ketones

CO, O2, MeOH, HCl, PdCl2, CuCl2

1.2 N HCl, reflux, 9h, 61-77% yield

85% Hydrazine, 70C, 15h, 68% yield

Trifluoroacetamide (TFA) R2NCOCF3 considered as one of the more

useful amides since it can be removed under mildly basic conditions.

Protection:

CF3CO2Et, Et3N, CH3OH, 25C, 15-45h, 7595% yield. Selectively protects a primary amine in the

Protection:

presence of a secondary amine. With DMAP catalysis

primary anilines are efficiently acylated with 75-98% yield

TFA, Ph3P, NBS, CH2Cl2, Pyr, 81-99% yield.

This method can be used to prepare other amides from
carboxylic acid

Deprotection:
o K2CO3 or Na2CO3, MeOH, H2O, rt, 55-95%
yield. TFA has been cleaved in the presence of methyl
ester which illustrates the ease of hydrolysis of the TFA
group.

t-Butyldimethylsilylalkyne and Thexyldimethylsilylalkyne

(TBDMS- and TDS- alkyne)

LiOHH2O, THF, MeOH, H2O, rt, 24h,

100% yield

for the TBDMS group, the TDS group behaves similarly

except that it is slightly more hindered, LHMDS can also be
used as base.

Benzamide R2NCOC6H5

Protection:
o PhCOCl, Pyr, 0C, high yield
o
PhCOCN, CH2Cl2, -10C, 92% yield. This
reagent readily acylates amines in the presence of alcohols

Deprotection:
o 6 N HCl, reflux, 48h or HBr, AcOH, 25C,
72h, 80% yield
o Ph3P, Cl2, TEA, CH2Cl2, -30C, then
ethylene glycol, 90% yield. This is a general
method applicable for a variety of amides

Alkyne Protecting Groups

Alkynes can be protected by adding a Grignard or lithium
reagent to the compound and forming an alkynyl Grignard or
alkynyl lithium reagent. Once you have an alkynyl Grignard or
alkynyl lithium reagent, you can react it with carbonyls, OTs,
TMS, etc.

Fig. 7. Example of protection and reaction of alkyne

Trialkylsilylacetylenes
Acetylenic hydrogen is often necessary bc of its acidity. The bulk of a silane can
protect acetylene against catalytic hydrogenation bc of the rate of difference bet olefin
and more hindered alkyne
Trialkylsilanes are usually formed by reacting silyl chlorides with Grignard or lithium
reagent.often used asa convenient method for introduction of acetylenic unit bc they
tend to be easily handled by solids or liquids compared to gaseous acetylene
Silyl acetylenes are prepared from alkynyl copper(I) reagents

Protection:
o KHMDS, THF, TBDMSOTf, -78C, 98% yield

TBDMSH, Ir4(CO)12, Ph3P, 120C, 40h, 95%

yield. This method works for the introduction of other silyl
ethers ex. TES derivative, but hydrosilylation occurs
sometimes to form vinylsilanes.

Deprotection:
o Bu4NF, THF, -23C, 75% yield
o Bu4NF, 2-nitrophenol, THF, 0-23C, 87%
yield. The 2-nitrophenol was added as a
weak acid to prevent the elimination of a
vinyl bromide.

Hydroxymethylalkyne (alkyne-CH2OH)

Protection:
o 2-methyl-2-hydroxy-3-butyne (source of
acetylyne)
Deprotection:
o NaOH, benzene, reflux, >96% yield
o For the hydroxymethyl derivative: MnO2,
KOH, Et2O, rt, 88% yield.