Chem 634 Fall 2013

Introduction to Protecting Groups

Prof. Donald Watson
"
Assistant Professor"
"
"

Protecting Groups
Protecting groups are groups of atoms that are attached to (and later removed
from) a functional group to mask it from competitive undesired reactions.
Without Protection:
R FG

Chemistry
to modify R

R FG P

Chemistry
to modify R

R' Y

With Protection:
R FG

R'

FG P

R'

FG

Advantages: Allows reactions that otherwise would not be possible.

Disadvantages: extra steps (at least 2 - protection and deprotection), lowered
yield, low atom economy, added mass of PG on substrate.
Considerations: protecting group and both protection / deprotection sequences
must be compatible with all other desired steps and other functional groups.

Protecting Groups

Bible of protecting groups:

Protective Groups in Organic Synthesis
by Theodora Green & Peter Wuts
Published by Wiley

Make sure you have access to this book

Note From Don

This lecture has a lot of different reactions, most of the mechanism are
very simple, or will be once we have covered a little more material in the
class.
For the sake of time, I have not included many mechanisms in this
lecture. However, do not mistake this for me thinking that they are not
important.
You need to be able to draw out every mechanism for every reaction in
this lecture.
Not only will this help you understand the material more deeply, but by
knowing what each reaction is doing, it will help you remember the
reagents needed for it.

ROH Protecting Groups

Silyl Protecting Groups

R O SiR3
Most Common:

SiR3

Name

Abbrevia.on

SiMe3

trimethylsilyl

"TMS"

SiEt3

triethylsilyl

"TES"

SitBuMe2

tertbutyldimethylsilyl

"TBDMS" or "TBS"

Si(iPr)3

triisopropylsilyl

"TIPS"

SitBuPh2

tert-butyldiphenylsilyl

"TBDPS"

ROH Protecting Groups

Silyl Ether Formation

R OH

R'3SiCl

R OSiR'3

imid or Et3N

R OH

R'3SiOTf
2,6-lutidine

R OSiR'3

imid = imidazole =
HN

Corey, JACS, 1972, 94, 6190

2,6-lutidine =
Me

Me

Corey, TL, 1981, 22, 3455

Note: Formation becomes harder as substitution of alcohol increases, and

size of silyl group increases. For example, TMS ethers are difficult with form
on 3 alcohols, others are nearly impossible.

ROH Protecting Groups

Stability of Silyl Ethers

Basic:
OH (5% NaOH/MeOH)
T1/2: TMS < TES < TBS < TIPS < TBDPS
1 min
24 h

Acidic:
H

(1% HCl/MeOH)

T1/2: TMS < TES < TBS < TIPS < TBDPS
<1 min
<1 min ~1 h
~4 h

R OSiR3'

R OH

(1)

Note: This data is for silyl ethers of

primary alcohols, gives relative
stabilities.
Also note: TMS is not a protecting
group for 1 alcohols. Too unstable!

ROH Protecting Groups

Deprotection of Silyl Ethers With Fluoride:
Fluoride:
F- (TBAF 0.06 M)

R OSiR3'

TBAF = Bu4NF

R OH

(1)
R OSiR3'

R OH2 + F SiR3'

Driven by strength of Si-F bond

strongest bond known.

T1/2: TMS < TES < TBS < TIPS < TBDPS
2.5 h
6.5 h

Other F- Sources:
Protic: TBAF (contains water), HFPy, Et3NHF, HF(aq), HOAc/CsF
Aprotic: (anhydrous)
TSAF= Ph3SiF2 S(NMe)3
TBAT= Bu4N Ph3SiF2

ROH Protecting Groups

Esters:
O

O
=
RO

CF3
(TFA)

R'

O
Ph
(Bz)

why ?

Formation:

Deprotection:
O

O
X
R'
base

O
RO

Me
Me
(Piv) Me

Me
(Ac)

Increasing Stability

ROH

NaOH
R'

RO
R'
O
RO

or
H

LiAlH4
R'

ROH

ROH

ROH Protecting Groups

Carbonates:
O
RO

OR'

Me
CH3
R'=
Me
methyl carbonate
Me
tBu
tert-butyl carbonate
(Boc)

allyl
(alloc)
9-Fluorenyl methyl carbonate
(Fmoc)

Cl
Cl
benzyl
(Cbz)

Cl
2,2,2-trichloroethyl
(Troc)

OTMS
(TEOC)

ROH Protecting Groups

Carbonate Formation:

O
R OH

Cl
or
O

OR'
O

R'O
O
OR'
base, (DMAP)

RO

OR'

ROH Protecting Groups

Carbonate Deprotection:
O
RO

K2CO3/MeOH

R OH

OMe

R O(Fmoc)
R O(Troc)
R O(Teoc)
R O(alloc)
R O(Cbz)
R O(Boc)

Et3N or Py
Zn/AcOH
F
Pd0 Et2NH
Pd/C, H2
H or

R OH
R OH
R OH
R OH
R OH
R OH

Carbonates (like many classes of protecting groups) have different conditions for
deprotection depending on the exact carbonate involved. This is advantageous
because many of the conditions are orthogonal, meaning you can remove one
without effecting the others. You need to learn the conditions for removing all of these
procecting groups. By the end of the course, you should be able to draw
mechanisms for each.

ROH Protecting Groups

Acetals:

RO
OMe
methoxy methyl ether
(MOM)

RO

Benzyoxy methyl ether

(BOM)

Me
RO
O
-Methoxyethoxymethyl ether
(MEM)

RO

TMS

2-trimethyl silyl ethoxy methyl ether

(SEM)

ROH Protecting Groups

Acetals:
Formation:
R OH

R'O

Cl

NaH, etc

RO

R'

Cleavage:
HCl
R OMOM

R OBOM

R OSEM

or Lewis acid
Na/NH3
or H2, Pd/C
F

R OH

R OH

R OH

ROH Protecting Groups

Cyclic Acetals:
tetrahydropyran
Formation:
O
R OH

H+

RO

tetrahydropyran "THP"
Note! mixture of epimers

Cleavage:
dilute H
R OTHP

H2O

R OH

ROH Protecting Groups

Ethers:

RO

RO
allyl

benzyl (Bn)

RO
OMe
p-methoxyl benzyl
"PMB"

Formation:

R OH

R'X
NaH, etc

RO R'

RO CPh3
trityl (Tr)

ROH Protecting Groups

Ethers:
Cleavage:
R

L4Pd0
HCO2Na

R OBn

R OPMB

R OH
or other reductant

H2, Pd/C
or Na/NH3
or DDQ (hard to do)
DDQ

R OH

R OH

O
DDQ= 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone =
(mild oxidant)

NC

Cl

NC

Cl
O

Protecting Groups for Diols

All ROH protecting groups work, but 1,2- or 1,3- can be protected in unique ways.
Acetals:
O
OH
OH
n=1 or 2
n

R
R'
cat. H+

can also use:

R'

R=R'=Me
"acetonide"

What is the mechanism?

MeO

MeO OMe
R

or
R

OMe
Me

Common:

Ph

Me
O

R
R
acetonide

O
R

benzylidine
acetal

O
R

O
R

p-methoxybenzyidine acetal

ROH Protecting Groups

Acetal Cleavage:
Me

Me

H
MeOH

HO

OH
n

Ph
O

Pd/C
or Na/NH3

HO

OH
n

OMe
DDQ

HO

OH
n

Protecting Groups for Carbonyls

O
R

O
R'

Common:

MeO OMe
R

R'

dimethyl acetal

MeS SMe
R

R'

R R'
1,3 dioxane

R'
1,3 dioxalane

Me Me
R R'
1,3 dithiane 1,3 dithiolane

Protecting Groups for Carbonyls

Acetal Formation:
MeOH

O
R

MeO OMe

or

R'

Me

Me

or

R'

HO

OH

anhydrous HCl
or Lewis acid
TMSOMe

O
R

MeO OMe

cat TMSOTf

R'

R'

Acetal Cleavage:

MeO OMe
R

R'

TsOH, acetone
or
HCl, H2O

O
R

R'

Protecting Groups for Carbonyls

Thioacetals:
Formation :
R'SH

O
R

SR'

SR'

R'

or

Me

Me

or

HS

SH

HCl
or Lewis acid

Cleavage:
SR'

SR'

R'

cond.
R

R'

(Generally
Oxidative)

Difficult!
Conditions: Hg(ClO4)2, CuCO3; NBS, AgNO3;
CuCl2, CuO, ; H2O2, NaOH; DDQ, BF3
No not worry about these mechanisms.

Thioacetals are robust

protecting groups, but often
very hard to remove. The
oxidative conditions for
removal often destroy
complex molecules. Use
only with proper planning
and foresight.

Note about Thioacetals

SR'

SR'

useful nucleophile,
synthetic equiv for

SR'

nBuLi
R

SR'
R

mildy acidic

Li

SR'
R1

R2

SR'

SR'

SR'

R2

R1

O
R2

R1

Note: As carbonyls are normally electrophilic, this is known as an umpolung strategy

(from German verb umpolen meaning reversed polarity).

Protecting Groups for Amines

RNH2, R2NH
Carbamates (very common):
O
R2'N

R'= Me, tBu, etc.

OR'

formation and removal same as for corresponding with carbonates

Protecting Groups for Amines

Alkyl Protecting Groups
Formation:
RNH2
P X , base
or
1 and 2:
R2NH P= Bn, allyl, Tr

RNHP
or
R2NP

note: over alkylation is a probelm with primary amines

O
1: RNH2

PG

RHN

NaBH4
prevents over alkylation

OAc
RR'NH

Pd(0)

RR'N

Removal is the same as with the alkyl ether PG's.

Protecting Groups for Amines

Amides
O
R'

N
R

Most common
(others hard to remove)

CF3

trifluoroacetomide

Formation:

O
R'

N
R

F3C

O
O

CF3

O
R'

Et3N

N
R

1 or 2

Removal:

O
R'

N
R

NaOH
CF3

R'

N
R

CF3

Protecting Groups for Amines

Sulfonamides (Avoid where possible)
O
N S
R O

R'

Me
Tosyl- "Ts'

Formation (easy):
R'
N H
R

TsCl
py

R'
N Ts
R

Removal (typically very hard with destroying substrate):

R'

Li/NH3
or SmI3

N Ts
R
strong reducing
conditions

R'
N H
R

Protecting Groups for Amides

(not a lot of options)

Alkyl Protecting Groups

Formation:
O
Cl

O
R

R
NHR

N
R

NaH or
C2CO3

O
BnBr or PMBCl

O
R

NHR

NaH or
C2CO3

N
R
R'
R' = H or OMe

Protecting Groups for Amides

Removal of Alkyl Protecting Groups from Amides
O
R

Pd (0)
N
R

red.

O
R

NHR

usually best option

O
R

N
R

H2, Pd/C
O

or tBuLi, O2 R
NHR

(Hard to remove from amides)

O
R

N
R

CAN

R
NHR
OMe
CAN = ceric ammonium nitrate = strong oxidant

Protecting Groups for Amides

Indirect Methods:
formation
Me
Me
Me

O
R

removal

NH2

O
R

Cl

TfOH
N
H

tBu

NH2

NHR'
O
R

MeO
Cl

OMe

O
R

N
R'

CAN
R

N
H

R'

para-methoxyphenyl
(PMP)

Note: these protecting groups are hard to install from an existing amide