7 protective groups

Myers

Chem 115

Protective Groups – Silicon-Based Protection of the Hydroxyl Group

• In general, the stability of silyl ethers towards acidic media increases as indicated:

General Reference:
4th ed. John Wiley & Sons:
Greene, T. W.; Wuts, P. G. M. Protective Groups In Organic Synthesis, 3rd

TMS (1) < TES (64) < TBS (20,000) < TIPS (700,000) < TBDPS (5,000,000)
• In general, stability towards basic media increases in the following order:

York, 1991.
New Jersey,
2007.

TMS (1) < TES (10-100) < TBS ~ TBDPS (20,000) < TIPS (100,000)
Important Silyl Ether Protective Groups:
CH3
RO Si CH3
CH3

Et
RO Si Et
Et

Trimethylsilyl (TMS)

Triethylsilyl (TES)

CH3
RO Si i-Pr
CH3
Dimethylisopropylsilyl
Isopropyldimethylsilyl (IPDMS)

Greene, T. W.; Wuts, P. G. M. Protective Groups In Organic Synthesis, 3rd ed.
John Wiley & Sons: New York, 1991.
Half Life
Half Life
Silyl Ether
(5% NaOH–95% MeOH)
(1% HCl–MeOH, 25 °C)
n-C6H13OTMS

”1 min

”1 min

n-C6H13OSi-i-Bu(CH3)2

2.5 min

”1 min

Stable for 24 h

”1 min

”1 min

14 min

n-C6H13OTIPS

Stable for 24 h

55 min

n-C6H13OTBDPS

Stable for 24 h

225 min

n-C6H13OTBS
n-C6H13OSiCH3Ph2

CH3
RO Si t-Bu
CH3

Et
RO Si i-Pr
Et
Diethylisopropylsilyl (DEIPS)

t-Butyldimethylsilyl (TBS)

Ph
RO Si t-Bu
Ph
t-Butyldiphenylsilyl (TBDPS)

Davies, J. S.; Higginbotham, L. C. L.; Tremeer, E. J.; Brown, C.; Treadgold, J.
Chem. Soc., Perkin Trans . 1 1992, 3043.
• A study comparing alkoxysilyl vs. trialkylsilyl groups has also been done:

i-Pr
RO Si i-Pr
i-Pr

Triisopropylsilyl (TIPS)

R
R

i-Pr
O Si i-Pr
O
O Si i-Pr
i-Pr

R
O t-Bu
Si
O t-Bu
R

Di-t-butylsilylene (DTBS)
(DTBS)
Tetraisopropyldisilylene (TIPDS)
Tetraisopropyldisiloxanylidene
(TIPDS)Di-t-butyldimethylsilylene

General methods for the formation of silyl ethers:

ROH

R'3SiCl

Half Life
Bu4N+F– (0.06 M, 6 equiv)

Half Life
HClO4 (0.01 M)

n-C12H25OTBS

140 h

1.4 h

n-C12H25OTBDPS

375 h

> 200 h

n-C12H25OSiPh2(Oi-Pr)

<0.03 h

0.7 h

n-C12H25OSiPh2(Ot-Bu)

5.8 h

17.5 h

n-C12H25OPh(t-Bu)(OCH
OSiPh(t-Bu)(OCH
3) 3 )

22 h

200h

Silyl Ether

Gillard, J.W.; Fortin, R.; Morton, H. E.; Yoakim, C.; Quesnell, C. A.; Daignault, S.;
Guindon, Y. J. Org. Chem. 1988, 53, 2602.
ROSiR'3

imidazole, DMF

• Silyl groups are typically deprotected with a source of fluoride ion. The Si–F bond stength is

about 30 kcal/mol stronger than the Si–O bond.
Fluoride sources:

Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.

ROH

R'3SiOTf

ROSiR'3

2,6-lutidine,
2,6 lutidine, CH2Cl2
Corey, E. J.; Cho, H.; Rücker, C.; Hua, D. H. Tetrahedron Lett. 1981, 22, 3455.

Tetrabutylammonium fluoride, Bu4N+F– (TBAF)
Pyridine•(HF)x
Triethylamine trihydrofluoride, Et3N•3HF
Hydrofluoric acid
Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF)
Ammonium fluoride, H4N+F–
P. Hogan

1


• Monosilylation of symmetrical diols is possible, and useful.
NaH, TBSCl, THF

OH

HO
n

• Selective
Selective
deprotection
silyl
ethers
also
important,
and
also
subject
deprotection
ofof
silyl
ethers
is is
also
important,
and
is is
also
subject
toto
empirical
empirical determination.
determination.

OH

TBSO
n

75-97%
n = 2-6,10

McDougal, P.G.; Rico, J.G.; Oh, Y.; Condon, B. D. J. Org. Chem. 1986, 51, 3388.
HO

TBDPSCl, i-Pr2NEt, DMF, 23 °C

OH
n

TBDPSO

H 3C

CH 3

TBSO
TBSO

OH

75-86%

TESO

TESO

n

CH
CH33
O

n = 2,3,5,7,9

CH
3OBOM
CH
3 OBOM

H
O
AcO

O

Hu, L.; Liu, B.; Yu, C. Tetrahedron Lett. 2000, 41, 4281.
CH3
CH3
BuLi, THF; TBSCl
OHOH
OTBS OTBS
HO
HOHO
HO

88%
99%
CH3
CH3
Roush, W. R.; Gillis, H. R.; Essenfeld, A. P. J. Org. Chem. 1983,
1984 49, 4674.

H33C

H

CH3

N

OH
CH3

O

N
OTES
O

O

H

O

H

CH2Cl2, –78 °C
97%

H

H3C

CH2

HO

O

Ph

OH

H3C

H

H
O

N

O

H
H

O

O

H
H

CH3
O
CH3

O

H

N
OH
OH H
O

O

H
H

O

H
H

O
O

CH 2
O

OTES

OCH3

H
CH2

O

O
CH33

OH

CH3

OH

H
BzOAcO
BzO

O

Holton, R. A., et al. J. Am. Chem. Soc., 1994, 116, 1599.

Cl2CHCO2H
AcO

H

HO

CH3

Taxol
Taxol

OTIPS

N

O H3C

HO

H

OH

H

H
O
AcO

O

N
H

CH3

N
OTES
O

O

O
O
AcO

CH3

O
OH • TESCl/imidazole and
H
• TESCl/imidazole
TESOTf,
2,6-lutidine and

both
TESOTf,
2,6-lutidine
both
gave
the bis-silylated
product.
gave the bis-silylated product.
OCH3
O

H

H
O

CH
3OBOM
CH
3 OBOM

CH
CH33

0 °C, 11 h, quant.

O

O
TESCl, 2,6-lutidine

CH3

TBSO
TBSO

pyr•HF, CH3CN

• Selective protection of alcohols is of great importance in synthesis. Conditions often must be
determined empirically.
OTIPS
O
H
H
O

HO
HO

H3C

TBSO
H

OAc
O
O

HO
OTBS

AcO

90%

OAc

TBSO
H

CH3

OAc
O
O

HO
OH

OAc

CH3

CH3
O
O

OH

HO2C

O
HO2C
O
CO H
HO 2

OAc

CH3

Zaragozic acid

CH3
Br

Carreira, E. M.; Du Bois, J. J. Am. Chem. Soc. 1995, 117, 8106.

OCH3
OCH3

Phorboxazole B

Evans, D. A.; Fitch, D. M. Angew. Chem., Int. Ed. Engl. 2000, 39, 2536.

• Selective deprotections in organic synthesis have been reviewed: Nelson, T. D.;
Crouch, R. D. Synthesis 1996, 1065.
P. Hogan

2

Protective Groups – Protection of Hydroxyl Groups, Esters, and Carbonates

Myers
Esters and Carbonates

General methods used to form esters and carbonates:

O

O

RO

O

RO

O

Dichloroacetate

O
F

O
ROH

R'

O

O

pyr, DMAP
R'

O

RO

O
ROH

Benzoate (Bz)

Pivaloate (Piv)

Cl

O

pyr
OR'

RO

R

p-Methoxybenzoate

N

O

O

R'

RO

OCH3
Trifluoroacetate (TFA)

R'

RO

O

RO

CH3
H3C CH3

F F

R'

Cl

Trichloroacetate

O

RO

O

pyr, DMAP

Cl
Cl Cl

Cl

RO

ROH

RO
Cl

Cl
Chloroacetate

O

O

RO

CH3
Acetate (Ac)

Chem 115

OR'

O
X–

N

DMAP = 4-Dimethylaminopyridine:

RO

RO

O

O

O
H3C

RO

RO

N

CH3

O

9-(Fluorenylmethyl) Carbonate
(Fmoc)

RO

RO

O
Cl
Cl Cl

Allyl Carbonate
(Alloc)

O

O

RO

O

O
Si(CH3)3

2,2,2-Trichloroethyl Carbonate

2-(Trimethylsilyl)ethyl Carbonate

(Troc)

(Teoc)

• In general, the susceptibility of esters to base-catalyzed hydrolysis increases with the
acidity of the product acid.

O
RO
O

CH3
CH3
CH3

Benzyl Carbonate t-Butyl Carbonate
(Cbz)

DMAP is used to accelerate reactions between nucleophiles and activated esters. Neises,
B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522.

(Boc)

O

O
H3C
H3C

<

OCH3
CH3

O
OCH3

O

N CH3

OCH3

OCH3

O

O
<

H3C

<

<

CH3O

S
RO
H3C

CH3

• Proposed intermediate

Br
Methyl Carbonate

N

O

OCH3

p-Bromobenzoate

H3C

Cl

<
OCH3

Cl

Cl

O
OCH3

Cl

<

F
F

OCH3
F

Dimethylthiocarbamate (DMTC)

P. Hogan/Seth B. Herzon

3


Acetate Esters:
• Good selectivity can often be achieved in the selective deprotection of different esters.

• Several methods for forming and cleaving acetate esters have been developed. Lipases can often
be used for the enantioselective hydrolysis of acetate esters. The enantioselective hydrolysis of
meso diesters is an important synthetic transformation and racemic esters have been kinetically
resolved using lipases.

OAc

OH

H 3C
H3C

O

Acetyl cholinesterase

PCC

O

H3 C
H3C

O
O

O
O
O

94%, 99% ee
OAc

OAc

OAc

O

HO

OH

O
O

Deardorff, D. R.; Matthews, A. J.; McMeekin, D. S.; Craney, C. L. Tetrahedron Lett. 1986,
27, 1255.
• Lipases can also be effective for deprotection under very mild conditions, as in the case shown
below, where conventional methods were unsuccessful.

Cl

O
O

71%

OH

O
CH3O

O
OH

CH3

CH3

O

O
OAc

O

n-PrNH2

O

CH3O

HO

Cl

O

CH3
CH3

Lipase MY
0.1 M pH 7.2 buffer

Cl

O

O

OH
O

28 °C, 4 days

CH3
CH3

O

OH
O

O
O

O

Sakaki, J.; Sakoda, H.; Sugita, Y.; Sato, M.; Kaneto, C. Tetrahedron: Asymmetry, 1991, 2, 343.

CH3
O
OCH3

• A potentially general method for selectively acylating the primary hydroxyl group of a 1,2-diol
makes use
use of
of stannylene
stannylene acetals
acetals as
as intermediates:
intermediates:
makes
Bu2SnO,
HO

OBn
HO

toluene, 100 °C

CH3 N

AcCl,
O

AcO

OBn

O
Bu Sn
Bu

CH2Cl2, 0 °C

OBn
HO

CH3
O
HO
H
OH

Neocarzinostatin Chromophore
Myers, A. G.; Liang, J.; Hammond, M.; Wu, Y.; Kuo, E. Y. J. Am. Chem. Soc. 1998, 120,
5319.

Hanessian, S.;
1985,
41,41,
643.
Review: Hannessian,
S.;David,
David,S.S.Tetrahedron
Tetrahedron,
1985,
643.

P. Hogan

4

• When one protective group is stable to conditions that cleave another and the converse is also true,
these groups are often said to bear an orthogonal relationship. This concept is illustrated well in the
context of carbonates (and carbamates).

Allyl Carbonate:
O

Summary of methods for deprotecting carbonates:

Pd2(dba)3, dppe, Et2NH, THF

RO

ROH

O
Methyl Carbonate:
O

K2CO3, MeOH

RO

Genet, J.P.; Blart E.; Savignac, M.; Lemeune, S.; Lemaire-Audoire, S.; Bernard, J. Synlett 1993,
680.

ROH

OCH3

2-(Trimethylsilyl)ethyl Carbonate:
Meyers, A. I.; Tomioka, K.; Roland, D. M.; Comins, D. Tetrahedron Lett. 1978, 19, 1375.

O

TBAF, THF

RO
Si(CH3)3
• The pKa of fluorene is ≈ 10.3

O
RO

Et3N, pyr

O

ROH

O

9-Fluorenylmethyl Carbonate:

H

ROH

Gioeli, C.; Balgobin, S.; Josephson, S.; Chattopadhyaya, J. B. Tetrahedron Lett. 1981, 22, 969.

H

fluorene =
Benzyl Carbonate:
O

H2, Pd–C, EtOH

RO

ROH

O
Chattopadhyaya, J. B.; Gioeli, C. J. Chem. Soc., Chem. Comm. 1982, 672.
Trichloroethyl Carbonate:
Daubert, B. F.; King, G. C. J. Am. Chem. Soc. 1939, 61, 3328.

O

Zn, AcOH

RO

Dimethylthiocarbamate (DMTC):
ROH

O

S
Cl

Cl Cl

RO
N CH3
H3C

Windholz, T. B.; Johnston, D. B. R. Tetrahedron Lett. 1988, 29, 2227.

NaIO4 or

ROH

H2O2, NaOH

• The DMTC group is stable to a variety of reagents and reaction conditions (PCC oxidations,
Swern oxidations, chromium reagents, Grignard and alkyllithium reagents, phosphorous
ylides, LAH, HF, TBAF, and borane).
• The protecting group is introduced using thiocarbonyldiimidazole followed by treatment with
dimethylamine, or by reaction with commercially available ClCSN(CH3)2.
Barma, D. K.; Bandyopadhyay, A.; Capdevilla, J. H.; Falck, J. R. Org. Lett. 2003, 5, 4755.
P. Hogan/Seth B. Herzon

5


Myers

Cleavage of acetal protective groups:

Acetals as Protective Groups:

RO

Chem 115

Protective Groups – Protection of Hydroxyl Groups, Acetals

RO

OCH3

RO

O

Methoxymethyl Ether

Benzyloxymethyl Ether

(MOM)

(BOM)

O

CCl3

Methoxymethyl Ethers:
RO

2,2,2-Trichloroethoxymethyl Ether

ROH

OCH3

1. Conc. HCl, MeOH. Weinreb, S.; Auerbach, J. J. Chem. Soc., Chem. Comm. 1974, 889.
RO

OCH3

O

RO

RO

SCH3

O
OCH3

2-Methoxyethoxymethyl Ether

Methylthiomethyl Ether

p-Methoxybenzyloxymethyl
p-Methoxybenzyl EtherEther

(MEM)

(MTM)

(PMBM)

RO

O

H 3C
CH3
Si
CH3

O

2. Bromocatechol borane. This reagent cleaves a number of protective groups in
approximately the following order: MOMOR ʜ MEMOR > t-BuO2CNHR > BnO2CNHR ʜ
t-BuOR > BnOR > allylOR > t-BuO2CR ʜ 2° alkylOR > BnO2CR > 1° alkylOR >>
alkylO2CR. Boeckman Jr., R. K.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411.
3. LiBF4, CH3CN, H2O. Ireland, R. E.; Varney, M. D. J. Org. Chem. 1986, 51, 635.

Benzyloxymethyl Ethers:

OR

2-(Trimethylsilyl)ethoxymethyl Ether

Tetrahydropyranyl Ether

(SEM)

(THP)

RO

O

ROH

1. Na, NH3. Stork, G.; Isobe, M. J. Am. Chem. Soc. 1975, 97, 6260.
General methods for forming acyclic, mixed acetals:

ROH

R'OCH2X

2. H2, Pd–C. D. Tanner, D.; Somfai, P. Tetrahedron 1987, 43, 4395.
3. Dowex 50W–X8, acidic ion exchange resin. Roush, W. R.; Michaelidies, M. R.; Tai, D. F.;
Chong, W. K. M. J. Am. Chem. Soc. 1987, 109, 7575.

Base,
Solvent

RO

OR'

Base-solvent combinations are often diisopropylethylamine-CH2Cl2, NaH-THF, or NaH-DMF.
Sometimes a source of iodide ion is added to enhance the reactivity of the alkylating reagent. Typical
sources include Bu4N+F

LiI,or
orNaI.
NaI.
I––, ,LiI,

4-Methoxybenzyloxymethyl Ether:

RO
General methods for introducing 2-tetrahydropyranyl ethers:

OCH3

TsOH
ROH
O

or
PPTS

ROH

O

1. DDQ, H2O. Kozikowski, A. P.; Wu, J.-P. Tetrahedron Lett. 1987, 28, 5125.
O

OR

PPTS = Pyridinium
Pryidinium p-toluenesulfonate

Grieco, P. A.; Yoshikoshi, A.; Miyashita, M. J. Org. Chem. 1977, 42, 3772, and references
cited therein.

P. Hogan

6


2,2,2-Trichloroethoxymethyl Ether:

RO

O

CCl3

Tetrahydropyranyl Ether:

ROH
ROH

1. Zn–Cu or Zn–Ag, MeOH. Jacobson, R. M.; Clader, J. W. Synth. Commun. 1979, 9, 57.

O

OR

T. J.
2. 6% Na(Hg), MeOH, THF. Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T.J.
J. Am. Chem. Soc. 1990, 112, 7001.

1. PPTS, EtOH, 55 °C. Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem., 1977, 44, 1438.
2. TsOH, MeOH, 25 °C. Corey, E. J.; Niwa, H.; Knolle, J. J. Am. Chem. Soc. 1978, 100, 1942.
2-Methoxyethoxymethyl Ether:

RO

O

OCH3

ROH

1. ZnBr2, CH2Cl2. Corey, E. J.; Gras, J.-L.; Ulrich, P. Tetrahedron Lett. 1976, 809.

Methylthiomethyl Ether:

RO

SCH3

ROH

2. Bromocatechol borane. Refer to the section on MOM ethers.
3. PPTS, t-BuOH, heat. Monti, H.; Leandri, G.; Klos-Ringuet, M.; Corriol, C. Synth. Comm.
1983, 13, 1021.

1. HgCl2, CH3CN, H2O. Corey, E. J.; Bock, M. G. Tetrahedron Lett. 1976, 17, 3269.
2. AgNO3, THF, H2O, 2,6-lutidine. Corey, E. J.; Bock, M. G. Tetrahedron Lett. 1976, 17, 3269.
3. MgBr2, n-BuSH, Et2O. Kim, S.; Kee, I. S.; Park, Y. H.; Park, J. H. Synlett, 1992, 183.

2-(Trimethylsilyl)ethoxymethyl Ether:

RO

O

H 3C
CH3
Si
CH3

ROH

1. n-Bu4N+F–, THF. Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343.
2. TFA, CH2Cl2. Jansson, K.; Frejd, J.; Kihlberg, J.; Magnusson, G. Tetrahedron Lett. 1988,
29, 361.

P.Hogan

7


Myers

Chem 115

Protective Groups – Protection of Hydroxyl Groups, Ethers
Formation of trityl ethers:

Ethers as Protective Groups:

HO

TrO
O

HO
RO

OCH3
OH

O

Ph3CCl, DMAP
DMF, 88%

HO

OH

RO

OCH3
OH

OH

Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 19, 95. In general, selective
protection of primary alcohols can be achieved.

Allyl Ether

Trityl Ether

1. Amberlyst 15-H, MeOH. Malanga, C. Chem. Ind. 1987, 856.

RO

RO

Cleavage of trityl ethers:

2. CF3CO2H, t-BuOH. MacCross, M.; Cameron, D. J. Carbohydr. Res. 1978, 60, 206.
OCH3
Benzyl Ether

Formation of benzyl ethers:

p-Methoxybenzyl Ether

RO
ROH
R'

allyl ether formation:
Allyl

R' = H or OCH3

ROH

RO

1. NaH, allyl bromide, benzene. Corey, E. J.; Suggs, W. J.; J. Org. Chem. 1973, 38, 3224.
2. CH2=CHCH2OC(=NH)CCl3, H+. This procedure is useful for base-sensitive substrates.
Wessel, H.-P.; Iverson, T.; Bundle, D. R. J. Chem. Soc., Perkin Trans. 1 1985, 2247.

1. NaH, benzyl bromide, THF.
THF. Czernecki,
Czernecki,S.;
S.;Georgoulis,
Georgoulis,C.;
C.;Provelenghiou,
Provelenghiou,C.
C.
Tetrahedron
Lett. 1976,
1976,17,
Tetrahedron Lett.
17, 3535.
Theseare
areuseful
usefulconditions
conditionsfor
forbase-sensitive
base-sensitive
2. p-CH3OC6H4CH2OC(=NH)CCl3, H+. These
substrates.
Yonemitsu, O.
O. Tetrahedron

TetrahedronLett.
Lett.1988,
1988,29,
29,4139.
4139.Similar
Similar
substrates. Horita, K.; Abe, R.; Yonemitsu,
conditions
conditionshave
havebeen
beendeveloped
developedfor
forbenzyl
benzylethers:
ethers: White, J. D.; Reddy, G. N.;
Spessard,
Spessard,G.
G.O.
O.J.J.Am.
Am. Chem.
Chem. Soc.
Soc. 1988,
1988, 110,
110, 1624.
1624.
Marco,J.J.L.;
L.;Hueso-Rodriguez,
Hueso-Rodriguez,J.J.A.
A.Tetrahedron
Tetrahedron

3. p-CH3OC6H4CH2Cl, NaH, THF. Marco,
Lett.
Lett.1988,
1988,29,
29,2459.
2459.

allyl ether cleavage:
Allyl
1. The use of allyl ether protective groups in synthesis has been reviewed: Guibe, F. Tetrahedron 1998,
54, 2967.
2. Pd(Ph3P)4, RSO2Na, CH2Cl2. Honda, M.; Morita, H.; Nagakura, I. J. Org. Chem. 1997, 62, 8932.

Cleavage of benzyl ethers:
1. H2/ Pd-C, EtOH. Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746.
Ammonium formate is often used as a source of H2: Bieg, T.; Szeja, W. Synthesis
1985, 76.
Cleavage of 4-methoxybenzyl ethers:
1. DDQ, CH2Cl2. Benzyl ethers are stable to these conditions. Horita, K.; Yoshioka, T.;
Tanaka, T.; Oikawa, Y. Yonemitsu, O. Tetrahedron 1986, 42, 3021.
P. Hogan

8


Myers

The relative rates of hydrolysis of 1,2-O-alkylidene-_-glucofuranoses have been studied.

Protection of 1,2- and 1,3- Diols:

CH3
O
R'

HO H O

H3C CH3
O

O

Ethylidene Acetal

O

O

R'

n R

O

R'
R'

n R

O

nn R

O

R'
R'

Cyclopentylidene Ketal

Acetonide

R'

O

n R

R'

O

HO

Cyclohexylidene Ketal

O

O
R'

n R

O

O
R'

n R

3,4-Dimethoxybenzylidene
Acetal

Benzylidene Acetal 4-Methoxybenzylidene
Acetal

HO H O
HO

O

O
n R

Cyclic Carbonate

O

H 3C

CH3

H+
R'

R'

H3C CH3
CH3O OCH3
H3C

CH3

HO
R'

OH

O

H+
R'

n R

O
n R

Lewis acid plus hydride donor

O

R'

OCH3
H 3C

CH2

HO
R'

OH
n R

O

H+
R'
R'

O
nn R

R R''

H

O

n R

O
n R

R''

H

OH O

OH
R'

n R

O
[O]

O
O

R'

OH O

OH
n R

R'

R''

n R

Selective protection of polyols:
• In general, acetonide formation with 1,2-diols occurs in preference protection
to 1,3-diols;
to 1,3-diols;
benzylidene acetals
acetals display
display reversed
reversed selectivity.
selectivity. ItIt isis often
benzylidene
often possible
possible to
to discriminate
discriminate between
between
1,2- and of
1,3-diols
of a triol group.
1,2and 1,3-diols
a triol group.
OH OH

H3C
CH3
H3C CH3

n R

R'

n R

O

OH

R' R''

R'' H

O
n R

HO

n R

O

H3C CH3

n R

O
OH
HO

t1/2 = 124 h

HO

H+, H2O (ROH)

O

R'

R'

O

R' R''

General methods used to form acetals and ketals (illustrated for acetonides):

O

HO H O

O
OH
HO
t1/2 = 10 h

R' R''

OH

OH
HO
t1/2 = 20 h

General methods of cleavage:

• Generally, n = 0 or 1.

HO

CH3
CH3

O

Van Heeswijk, W. A. R.; Goedhart, J. B.; Vliegenthart, J. F. G. Carbohydr. Res. 1977, 58, 337.

R'

O

O

HO

OH
HO
t1/2 = 8 h

n R

O
O

HO H O

O

OCH3
OCH3

OCH3

O

Chem 115

Protective Groups – Protection of 1,2- and 1,3-Diols

acetone, TsOH

HO
CH3

CH3
H 3C
O
O

H3C CH3
O

OH

O

HO
CH3

CH3
5:1

Williams, D.
J. J.
Am.
Chem.
Soc.
1984,
106,206,
2949.
Williams,
D.R.;
R.;Sit,
Sit,S.-Y.
S.-Y.
Am.
Chem.
Soc.
1984,

2949.

P. Hogan

9


O

O
S
S

1) (CH3)2CO, CuSO4, TsOH

OH OH
Cl

S

2) NaOH, EtOH
3) CuI,
MgBr

OH

82%

O
H3C O

HH33CC O
H3C O

S

S
SOH
OH

CSA, H2O;

H
CH2
CH2

H

p-(CH
p-(CH
3O)C
6H
4(OCH3)23)2
3O)C
6H
4CH(OCH
67% over two steps
OTBDPS
CSA = camphorsulfonic acid
CH3
H 3C

O
OH

O HO
HO
O

CH3O

Mortlock, S. V.; Stacey, N. A.; Thomas, E. J. J. Chem. Soc., Chem. Comm. 1987, 880.
O
SO3H

• In the case of a 1,2,3-triol, careful analysis must be performed to accurately predict the site of
acetonide formation. The more substituted acetonide will be favored in cases where the substiuents
substituents
on the resultant five-membered ring will be trans. If the substituents on the five-membered ring would
be oriented cis, then the alternative, less substituted acetonide may be favored.

O

H3C

HO HO
HO
OH

OH

Ingenol analog
CH3
O

CH3

TsOH

O
1:10

OH

H3HC3C
CH
CH
3 3
OO
HH
O
O
HO
HO
HH
H3HC3C

OH OH

H

HO

CH3

O

CH3CN, PPTS

H

83%
OTBS

OH
H

H

O
OH

71%
N

OBn

OBn

CH3

CH3
CH3

OH
TrO

N
OH OH
O

N
H

O

TrO

O

MP

CH3
OH

O

N
N
H

O

MP = p-methoxyphenyl

N
OH OH

O

CH3

OH

O

N
O

PPTS, DMF, 23 °C, 96%
HO

CH3

OH

p-(CH3O)C6H4CH(OCH3)2,
N

HO
HO

Roush, W. R.; Coe, J. W. J. Org. Chem. 1989, 54, 915. See also, Mukai, C.; Miyakawa, M.;
Hanaoka, M. J. Chem. Soc., Perkin Trans. 1 1997, 913.

O

H
N

Frankowski, A.; Deredas, D.; Le Noen, D.; Tschamber, T.; Strieth, J.
Helv. Chim. Acta. 1995, 78, 1837.

OTBS

O
O
CH3
H3C

ZnCl2, PhCHO

OH

N
H 3C

OH

Ingenol

Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999,

121, 296.

H
N

O

C 3
H3CH
H
CH3
O
H
H
H

H3C

H
BzO HO
OH

H3 C

OTBDPS

N

O

N
O
H
Lampteroflavin, a source of bioluminescence.
Isobe, M.; Takahashi, H.; Goto, T. Tetrahedron Lett. 1990, 31, 717.
P. Hogan

10


Myers

Chem 115

Protective Groups – Selective Protection of Carbohydrates

• Selective protection methods are central to carbohydrate chemistry. The most common protective
groups in carbohydrate chemistry are acetonides, benzylidene acetals, and substituted benzylidene
acetals. This
This subject
subject has
has been
been reviewed:
reviewed: Calinaud,
Calinaud, P.;
P.;Gelas,
Gelas,J.J.ininPreparative
PreparativeCarbohydrate
Carbohydrate
Chemistry.

York, 1997.
1997.
Chemistry. Hanessian, S. Ed. Marcel Dekker, Inc.: New York,

OCH3

HO
O

OH

HO

H2 C

OH

CH3

O
H 3C
H3C

67%

OH
Selective Protection: thermodynamic control
HO
5 O 1 OH
6

acetone, H2SO4

H3C
H 3C

O H4

O 1

3
HO

O

2 O

CH3

• This reaction can be applied to many hexoses, including mannose, allose, and tallose
Kinetic vs. thermodynamic control with a pentose

CH3

1,2:5,6-Di-O-isopropylidene-D-glucopyranose

O
HO

H

O

O

p-TsOH,

OH

DMF, 64%

O

H3C CH3

H

OH
OH

Kinetic control
2-methoxypropene

HO
O

OH

OH

methyl-_-D-glucopyranoside

O
O
HO

• Note the preference for 1,3-diol protection with the
benzylidene acetal. The phenyl group is oriented
exclusively as shown, in an equatorial orientation.

HO

O
HO

OH

O
H 3C

slow

OCH3

O

methyl 4,6-benzylidene-_-D-glucopyranoside

OH

O
H

p-TsOH, DMF, 50%

Evans, M. E. Carbohydr. Res. 1972, 21, 473.

O

Leonard, N. J.; Carraway, K. L. J. Heterocycl. Chem. 1966, 3, 485.

3

OCH3

H
O

D-ribose

OCH3

OH

H

2-methoxypropene, HCl
70%

OH

HO

O

acetone, MeOH

OH

Schmidt, O. T. Methods Carbohydr. Chem. 1963, 2, 318.

OCH3
OCH3
OCH3
OCH

HO

Thermodynamic control

HO
O

HO

OH
OH

• Note that under kinetic control the most sterically accessible
(primary) alcohol
alcohol preferentially
is preferentially

attacked.
(primary)
reacted.

5
6

D-glucose

H

OH

Gelas, J.; Horton, D. Carbohydr. Res. 1979, 71, 103.

O

55%

3 2 OH
OH

O

O

D-galactose

4
HO

H

p-TsOH

O

H

OH

CH3

OH

fast
HO

OH
OH

The major isomer in solution is the pyranose form (ʜ 80%). Under
conditions that favor kinetic control, the least sterically encumbered
alcohol in this form reacts preferentially. Isomerization is proposed to
be slower than acetonide formation. This procedure also works well
with arabinose:

Selective Protection: kinetic control

OCH3

HO
O
HO

OH
OH

OH

H 2C

CH3

p-TsOH
95%

H
O
H 3C
H 3C

O

H

O

OH
OH

OH

D-glucose
Wolfrom, M. L.; Diwadkar, A. B.; Gelas, J.; Horton, D. Carbohydr. Res. 1974, 35, 87.

O

OH

O

2-methoxypropene

OH

H
HO

OH

p-TsOH, DMF, 60-70%

OH
D-arabinose

O
H3 C

O

H

OH

CH3

Gelas, J.; Horton, D. Carbohydr. Res. 1975, 45, 181.
P. Hogan

11


HO
O

Protection of cis-vicinal diols:

O

OCH3

OAc
AcO

H 3C
O

AcO
O

HO

_,_'-dichlorotoluene,

OCH3

O
O

pyr, reflux, 58%

OH

OCH3

H
H

OH

O
X

HO

H

• In general, cis-fused 5,6-systems
are formed faster than trans-fused
5,6-systems.

OH
OH
methyl-_-D-mannopyranoside

O
CH3O

O

O

H

H

O
O

dl-camphorsulfonic acid

O

OCH3
methyl-_-L-fucopyranoside
(derived from L-fucose)

O

OH

H

OH

AcOH, H2O
O

80 °C, 85%
H

O

O

CH3O

O

O

H

O

O

Kishi, Y.; Stamos, D.P. Tetrahedron Lett. 1996, 37, 8643
O

CH3

HO

OCH3

• Hydrolysis of the less substituted dioxane or dioxolane ring occurs preferentially in
substrates bearing two such groups.

O

Formation of dispiroacetals as a protective group for vicinal trans diequatorial diols:

HO

OH
O

Generalities concerning the selective removal of acetals and ketals:

O

Garegg, P. J.; Maron, L.; Swahn, C. G. Acta. Chem. Scand. 1972, 26, 518.

O

CSA, CH(OCH3)3, MeOH, reflux.
95%

HO

Hense, A.; Ley, S. V.; Osborn, H. M. I.; Owen, R. D.; Poisson, J.-F.; Warriner, S. L.;
Wesson., K. E. J. Chem. Soc., Perkins Trans. 1 1997, 2023.

OCH3
H

H

OH

O

OCH3
H 3C
OO
H3C
OCH3

BF3•OEt2 is also an effective catalyst at 23 °C.

AcO
OAc

OH

HO

(2,3-butanedione,
CH3 commercially

available)

OO
O

76%

OCH3
O
HO

H3C
H 3C

CH3

O H

O
HO

O

H

H
O
O

pH = 2, 40 °C

CH3
CH3

HO H
HO

4h
55% from
glucose

O

HO

H

H
O
O

CH3
CH3

Ley, S. V.; Leslie, R.; Tiffin, P. D.; Woods, M. Tetrahedron Lett. 1992, 4767.

Schmidt, O. T. Methods Carbohydr. Chem. 1963, 2, 318.

alsobeen
beendeveloped:
developed:

A cheaper alternative has also

• 2,2-disubstituted
2,2-disubstittued 1,3-dioxanes (6-membered rings) are generally hydrolyzed faster than the
corresponding dioxolanes (5-membered rings).
OH

HO
O
HO

OCH3

CH3O OCH3
CH3
H3C
CH3O OCH3

OH

OH
methyl-_-D-mannopyranoside

CSA, CH(OCH3)3, MeOH, reflux

O
OCH3
H 3C
OO
H3C

OCH3

91%

HO

OH
O

HO

1) 2-methoxypropene

OH

p-TsOH
2) Ac2O, py

OH

O
H3 C

O
CH3 H

D-mannose
OCH3
HO
HO

Montchamp, J.-L.; Tian, F.; Hart, M. E.; Frost, J. W. J. Org. Chem. 1996, 61, 3897.

H

OH

O

OAc

O
O
CH3
H3C

AcOH
H 2O
74% over
three steps

O

O
O
CH3
H 3C

CH3
H3C

O
O
O
H 3C

Horton, D.; Gelas, J. Carbohydr. Res. 1978, 45, 181.

OAc

O
O
OAc
CH3
P. Hogan

12


H
O
Special properties of benzylidene and substituted benzylidene acetals:

O

• In general, substitution of the ring of a benzylidene acetal with a p-methoxy substituent
increases the rate of hydrolysis by about an order of magnitude.

OCH3

is more rapidly hydrolyzed
hyrolyzed than
than
O

O

O

R'

O

R'

n R

n R

H

O

OCH3
OR'

Lewis acid

O

BnO

hydride donor

HO

OCH3

HO

OR'

OR

O

BnO

OCH3
OR'

OR

OR

A

B

R'

R'

Lewis acid

hydride donor

yield (regioisomer)

Ac

Ac

TFA

Et3SiH

95% (A)

Bn

Bn

TFA

Et3SiH

80% (A)

Bn

Bn

Bu2BOTf

BH3•THF

87% (B)

Bn

Bn

AlCl3

BH3•N(CH3)3

72% (A)

Bn

Bn

HCl, THF

NaBH3CN

82% (A)

Smith, M.; Rammler, D. H.; Goldberg, I. H.; Khorana, H. G. J. Am. Chem. Soc. 1962, 84, 430.

trifluoroaceticacid/triethylsilane
acid/triethylsilanereagent
reagentwas
wasineffective
ineffectivewith
withaagalactose
galactosederivative,
derivative,
• The trifluroacetic
however
and
other
ketals
and
acetals
however the
the others
others appear
apperartotobe
begeneral
generalmethods.
methods.Acetonides
Acetonides
and
other
ketals
and
acetals
can
can also

also be
be reduced,
reduced, so
so care
care in
in synthetic
synthetic planning
planning must
must be
be exercised.
exercised.

• Benzylidene acetals can also
can also
be cleaved
the reductively.
diol reductively.
be cleaved
fromfrom
the diol

Trifluoroacetic acid, triethylsilane :
DeNinno, M. P.; Etienne, J. B.; Duplantier, K. C. Tetrahedron Lett. 1995, 5, 669.

O
R'

O
n R

H2, Pd-C, AcOH

HO

or
NH3, Na (Birch reduction)

R'

OH
n R

Dibutylboron triflate, borane:
Chan, T. H.; Lu, J. Tetrahedron Lett., 1998, 39, 355.
Aluminum trichloride, borane trimethylamine complex;
Garegg, P. J. Pure. Appl. Chem. 1984, 56, 845.
HCl, sodium cyanoborohydride:
Qiao, L.; Vederas, J. C. J. Org. Chem. 1993, 58, 3480.

OCH3

TfOH, sodium cyanoborohydride
Kiessling, L. L.; Pohl, N. L. Tetrahedron Lett. 1997, 38, 6985.
O
R'

O
n R

Pd(OH)2, 25 °C, H2

HO
R'

OH
n R

Diisobutyl aluminum hydride is also an effective reagent for regioselective reduction of
benzylidene acetals. This reagent gives the more hindered ether.
Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593.
Oxidation of benzylidene and substituted benzylidene acetals:

• Methods have also been developed to cleave only one carbon-oxygen bond resulting in
in
the formation of a benzyl ether. This
Thisreaction
reactionhas
hasbeen
beenextensively
extensivelystudied
studiedin
inthe
thecontext
contextof
of
carbohydrate chemistry.

• Acetals containing a methine group may be oxidized at that position resulting in the formation
hydroxy
esters.

of a
hydroxy
esters.
R'
O
R

R'
O
n R

[O]

O

O
R

X
n R

• This transformation can be effected under a variety of condtions, and some
and some
variants
can be
variants
can be
used to further functionalize a substrate.
P. Hogan

13


General Reactions:

O

NBS

O

R

Proposed Mechanism:

O

O

n R

Br

R

n R

O
R

O

NBS

n R

H 2O

O

O
R

H

OH

O

n R

O

H

H
O

OCH3

O
•

NBS

OH

O

H

OH

O

OCH3
OH

OH

In the methyl 4,6-O-benzylidenehexopyranoside series, the oxidative formation of bromo
benzoates is a general reaction:
H
O
O

H

O

Br2

OCH3

NBS, BaCO3

OH

CCl4, 100%

O

Br

OCH3

O

OH

OH
O

Br
H

OH

H
O

H
O
O

H

O

OCH3

Br

NBS, BaCO3

OH

O

OH

O

O
H3C3
CH

H
H

O
H
H
H
O
O
O
H
OAc
OAc
OAc

AcO
AcO

NBS, bromotrichloromethane, then

O
O

H 3C

tetrabutylammonium
bromide
(anomerization)

CH3

O

O H
H
O

H
H
O
CH
H3C
3
AcO
AcO
AcO
AcO

O
O

O

OBz
O
OBz
H
O
O
H
OAc
OAc

H

O

O

H

OH
OH

O
CH
H3C3
AcO
AcO

O
O

OH
O

Br
Br

O
O
O
H

O O
O
O
O
H
OAc
OAc
OAc

79%
over two steps

H 3C

R'

CH3

O

O H
H
O

H
O
OH
HO

Collins, J. M.; Manro, A.; Opara-Mottah, E. C.; Ali, M. H.

J. Chem. Soc., Chem. Comm. 1988, 272.

OH

• Ozonolysis also cleaves acetals to hydroxy esters efficiently. This reaction has been
reviewed: Deslongchamps, P.; Atlani, P.; Frehel, D.; Malaval, A.; Moreau, C.
Can. J. Chem. 1974, 52, 3651.

CH3
CH3
Hg(CN)2

OCH3

O
H

O
O

Br

OCH3

OH

O

Br

• This reaction has also been used to generate glycosylating reagents
O
O

OH

O

OH

Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1035, 1045, and 1053.

H

H

OCH3

OH

O

CCl4, 67%

O

OCH3

O

O

H

O

O
CH3
CH3

R

O
O
n R

O3
–78 °C

R'

O
O

R

OH
n R

OH O

R

R'

n R

P. Hogan

14


H

O

O
O

• Hydroxy benzoates are obtained in the presence of water.
• The axial benzoate is usually obtained.

OCH3
CH3

NBS, BaCO3

OPiv

OO

Cl

O

TMS

OBz
OBz
X = Cl , 96%
X = Br, 93%

PMP = p-methoxyphenyl

DDQ =
NC

OPiv

Cl
O

O OH

O

H2O, 72%

O

O

X

MBzO
PMPCO
or
NBr–
DDQ, CuBr2, Bu4+NBr

OBz

NC
O

–

O

Binkley, R. W.; Goewey, G. S.; Johnston, J. C. J. Org. Chem. 1984, 49, 992

CH3

+

NCl
TMS DDQ, CuCl2, Bu4 NCl

OBz

H

CH33O
O

OCH3

O

Zhang, Z.; Magnusson, G. J. Org. Chem. 1996, 61, 2394.
2-electron
• 2electron oxidation
oxidation of
of 4-methoxybenzyl
4-methoxybenzyl groups
groups with
with DDQ
DDQ isis aa general
general reaction.
reaction.
• This has been used extensively to remove 4-methoxybenzyl ethers, and also to form
4-methoxybenzylidene acetals.
OCH3
CH3

O

OCH3

OCH3

OPiv

OO

CH3
H2O attacks exo face

O

OCH3
DDQ

OPv

OO
TBSO

HO

O

OH

H3C

H

CH3

TBSO

O

OH

H

OCH3
H3C

OTBS

CH3

OTBS

OCH3
• Only this lone pair is
available for donation
into the other C-O m*
orbital.

TBSO
TBSO

O

–H+

O

H

OCH3

H3C
CH3 CH3

A useful extension of this reaction has been developed to protect diols directly:

• Oxidation of 4-methoxybenzylidene acetals has also been studied:
H

O
CH3O

H

O

O
OBz

OBz

TMS

OTBS

Jones, A. B.; Yamaguchi, M.; Patten, S.; Danishefsky, S. J.; Ragan, J. A.; Smith, D. B.;

Schreiber, S. L. J. Org. Chem. 1989, 54, 17.

King, J. F.; Allbutt, A. D. Can. J. Chem. 1970, 48, 1754.

O

OCH3

OCH3
DDQ, AcOH, H2O

HO

O

MBzO

O

CH3

TMS

OBz
OBz

79% (19% of regioisomer)

OCOPh

CH3
HO

OH

CH3

CH3O

OCOPh

CH3
2.2 equiv DDQ
71%

O

O

MP H

Oikawa, Y.; Nishi, T.; Yonemitsu, O. Tetrahedron Lett. 1983, 24, 4037.
P. Hogan

15


Myers
Phenolic Protective Groups:

OCH3
Methyl Ether

O

Chem 115

Protective Groups – Protection of Phenols

SiR3

Silyl Ethers

t-Butyl Ether Formation:

CH3
CH3
O
CH3

O

O

t-Butyl Ether

Benzyl Ether

O

O

O

R

O

Phenyl Esters

O

Si

OH

Allyl Ether

1. Isobutylene, CF3SO3H, CH2Cl2, –78 °C. Holcombe, J. L.; Livinghouse, T. J. Org. Chem.
1986, 51, 11.
2. t-Butyl halide, pyr. Masada, H.; Oishi, Y. Chem. Lett. 1978, 57.

OR

Phenyl Carbonates

Ph

CH3
CH3

O
CH3

O

OR

Acetals

Ph
t-Bu

t-Butyldiphenylsilylethyl Ether

Methyl Ether Formation:

t-Butyl Ether Cleavage:
1. CF3CO2H, 25 °C. Beyerman, H. C.; Bontekoe, J. S. Recl. Trav. Chim. Pays-Bas.
1962, 81, 691.
• For the other phenol protective groups, the sections describing these groups in the context of
alcohols should be consulted. Most of the preparations used for alcohols are applicable to
phenols. Hydroxyl protective groups that are cleaved with base are generally more labile with
phenols.

t-Butyldiphenylsilylethyl (TBDPSE) ether formation:
DIAD, PPh3

OH

OCH3

OH

Ph
HO

Ph
Si

Ph
O

Si

Ph
t-Bu

t-Bu

1. MeI, K2CO3, acetone. Vyas, G. N.; Shah, N. M. Org Synth., Collect. Vol. IV 1963, 836.
2. Diazomethane, Et2O. Bracher, F.; Schulte, B. J. Chem. Soc., Perkin Trans. 1 1996, 2619.

• The TBDPSE group is stable to 5% TFA–CH2Cl2, 20% piperidine–CH2Cl2, catalytic
hydrogenation, n-BuLi, and lead tetraacetate.

Methyl Ether Cleavage:

• The TBDPSE group has been cleaved using TBAF (2.0 equiv, 40 °C, overnight) or 50% TFA–
CH2Cl2.

1. Me3SiI, CHCl3, 25-50 °C. This reagent also cleaves benzyl, trityl, and t-butyl ethers rapidly.
Jung, M. E.; Lyster, M. A. J. Org. Chem. 1977, 42, 3761.

Gerstenberger, B. S.; Konopelski, J. P. J. Org. Chem. 2005, 70, 1467.

2. EtSNa, DMF, reflux. Ahmad, R.; Saa, J. M.; Cava, M. P. J. Org. Chem. 1977, 42, 1228.
3. 9-Bromo-9-borabicyclo[3.3.0]nonane, CH2Cl2. Bhatt, M. V. J. Organomet. Chem. 1978,
156, 221.
P. Hogan/Seth B. Herzon

16


Myers

Protective Groups – Protection of the Carbonyl Group

Carbonyl protective groups:
OCH3
R
R' OCH3

Preparation of dimethyl acetals and ketals:

O
R
R' O

dimethyl acetal

O
R
R' O

1,3-dioxane

S,S'-dimethylthioacetal

1,3-dithiane

R

S
R
R' S

O
R
R' S

1,3-dithiolane

1,3-oxathiolane

3. Me3SiOCH3, Me3SiOTf, CH2Cl2, –78 °C. Lipshutz, B. H.; Burgess-Henry, J.; Roth, G. P.
Tetrahedron Lett. 1993, 34, 995.
4. Sc(OTf)3, (MeO)3CH, toluene, 0 °C. Ishihara, K.; Karumi, Y.; Kubota, M.; Yamamoto, H.
Synlett 1996, 839.

Approximate rates (L mol –1s–1 at 25-30 °C) for proton-catalyzed (HCl, water or dioxane-water)

cleavage of acetals and ketals.
H OEt

H OPh

OEt

OEt

OEt

OEt

O

5 X 103
O

O

O

H
H OEt

CH3

H

1. TFA, CHCl3, H2O. These conditions cleaved a dimethyl acetal in the presence of a

1,3-dithiane and a dioxolane acetal. Ellison, R. A.; Lukenbach, E. R.; Chiu, C.-W.
Tetrahedron Lett. 1975, 499.

H OEt
H

OEt

H 3C

Cleavage of dimethyl acetals and ketals:

3. 70% H2O2, Cl3CCO2H, CH2Cl2, t-BuOH; dimethyl sulfide. Myers, A. G.; Fundy, M. A.
M.; Lindstrom, Jr. P. A. Tetrahedron Lett. 1988, 29, 5609.

41

160

• Other dialkyl acetals are formed similarly.

2. TsOH, acetone. Colvin, E. W.; Raphael, R. A.; Roberts, J. S. J. Chem. Soc., Chem.
Commun. 1971, 858.

CH3O
6 X 103

O

OEt

PvO
PvO

5

1.2

R'

2. MeOH, LaCl3, (MeO)3CH. Acetals are formed efficiently, but ketalization is unpredictable.
Gemal, A. L.; Luche, J.-L. J. Org. Chem. 1979, 44, 4187.

aldehydes (aliphatic > aromatic) > acylic ketones ʜ cyclohexanones > cyclopentanones >
_!`-unsaturated ketones ʜ _!_"disubstituted ketones >> aromatic ketones.

H OEt
H

R

R'

1. MeOH, dry HCl. Cameron, A. F. B.; Hunt, J. S.; Oughton, J. F.; Wilkinson, P. A.; Wilson,
B. M. J. Chem. Soc. 1953, 3864.

General order of reactivity of carbonyl groups towards nucleophiles:

H3C OEt

CH3O OCH3

O

1,3-dioxolane

S
R
R' S

SCH3
R
R' SCH3

Chem 115

1.6

1.5 X 10–4

• In general, cyclic acetals are cleaved more slowly than their open chain analogs

TBSO
TBSO

• In general, dithio acetals are not cleaved by Brønsted acids.

O

O
H

H OCH
3

70% H2O2
Cl3CCO2H
t-BuOH, CH2Cl2

PvO
PvO
TBSO
TBSO

H

Me2S

H OOH

MeOH
80%

OCH33

Rates of acid-catalyzed cleavage of mono thioacetals and acetals have been determined:
H OEt

H SEt

OEt

160

H SEt

OCH3

41

H SEt

OEt

1.3

OCH33

PvO
PvO
TBSO
TBSO

H
O
O
H

• Other methods resulted in cleavage of the epoxide.

SEt

3.5 X 10–4

Satchell, D. P. N.; Satchell, R. S. Chem. Soc. Rev. 1990, 19, 55.
P. Hogan

17


Cyclic acetals and ketals:

ã When protecting _,ò-unsaturated ketones, olefin isomerization is common.

Relative rates of ketalization with common diols:
H3C CH3
HO
OH

>

CH3

OH

HO

HO

>

OH

OH

Cleavage of 1,3-dioxolanes vs. 1,3-dioxanes:

RR
R'
R'

O

R
R'

>
O

R
R'

O
O

>

O
O

O
O

A

B

Strong acids (pKa ʜ 1) tend to favor isomerization, while weaker acids (pKa • 3)
favor isomerization much less so, or not at all.
acid

pKa

%A

%B

O

fumaric acid

3.03

100

0

90

phthalic acid

2.89

70

30

90

oxalic acid

1.23

80

20

93

TsOH

< 1.0

0

100

100

CH3

R
R'

>

O

50,000

CH3
+

O

O

R
R'

CH3

OH
acid

O

Relative rates of cleavage for 1,3-dioxolanes:
CH3
CH3

HO

5000

% conversion

O
De Leeuw, J. W.; De Waard, E. R.; Beetz, T.; Huisman, H. O. Recl. Trav. Chim. Pays-Bas.
1973, 92, 1047.

O

• Generally, methods used for formation of 1,3-dioxolanes are also useful for formation of
1,3-dioxanes.

1

Okawara, H.; Nakai, H.; Ohno, M. Tetrahedron Lett. 1982, 23, 1087.
Cleavage of 1,3-dioxanes and 1,3-dioxolanes:
• In general, saturated ketones can be selectively protected in the presence of _!`-unsaturated ketones.

H 3C

O

O

O
O

CH3
Et

H 3C O O

OH

HO

1. PPTS, acetone, H2O, heat. Hagiwara, H.; Uda, H. J. Chem. Soc., Chem. Commun.
1987, 1351.
2. 1M HCl, THF. Grieco, P. A.; Nishizawa, M.; Oguri, T. Burke, S. D.; Marinovic, N.
J. Am. Chem. Soc. 1977, 43, 4178.

O

3. Me2BBr, CH2Cl2, –78 °C. This reagent also cleaves MEM and MOM ethers.
Guindon, Y.; Morton, H. E.; Yoakim, C. Tetrahedron Lett. 1983, 24, 3969.

p-TsOH•H2O, 95%
Bosch, M. P.; Camps, F.; Coll, J.; Guerrero, T.; Tatsuoka, T.; Meinwald, J.
J. Org. Chem. 1986, 51, 773.
• Conditions have been developed to protect _!`-unsaturated ketones selectively.
H 3C
O

O
TMSO

H 3C

OTMS

TMSOTf, CH2Cl2
–78 °C, 92%

4. NaI, CeCl3•7H2O, CH3CN. Marcantoni, E.; Nobili, F.; Bartoli, G.; Bosco, M.;
Sambri, L. J. Org. Chem. 1997, 62, 4183. This method is selective for
cleavage of ketals in the presence of acetals. It is also selective for ketals
of _,ß-unsaturated ketones over ketals of saturated ketones.

O
CH3 O
H3C
O

O
O

Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357.

H 3C

H
H

O
O

H

CH3 O

H3C
O

NaI, CeCl3•7H2O
CH3CN
23 °C, 2h
88%

H3C

H
H

H

O
P. Hogan

18


Dithioacetals:

S,S'-dialkyl
In addition to serving as a protective group, S,
S'-dialkyl acetals
acetals serve
serve as
as an
an umpolung

umpolung
synthon in the construction the
of carbon-carbon
bonds.
of carbon-carbon
bonds.

General methods of formation of S,S''-dialkyl acetals:
O

see below

O
R

R

S

SR

S

R
R' S

R
R' SR

R

R' S

1. RSH, HCl, 20 °C. Zinner, H. Chem. Ber. 1950, 83, 275.

R

CH3O

O

2. RSSi(CH3)3, ZnI2, Et2O. Evans, D. A.; Truesdale, L. K.; Grimm, K. G.; Nesbitt, S. L. J. Am.
Chem. Soc. 1977, 99, 5009.
3. RSH, BF3•Et2O, CH2Cl2. Marshall, J. A.; Belletire, J. L. Tetrahedron Lett. 1971, 871. See also
Hatch, R. P.; Shringarpure, J.; Weinreb, S. M. J. Org. Chem. 1978, 43, 4172. _!`-Unsaturated
ketones are reported not to isomerize under these conditions. However, with any of the above
mentioned conditions conjugate addition is a concern.

• A variety of methods has been developed for the cleavage of S,S''-dialkyl acetals, largely
due to the fact that these functional groups are often difficult to remove.

SR
=

CH3

Li
S

O

O

R

SR

O

CH3O

Cl

60%

CH3O

CH3

O

O

CH2

CH3O

CH3O

CH3
S

CH2

S
S

O

CH3

CH3

O

O
CH3O
General methods of cleavage of S,S''-dialkyl acetals:

Cl

O

Radicicol dimethyl ether
1. Hg(ClO4)2, MeOH, CHCl3. Lipshutz, B. H.; Moretti, R.; Crow, R. Tetrahedron Lett. 1989, 30,
15, and references therein.
2. CuCl2, CuO, acetone, reflux. Stutz, P.; Stadler, P. A. Org. Synth. Collect. Vol. 1988, 6, 109.

Garbaccio, R. M.; Danishefsky, S. J. Org. Lett. 2000, 2, 3127.

3. m-CPBA; Et3N Ac2O, H2O. Kishi, Y.; Fukuyama, T.; Natatsuka, S. J. Am. Chem. Soc. 1973,

95, 6490.
4. (CF3CO2)2IPh, H2O, CH3CN. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.

P. Hogan

19


Myers
Carboxyl Protective Groups:

R

OCH3

Methyl Ester

O

R

O

R

CF3

R

O

Allyl Ester

O
R

R

O
R

O

SiR3

Phenyl Ester

R'

Benzyl Ester

R'
O

O

Ortho Ester

Cl
O

N
P
O
O

Formation:
O

O
R

OH

OCH3

O
O

O

O
R''

1,3-Dioxalone

N

OR'

Methyl esters:

R'

R''
Silyl Ester

O
O

4-Methoxybenzyl Ester

O

R

CH2Cl2

BOPCl =

R

OR
OR
OR

O

Diago-Meseguer, J.; Palomo-Coll, A. L.; Fernandez-Lizarbe, J. R.; Zugaza-Bilbao, A.
Synthesis, 1980, 547.

OCH3
2,2,2-Trifluoroethyl Ester

OH

O

O
O

BOPCl, Et3N,

R'OH

1,1-Dimethylallyl Ester

O
O

R

O CH3 CH3

O

CH3
CH3

t-Butyl Ester

O
R

O

O CH3

O
R

Chem 115

Protective Groups – Protection of the Carboxyl Group

1. TMSCHN2, MeOH, benzene. Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm.
Bull. 1981, 29, 1475. This is considered a safe alternative to using diazomethane.
2. MeOH, H2SO4. Danishefsky, S.; Hirama, M.; Gombatz, K.; Harayama, T.; Berman, E.;
Schuda, P. J. Am. Chem. Soc. 1978, 100, 6536.

1,3-Dioxanone
Cleavage:

Specific to !- and "-hydroxy acids

General preparations of esters:

1. LiOH, MeOH, 5 °C. Corey, E. J.; Szekely, I.; Shiner, C. S. Tetrahedron Lett. 1977, 3529.
2. Pig liver esterase. This enzyme is often effective for the enantioselective cleavage of a
meso diester.
O

O
R

OH

R'OH

EDC•HCl or DCC, DMAP

OCH3
OCH3

O
R

O
PLE

O

OR'

OH
OCH3

pH = 6.8
98%, 96% ee

O

Kobayashi, S.; Kamiyama, K.; Iimori, T.; Ohno, M. Tetrahedron Lett. 1984, 25, 2557.
EDC•HCl = 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride
H3C

N
N C N Et
CH3 •HCl

O

CH3O

PLE

O
OCH3

OCH3
O

O

DCC = dicyclohexylcarbodiimide

O

CH3O
N C N

EDC•HCl is more expensive, but the urea by-product is water soluble and simplifies the
purification of products

O

O

CH3O

O
OH

O

er = 21.5

Mohr, P.; Rosslein, L.; Tamm, C. Tetrahedron Lett. 1989, 30, 2513.
P. Hogan/Seth B. Herzon
65

20


t-Butyl esters

1,1-Dimethylallyl esters

Formation:

Formation:

O

O

OH

R

R

CH3
O

1. CH3 CH3

CH3
CH3

Cl

R

O CH3 CH3

CuI, Cs2CO3

O
1. Isobutylene, H2SO4, Et2O, 25 °C. McCloskey, A. L.; Fonken, G. S.; Kluiber, R. W.; Johnson,
W. S. Org. Synth., Collect. Vol. IV. 1963, 261.

OH

2. H2, Lindlar's cat.

R

O

2. 2,4,6-trichlorobenzoyl chloride, Et3N, THF; t-BuOH, DMAP, benzene, 20 °C. Inanaga, J.;
Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
3. t-BuOH, EDC•HCl, DMAP, CH2Cl2. Dhaon, M. K.; Olsen, R. K.; Ramasamy, K. J. Org. Chem.
1982, 47, 1962.
4. i-PrN=C(O-tBu)NH-i-Pr, toluene, 60 °C. Burk, R. M.; Berger, G. D.; Bugianesi, R. L.; Girotra,
N. N.; Parsons, W. H.; Ponpipom, M. M. Tetrahedron Lett. 1993, 34, 975.

• The 1,1-dimethylallyl ester is removed under the same conditions as an allyl ester, but is less
susceptible to nucleophilic attack at the acyl carbon.
Sedighi, M.; Lipton, M. A. Org. Lett. 2005, 7, 1473.

Benzyl esters
Cleavage:
1. CF3CO2H, CH2Cl2. Bryan, D. B.; Hall, R. F.; Holden, K. G.; Huffman, W. F.; Gleason, J. G.
J. Am. Chem. Soc. 1977, 99, 2353.

O

O
R

OH

R

O

2. Bromocatechol borane. Boeckman Jr., R. K.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411.
Benzyl esters are typically prepared by the methods outlined in the general methods
section.
Allyl esters

Cleavage:

Formation:
O

O
R

1. H2, Pd–C. Hartung, W. H.; Simonoff, R. Org. React. 1953, 7, 263.
2. BCl3, CH2Cl2. Schmidt, U.; Kroner, M.; Griesser, H. Synthesis 1991, 294.

OH

R

O

Phenyl esters
Formation:

1. Allyl bromide, Cs2CO3, DMF. Kunz, H.; Waldmann, H.; Unverzagt, C. Int. J. Pept. Protein
Res. 1985, 26, 493.
2. Allyl alcohol, TsOH, benzene, (–H2O). Wladmann, H.; Kunz, H. Liebigs Ann. Chem.
1983, 1712.

O
R

O
OH

R

O

Cleavage:

Phenyl esters are typically prepared by the methods outlined in the general methods section.
They have the advantage of being cleaved under mild, basic conditions.

1. The use of allyl esters in synthesis has been reviewed. Guibe, F.: Tetrahedron 1998,
54, 2967.
2. Pd(Ph3P)4, RSO2Na, CH2Cl2. Honda, M.; Morita, H.; Nagakura, I. J. Org. Chem. 1997,
62, 8932.

1. H2O2, H2O, DMF, pH = 10.5. Kenner, G. W.; Seely, J. H. J. Am. Chem. Soc. 1972, 94,
3259.
P. Hogan/ Seth B. Herzon

21


Ortho Esters:
The synthesis of simple ortho esters has been reviewed: Dewolfe, R. H. Synthesis, 1974, 153.
OBO ester
O

O
R

OH

HO

1. Esterification

R

O

2. BF3•OEt2, CH2Cl2
–15 °C.

CH3

O
O

CH3

Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571.
Alternatively, ortho esters can be prepared from a nitrile:

1. HCl, MeOH
Br

CN

2.

O

Br

O

OH

HO

O

OH
68%

Voss, G.; Gerlach, H. Helv. Chim. Acta. 1983, 66, 2294.

Special Carboxylates, !-Hydroxy and "-Hydroxy:
n

R

O

OH OH

n

R
O

O

O
R''

Formation:
1. Ketone or aldehyde, Sc(NTf2)3, CH2Cl2, MgSO4. Ishihara, K.; Karumi, Y.; Kubota, M.;
Yamamoto, H. Synlett 1996, 839.
2. Pivaldehyde, acid catalyst. Seebach, D.; Imwinkelried, R.; Stucky, G. Helv. Chim. Acta. 1986,
70, 448, and references cited therein.

P. Hogan

67
22


Myers

Protection of amines:

Formation of benzylamines:

O

O

O

RR'N

Chem 115

Protective Groups – Protection of the Amino Group

O

RR'N

RR'N
RO
OCH3

O

O

CH3
CH3

CH3

RR'N
O
CCl3

9-Fluorenylmethyl
Carbamate
9-Fluorenylmethyl Carbamate 2,2,2-Trichloroethyl Carbamate t-Butyl
Methyl
Methyl Carbamate
Carbamate
Carbamate
2,2,2-trichloroethyl Carbamate t-Butyl Carbamate
(Fmoc)
O

O

O

RR'N

RR'N

If primary amines are the starting materials, dibenzylamines are the products.
O
RNH2

H

RHN

Mix and remove water;
NaBH4, alcoholic solvent

RR'N
O

O

Base
X = Cl, Br

O

RR'N

RR'N
O

(Boc)

(Troc)

X

RR'NH

CF3

Si(CH3)3

Formation of allylamines:
Allyl Carbamate

2-(Trimethylsilyl)ethyl Carbamate

Benzyl carbamate

(Alloc)

(Teoc)

Trifluoroacetamide

Br

RR'NH

(Cbz)

Base
RR'N

If primary amines are the starting materials, diallylamines are the products.
RR'N

RR'N

RR'N
OAc

RR'NH

Allylamine

Benzylamine

Tritylamine

Diisopropylamine,
Pd(PPh
Pd(Ph
3)4
3P)

RR'N

Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993, 58, 6109.

General preparation of carbamates:
O
RR'NH

RR'NH

Base

RO

Cl

O

O

RO

O

RO

Formation of tritylamines:

OR

Base
OR

O
RR'NH

O
RR'N

Su = succinimide

RR'N

CHCl3, DMF
RR'NH

Br

RR'N

OR
Base

O–Su

O

O
RR'N
OR

Mutter, M.; Hersperger, R. Synthesis 1989, 198.

Bases that are typically employed are tertiary amines or aqueous hydroxide.
P. Hogan

23


2,2,2-Trichloroethyl Carbamate:

Cleavage of carbamates:

Methyl Carbamate:
O
RR'N
O

RR'NH

O

RR'N

CCl3

RR'NH

OCH3

1. TMSI, CH2Cl2. Raucher, S.; Bray, B. L.; Lawrence, R. F. J. Am. Chem. Soc. 1987, 109, 442.
2. MeLi, THF. Tius, M.; Keer, M. A. J. Am. Chem. Soc. 1992, 114 , 5959.

1. Zn, H2O, THF, pH = 4.2. Just. G.; Grozinger, K. Synthesis, 1976, 457.
2. Cd, AcOH. Hancock, G.; Galpin, I. J.; Morgan, B. A. Tetrahedron Lett. 1982, 23, 249.
2-Trimethylsilylethyl Carbamate:

9-Fluorenylmethyl Carbamate:

O

O
RR'N

RR'N

O

O

RR'NH
Si(CH3)3

RR'NH

+F–
NF,
KF•H
CH
5050
ºC.
Carpino,
L. A.;
Sau,
A.A.
C.C.
J. J.
Chem.
Soc.,
Chem.
, KF•H
CH
°C.

Carpino,
L. A.;
Sau
Chem.
Soc.,
Chem.
1. Bu4N
2O,
3CN,
2O,
3CN,
Commun. 1979, 514.

1. Amine base. The half-lives for the deprotection of Fmoc-ValOH have been studied:
studied
Atherton, E.; Sheppard R. C. in The Peptides, Udenfriend,
Udenfriend,S.
S.and
andMeienhefer
MeienheferEds.,
Eds.,
Academic Press: New York, 1987, Vol. 9, p. 1.
Amine base in DMF

Half-Life

20% piperidine

6s

5% piperidine

20 s

50% morpholine

1 min

50% dicyclohexylamine

35 min

2. CF3COOH, 0 °C. Carpino, L. A.; Tsao, J. H,; Ringsdorf, H.; Fell, E.; Hettrich, G. J. Chem.
Soc., Chem. Commun. 1978, 358.
3. Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), DMF. Roush, W. R.;
Coffey, D.S.; Madar, D. J. J. Am. Chem. Soc. 1997, 49, 2325.
t-Butyl Carbamate
carbamate:
O
RR'N
O

10% p-dimethylaminopyridine

85 min

50% diisopropylethylamine

10.1 h

2. Bu4+NF,
F–, DMF.
DMF.Ueki,
Ueki,M.;
M.;Amemiya,
Amemiya,M.M.Tetrahedron
TetrahedronLett.
Lett.1987,
1987,28,
28,6617.
6617.
3. Bu4+NF,
F–, n-C
n-C88H
H17
SH. Thiols
Thiolscan
canbe
beused
usedtotoscavenge
scavengeliberated
liberatedfulvene.
fulvene.
17SH.
Ueki, M.; Nishigaki, N.; Aoki, H.; Tsurusaki, T.; Katoh, T. Chem. Lett. 1993, 721.

CH3
CH3
CH3

RR'NH

1. CF3COOH, PhSH. Thiophenol is used to scavenge t-butyl cations. TBS and TBDMS ethers
are reported to be stable under these conditions. Jacobi, P, A.; Murphree, F.;
Rupprecht, F.; Zheng, W. J . Org. Chem. 1996, 61, 2413.
2. Bromocatecholborane. Boeckman Jr., R. K.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411.

P. Hogan

24


Benzylamine:

Allyl Carbamate:
O

RR'N

RR'N
RR'NH

O

1. Pd(Ph
– 100%yield.
yield.Dangles,
Dangles,
O.;
Guibe,

Balavoin,
Lavielle,
Pd(PPh
70–100%
O.;
Guibe,
F.;F.;
Balavoin,
G.;G.;
Lavielle,
3P)
3)4, Bu3SnH, AcOH, 70
S.; Marquet, A. J. Org. Chem. 1987, 52, 4984.
2. Pd(Ph3P)4, (CH3)2NTMS, 89 – 100% yield. Merzouk A.; Guibe, F. Tetrahedron Lett. 1992,
33, 477.

RR'NH

1. Pd–C, ROH, HCO2NH4. Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515.
2. Na, NH3. Bernotas, R. C.; Cube, R. V. Synth. Comm. 1990, 20, 1209.
Allylamine:

Benzyl Carbamate:

RR'N

RR'NH

O
RR'N

RR'NH

O

1. Pd(Ph3P)4, RSO2Na, CH2Cl2. Most allyl groups are cleaved by this method, including
allyl ethers and esters. Honda, M.; Morita, H.; Nagakura, I. J. Org. Chem. 1997, 62, 8932.
Tritylamine:

Bergmann,M.;
M.;Zervas,
Zervas,L.
L.Chem.
Chem.Ber.
Ber.1932,
1932,65,
65,1192.
1192.
1. H2/Pd–C. Bergmann,
Theseconditions
conditionscleave
cleavethe
thebenzyl
benzylcarbamate
carbamatein
inthe
thepresence
presenceof
ofaabenzyl
benzyl

2. H2/Pd–C, NH3. These
ether. Sajiki,
Sajiki,H.
H.Tetrahedron
TetrahedronLett.
Lett.1995,
1995,36,
36,3465.
3465.

RR'N

RR'NH

Org.
Chem.
1974,
39,
1427.
CH22Cl
Cl22.. Felix,
Felix,A.A.M.
M.J. J.
Org.
Chem.
1974,
39,
1427.
3. BBr3, CH
4. Bromocatecholborane. This reagent is reported to cleave benzyl carbamates in the presence

of benzyl ethers and TBS ethers. Boeckman
BoeckmanJr.,
Jr.,R.
R.K.;
K.;Potenza,
Potenza,J.J.C.
C.Tetrahedron
TetrahedronLett.
Lett.
1985, 26, 1411.

1. 0.2% TFA, 1% H2O, CH2Cl2. Alsina, J.; Giralt, E.; Albericio, F. Tetrahedron Lett. 1996,
37, 4195.

Trifluoroacetamide:

O
RR'N
CF3

RR'NH

1. K2CO3, MeOH. Bergeron, R. J.; McManis, J. J. J. Org. Chem. 1988, 53, 3108.

P. Hogan

25