Alcohol Protecting Groups

It has been presented in 59-331/333 that alcohols can be protected from much of their reactivity by
temporarily converted into a simple derivative, most often a type of ether. A reaction that is normally
incompatible with the alcohol can then be done on some other part of the molecule, and the end, the
alcohol can be recovered by ‘deprotection’ of the protecting group. The one protecting group that you
were given in 59-331 is the OTHP group, which is a type of acetal…

1) OTHP/OMOM Protecting Group

H
H +(cat) H
OH O O
+ + R
R such as p-TsOH,
O O
CH2Cl2, RT
dihydropyran ≡
OTHP
R

The OTHP protecting group is stable to many reagents that would normally consume an alcohol. These
include..

i) Bases such as NaH, KOtBu, LDA, LiTMP

ii) Nucleophiles such as NaOCH3, X-, lithium enolates, RLi (organilithiums), RMgBr (Grignards),
Ph3P=CH2 (Wittig reagents)
iii) Reductants such as H2 and Nio or Pdo, Na/NH3, NaBH4, LiAlH4, DIBAL-H (iBu2AlH)
iv) Oxidants such as OsO4, PCC/PDC, Swern, H2O2
-note that ozone (O3) does react

When it is desired to recover the alcohol, normally this is done via some combination of H+ and H2O,
taking advantage of the acid sensitivity of acetals.
CH3CO2H

O O THF-H2O, 45 o
R OH
R
p-TsOH
MeOH-H2O, RT
If you have taken alternative courses, you may be aware of other acetals that are very similar to the
OTHP, such as the OMOM protecting group.

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 O Cl
H3C
OH O OCH3 ≡ OMOM
R R R
i-Pr2NEt

CH2(OMe)2
O OCH3
R
p-TsOH, LiBr
Two sets of reagents have been given because chloromethyl methyl ether works really well, but the
reagent is a carcinogen.
In any event, the OMOM protecting group is stable and unstable to a similar set of reagents as the
OTHP. It also cleaves under acidic conditions, but the cleavage is slightly slower, so selectivity is possible.
On the other hand, if there were protecting groups that were cleaved under completely different types
of conditions, this selectivity business would be a lot easier. A selection of those protecting groups will
be covered here.
It is also worth mentioning that there are many ≡
other protecting groups that are slight variations on the R O OEt R OEE
same theme. One example is the ethoxyethyl group
ethoxyethyl
2) Benzyl (OBn) Protecting Group

A benzyl ether is a common and readily prepared protecting group for alcohols, with a conceptually
or chemically distinct (we’ll call this orthogonal) way of deprotecting. Since benzyl halides are
wonderful substrates for SN2 reactions, by far the most common way of making them is from the
alkoxide derived from the alcohol.

1) NaH _
O O Ph
R R
OH 2) X
R ≡
OBn
R
X = Br, Cl

O Ph
Note: Don't confuse this with OBz which is R
R
O
The O-benzyl group is stable to many of the same reagents as the OTHP, with the exception of a
couple (highlighted below). Furthermore, it is far more stable to acid that the OMOM or OTHP
group. Yes, very, very strong acids will cleave the OBn, traditional things like pH = 1 cause no
problems, whereas the OTHP and OMOM deprotect.

On the other hand, under conventional hydrogenation conditions, benzyl ethers tend to do a C-O
bond hydrogenolysis, and this is a very gentle way to do its deprotection. This is due to the fact the

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 benzyl substrate are excellent for oxidative addition reactions of Pdo or Nio. Of course, one has to
look out for any C=C or CΞC bonds elsewhere in the molecule, since they can hydrogenate
competitively.

H2, Pd/C, EtOH

O Ph OH
R +
or R H3C
H2, RaNi

Alternatively, benzyl ethers are also unstable to Birch reduction conditions (Na, NH3(l)). This is a
much less used method of deprotection, but can be used. With respect to both hydrogenolysis and
Birch conditions, the OMOM and OTHP groups are generally stable.

_
Na, NH3 (l) _
O Ph O H 2O
R O R OH
R • R

So an example of a selective deprotection is as follows.

R H2, Pd, EtOH R

THPO OBn THPO OH

3) p-Methoxybenzyl Protecting Group (R-OPMB)

The OPMB protecting group looks a lot like a normal benzyl ether, but with a catch. Certainly
though, since it’s also a type of benzyl ether, it is usually put on just like a benzyl ether.

1) NaH
OMe
OH 2) X ≡ OPMB
R O R
R
X = Br, Cl
The reactivity of this group to most things is just like a benzyl ether (including potential deprotection
by H2, Pd), but there is more electron donation now, to particularly stabilize a carbocation at the
benzylic site. If a reagent can be found to abstract H- (hydride), it can be deprotected with H2O. In
principle a simple benzyl ether could do this, but they are much less reactive so that they are
generally stable (or at least the PMB can be taken off first)

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 +
OMe -H- OMe OMe

O O O
R R R
+

H 2O

OMe OMe
OH + + H+
R O O
R
H OH
hemiacetal
The most common reagents to do this hydride abstraction are:

i) DDQ NC CN

O DDQ
O

Cl Cl

ii) Ph3C+ BF4- (commonly called trityl cation)

OMe DDQ
OTHP OTHP
O OH
R CH2Cl2, H2O, 40 min R

4) tert-Butyldimethylsilyl Ethers (R-OTBDMS or R-OTBS)

A completely different mode of deprotection is available if we leave the idea of using R-O-CR3 as the
alcohol protecting group, and go to R-O-SiR3. Certainly the protecting group R-O-SiMe3 is known, and
easy to make, but in this case the Si-O is too susceptible to H2O, and usually doesn’t survive things like
an aqueous workup of a reaction, or chromatography. On the other hand, these silyl ethers get more
stable if there are groups bulkier than methyl on silicon, and many such as R-O-SiEt3 and R-O-Si(iPr)3 (also
known as R-O-TIPS) as known. By far, the most commonly employed case has one of the methyl group of
TMS replaced by a tert-butyl group.

Bu-t
O O O
R Si Me ≡ R TBDMS
or R TBS
Me
The normal preparation uses imidazole as base and DMF as solvent. Otherwise, more conventional
bases and solvents can be used, but a more reactive replacement for TBDMS-Cl must be used as a
silylating reagent.

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 N , DMF
N Bu-t
H O
OH R Si Me
R
Cl-SiMe2Bu-t Me

Bu-t
OH N O
R 2,6-lutidine R Si Me
Me
t-BuMe2Si-OTf, CH2Cl 2

The deprotection of TBDMS ethers has a special feature. Certainly strong acids (pH 2) or strong bases
(pH >12) will remove silicon, but silicon has a tremendous affinity for fluoride ion that almost nothing
else has. As a result, a good F- source (particularly TBAF, n-Bu4N+F- ) will cleave the Si-O bond and affect
pretty much nothing else. This is normally highly selective.

Bu-t n-Bu4N+F- (TBAF)

O OH
R Si Me R
THF-H2O, RT
Me

Bu-t KF, 18-crown-6

O OH
R Si Me R
Me
The deprotection can be called “SN2-like”; I’d be interested in speculation as to why this term is used.

Once again, there are many useable variations on this protecting group, such the tert-
butyldiphenylsilyl group (TBDPS) and the triisopropylsilyl group (TIPS). These are more stable to acid
than the TBDMS, but also cleaved by F-.

5) Methyl Ethers (R-OMe)

Methyl ethers have been left last for a reason. For most of the methods it is the most robust of the
protecting group, and in most instances it is the ‘last’ group to come off. It is normally made by the
Williamson ether synthesis (involving an SN2 reaction of the alkoxide); the base employed vaies
with the substrate. Note for phenols, a weaker base can be used.

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 NaOH, n-Bu4N+I -

Me2SO4
OH KOH, DMSO OCH3
R R
MeI
1) NaH (or KH), THF

2) CH3-I or Me2SO4
OH K2CO 3, acetone, OCH3
R R
MeI, ∆
Or a specialty protocol that doesn’t use a base per se.
CH2N2, CH2Cl 2
OH OCH3
R R
HBF4 (or other acid)
These groups are stable to pretty much everything that has been discussed until this point. For
deprotection, generally a very strong acid is required, with a counterion that is nucleophilic (HBr, HI). In
practice, the (very strong) Lewis acid analogue is the one used synthetically. The most common version
is using BBr3:
OCH3 BBr3, CH2Cl2 OCH3
OCH3 or R OH or R
R R
low T to RT
The second most common reagents is Me3Si-I (TMSI):
OCH3 Me3Si-I, CHCl 3 OCH3
OCH3 or R OH or R
R R
RT
The ‘problem’ with this is, that these very aggressive conditions cleave pretty much all other protecting
groups.
For phenols only, there is an option stemming from the fact that phenoxide ion (the alkoxide derived
from phenol) is a leaving group, albeit a mediocre one. In these case, therefore, there is often success
employing reagents that are really good nucleophiles. Some examples are below:

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 EtSNa, DMF, ∆

LiI, collidine, ∆ OH
OCH3
R
R

1) Ph2P-Li +, THF, RT

2) HCl, H2O
Therefore, in general the methyl ethers can be cleaved more rapidly than ethers that aren’t as good at
SN2 reactions (ethyl, cyclohexyl ether, but not benzyl or allyl ethers).
It does mean that the presence of an electron withdrawing group on a benzene can be taken advantage
of…

EWG EWG
LiI, collidine, ∆

MeO HO
OMe OMe

This is mainly in introduction to selective protective group chemistry. For a far more extensive
version, with some really useful reactivity tables, see the Greene and Wuts books:
Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis” 2nd Ed. (1991), 4th Ed.
(2007)-my office; 3rd Ed (1999) Dr. Eichhorn’s office