Selective oxidation of benzylic alcohols and TBDMS ethers to carbonyl compounds with CrO3-H5IO6

Article abstract of DOI:10.1055/s-2005-869975

Benzyl alcohols and benzyl TBDMS ethers were efficiently oxidized to the corresponding carbonyl compounds in high yield with periodic acid catalyzed by CrO₃ at low temperature (-78°C). The oxidation procedure was highly functional group tolerant and very selective for the TBDMS group over the TBDPS group. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869975

PAPER
1757
Selective Oxidation of Benzylic Alcohols and TBDMS Ethers to Carbonyl
Compounds with CrO3–H5IO6
Selective
O
xid
u
ation of Ben
h
zylic
A
lcoho
o
ls and TBD
M
n
S
Ethers g Zhang, Liang Xu, Mark L. Trudell*
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
Fax +1(504)2806860; E-mail: mtrudell@uno.edu
Received 2 November 2004; revised 10 February 2005
Table 1 CrO3–H5IO6 Oxidation of Benzylic Alcohols at –78 °C
Abstract: Benzyl alcohols and benzyl TBDMS ethers were effi-
ciently oxidized to the corresponding carbonyl compounds in high
yield with periodic acid catalyzed by CrO3 at low temperature (–78
°C). The oxidation procedure was highly functional group tolerant
and very selective for the TBDMS group over the TBDPS group.
Key words: chromium, oxidation, benzylic alcohols, aldehydes,
ketones
Entry Ar
H5IO6
(equiv)
CrO3
(mol%)
Yield
2 (%)a
a
b
c
Ph
2
1
0.5
0.5
0.5
1
86
Chromium-based reagents have played a vital role in or-
ganic chemistry as oxidants for alcohols to carbonyl com-
pounds.1 These transformations typically employ a
minimum of a stoichiometric amount of chromium re-
agent and in some systems require large excesses to obtain
complete conversion.1,2 These transformations are most
frequently accomplished by using highly toxic Cr(VI)-
based reagents. The development of chromium-catalyzed
oxidations is of great interest due to concerns of function-
al group selectivity and environmental factors.3,4 In our
previous studies, we found that chromium catalyzed peri-
odic acid (H5IO6) oxidation is a mild and very efficient
method for the oxidation of alcohols to carbonyl com-
pounds.5 In addition, we have found that a variety of func-
tional groups can tolerate the oxidation conditions of
various chromium–H5IO6 catalytic systems at low tem-
peratures.6–8
4-CH3OPh
3-CH3OPh
2-CH3OPh
4-CH3Ph
1.5
1.5
1.5
2
90
90
d
e
91
88
f
2-CH3Ph
2
1
87
g
h
i
4-HOPh
2
1
91
2-HOPh
1.2
2
5
90b
93
3,5-(t-Bu)2-4-HOPh
4-ClPh
1
j
2
1
88
k
l
4-NO2Ph
3-NO2Ph
2-NO2Ph
4-CF3Ph
3
1
78
1.5
1.5
1.5
1.5
2.2
2
10
10
10
5
92b
91b
55b
85b
52c
76
The tert-butyldimethylsilyl (TBDMS) moiety has been
widely used as a protecting group for alcohols.9 However,
available methods for the one-pot oxidation of TBDMS
ethers to carbonyl compounds are limited and often re-
quire either high reaction temperatures or long reaction
times.3,10–14 A mild and practical method for this conver-
sion would be of great synthetic utility. It was envisaged
that mild oxidation conditions of the chromium–H5IO6
catalytic systems coupled with the acidic reaction media
would be ideally suited for the one-pot transformation
of silyl ethers to aldehydes or ketones. Herein, we report
the selective oxidation of benzylic alcohols and benzylic
TBDMS ethers to afford the corresponding aldehydes and
ketones with the CrO3–H5IO6 catalytic system at –78 °C.
m
n
o
p
q
4-CH3O2CPh
4-HOCH2Ph
2-naphthyl
10
1
a Isolated yield.
b Reaction temperature –40 °C.
c Yield of dialdehyde.
tive oxidation of benzyl alcohols using stoichiometric
CrO3-based reagents is well established.15–17 However,
there are few examples where catalytic chromium systems
have been successful in providing good yields of the de-
sired carbonyl compounds.3,18 To this end, the CrO3–
H5IO6 catalytic system at –78 °C was found to oxidize
benzylic alcohols to the corresponding aldehydes and ke-
tones in high yields (Table 1). The selective oxidations of
benzylic alcohols with electron-donating (Table 1, entries
Our initial investigation explored the oxidation of a series
of commercially available benzylic alcohols 1 to furnish
the corresponding benzaldehyde derivatives 2. The selec-
SYNTHESIS 2005, No. 11, pp 1757–1760
x
x.
x
x
.
2
0
0
5
Advanced online publication: 27.06.2005
DOI: 10.1055/s-2005-869975; Art ID: M08704SS
© Georg Thieme Verlag Stuttgart · New York

1758
S. Zhang et al.
PAPER
b–i) or electron-withdrawing substituents (Table 1, en- under these oxidation conditions. Most of the starting ma-
tries j–o) were quick and efficient. Typically, 1 mol% of terial was recovered from the oxidations of these ethers.
catalyst and two equivalents of H5IO6 were required for However, at room temperature the TBDPS ethers
complete conversion within one hour. However, sub- (Table 2, entries g and h) were readily converted into the
strates with strong electron-withdrawing groups (Table 1, corresponding carbonyl compounds without over-oxida-
entries k–o) typically required higher catalyst loading to tion. These results suggested that at low temperature the
achieve the same reaction times. No over-oxidation prod- CrO3–H5IO6 oxidation offered a method for the selective
ucts were observed at this temperature even after extended conversion of the TBDMS group into a carbonyl group in
reaction times. It is noteworthy that the oxidation of phe- the presence of a TBDPS group or other protecting groups
nolic benzyl alcohols (Table 1, entries g–i) as well as the (BOC20 or MOM21). To this end, the TBDPS-TBDMS-
2-naphthalenemethanol (Table 1, entry q) gave clean dibenzyl ether (Table 2, entry k) was readily converted
products and high yields without competing formation of into a-(t-butyl-diphenylsilyloxy)tolualdehyde in 90%
quinone side-products.3,4
yield.
The ease with which the benzylic alcohols were oxidized The oxidation of non-benzylic TBDMS ethers 5 and 6
and the mildly acidic environment of the CrO3–H5IO6 ox- (Figure 1) was also investigated. At –78 °C after extended
idation conditions prompted further investigation into de- reaction times (1–3 h) a very small amount of the corre-
veloping a tandem silyl ether cleavage/oxidation sponding carbonyl compounds was observed (TLC) while
procedure for benzylic silyl ethers. The TBDMS group the majority of the reaction mixtures were comprised of
was the focus of this study because of its versatility and mostly alcohol resulting from hydrolysis of the TBDMS
utility in organic synthesis. The TBDMS ethers 3 em- ether. These results further demonstrate the high
ployed in this study were readily prepared from commer- chemoselectivity of the CrO3–H5IO6 system at –78 °C for
cially available benzylic alcohols using established benzylic TBDMS ethers and alcohols. At this low temper-
procedures.19 The results for the one-pot oxidation of ature the mildly acidic reaction media readily hydrolyzed
TBDMS ethers are summarized in Table 2. Primary and the primary and secondary TBDMS ethers but the result-
secondary benzylic TBDMS ethers 3 were quickly and ef- ant alcohols were virtually unreactive toward the concom-
ficiently oxidized to yield the corresponding carbonyl itant oxidation.
compounds 4 when treated with CrO3 (1 mol%) and H5IO6
(3 equiv) at –78 °C. The TBDPS, MOM and BOC
(Table 2, entries g–j) protecting groups were not affected
Table 2 CrO3–H5IO6 Oxidation of Benzylic TBDMS Ethers
Figure 1
In summary, we have developed a mild and efficient
method for the oxidation of benzylic alcohols to benzalde-
hydes. In addition, a direct oxidation method for the con-
version of TBDMS ethers into carbonyl compounds with
CrO3–H5IO6 at –78 °C was developed. This method is su-
perior to other methods currently available, offering high-
er yields and shorter reaction times. The method is highly
selective for the TBDMS group over the TBDPS group
and is orthogonal to other traditional hydroxyl protecting
groups.
Entry
X
R
P
Yield (%)a
a
b
c
d
e
f
H
H
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDPS
TBDPS
MOM
85
Cl
H
86
CH3
H
88
OCH3
H
91
NO2
H
90b
95
All chemicals were purchased from Aldrich Chemical Co., Milwau-
kee, WI, unless otherwise noted. Anhydrous MeCN and CH2Cl2
were purchased from Mallinckrodt-Baker, Inc. Chromatography re-
fers to column chromatography on silica gel (Silica Gel 60, 230–
400 mesh). NMR spectra were recorded on a Varian-Gemini 400
MHz spectrometer. Chemical shifts are reported as d values with
TMS employed as the internal standard.
H
CH3
H
g
h
i
H
0c (86)d
0c (94)d
0c
H
CH3
H
H
j
H
H
BOC
0c
Method A: Oxidation of Benzyl Alcohols 1 to Benzaldehydes 2;
Typical Procedure
k
CH2OTBDPS
H
TBDMS
90
CrO3 (5 mg, 1 mol%) and H5IO6 (2.3 g, 10 mmol) were dissolved in
MeCN (30 mL) by vigorous stirring at r.t. for 0.5 h. The solution
was syringed into the pre-cooled solution of the benzyl alcohol (5.0
mmol) in CH2Cl2 (40 mL) at –78 °C over a period of 20 min. After
the addition was complete, the reaction mixture was stirred at –78
a Isolated yield.
b Reaction conditions: H5IO6–CrO3 (3 equiv, 5 mol%), –40 °C.
c Starting material recovered (>90%).
b Reaction conditions: 10 h at r.t.
Synthesis 2005, No. 11, 1757–1760 © Thieme Stuttgart · New York

PAPER
Selective Oxidation of Benzylic Alcohols and TBDMS Ethers
Benzyl Methoxymethyl Ether (3i)
1759
°C for an additional 1 h, quenched with sat. aq Na2S2O3 solution (5
mL) and filtered. The filtrate was concentrated under vacuum and
the residue was diluted with EtOAc (60 mL), washed with water,
sat. aq Na2S2O3 solution and brine, and then dried over Na2SO4. The
solvent was removed under reduced pressure and the residue was
purified by flash chromatography (hexanes–EtOAc, 2:8). 1H NMR
and comparison with authentic commercial samples confirmed the
structure and purity of compounds 2a–q.
Compound 3i was prepared according to the literature and isolated
as a colorless oil.26 Registry number: 31600-55-2. Spectral data
were consistent with those reported in the literature.26
Benzyl tert-Butylcarbonate (3j)
Compound 3j was prepared according to the literature and isolated
as a colorless oil.20 Registry number: 69470-15-7. Spectral data
were consistent with those reported in the literature.20
Method B: Synthesis of TBDMS Ethers 3; Typical Procedure19
TBDMSCl (15 mmol, 1.5 equiv) and imidazole (20 mmol, 2 equiv)
were added to a DMF (10 mL) solution of benzyl alcohol (10
mmol). The mixture was stirred overnight at r.t. A solution (40 mL)
of sat. NaHCO3, H2O and Et2O (1:1:2) was added to the reaction
mixture with continuous stirring until the solution became clear.
The mixture was extracted with Et2O (3 × 50 mL) and the combined
organic portions were dried over Na2SO4. The solvent was removed
under reduced pressure and the residue was purified by chromatog-
raphy (hexanes–EtOAc, 1:9). All of the TBDMS silyl ethers have
been previously reported.
4-[(tert-Butyldimethylsilyloxy)methyl]-1-[(tert-butyldiphenyl-
silyloxy)methyl]benzene (3k)
Compound 3k was prepared from 4-(tert-butyldiphenylsilyloxyme-
thyl)benzylalcohol27 using Method B. Registry number: 146952-
72-9.
1H NMR (CDCl3): d = 7.71–7.69 (m, 2 H), 7.43–7.36 (m, 10 H),
7.35–7.30 (m, 2 H), 4.77 (s, 2 H), 4.75 (s, 2 H), 1.10 (s, 9 H), 0.95
(s, 9 H), 0.11 (s, 6 H).
tert-Butyldimethylsilyl 4-Phenylbutyl Ether (5)
Compound 5 was prepared by Method B and isolated as a colorless
oil. Registry number: 72064-43-8. Spectral data were consistent
with those reported in the literature.10
Benzyl tert-Butyldimethylsilyl Ether (3a)
Compound 3a was prepared by Method B and isolated as a colorless
oil. Registry number: 53172-91-1. Spectral data were consistent
with those reported in the literature.22
tert-Butyldimethylsilyl 4-Phenyl-2-butyl Ether (6)
Compound 6 was prepared by Method B and isolated as a colorless
oil. Registry number: 150272-59-6. Spectral data were consistent
with those reported in the literature.28
tert-Butyldimethylsilyl 4-Chlorobenzyl Ether (3b)
Compound 3b was prepared by Method B and isolated as a colorless
oil. Registry number: 256521-85-4.
1H NMR (CDCl3): d = 7.07 (d, J = 8.0 Hz, 2 H), 6.99 (d, J = 8.0 Hz,
2 H), 5.05 (s, 2 H), 0.96 (s, 9 H), 0.11 (s, 6 H).
Method C: Oxidation of TBDMS Ethers 3 to Carbonyl Com-
pounds 4; Typical Procedure
CrO3 (5 mg, 1 mol%) and H5IO6 (3.4 g, 15 mmol) were dissolved in
MeCN (40 mL) by vigorous stirring at r.t. for 0.5 h. The solution
was syringed into the pre-cooled solution of the benzyl TBDMS
ether (5.0 mmol) in CH2Cl2 (40 mL) at –78 °C over a period of 20
min. After the addition was complete, the reaction mixture was
stirred at –78 °C for an additional 1 h, quenched with sat. aq
Na2S2O3 solution (5 mL) and then filtered. The filtrate was concen-
trated under vacuum and the residue was diluted with EtOAc (60
mL), washed with water, sat. aq Na2S2O3 solution, brine, and then
dried over Na2SO4. The solvent was removed under reduced pres-
sure and the residue was purified by flash chromatography (hex-
anes–EtOAc, 2:8). 1H NMR and comparison with authentic
commercial samples confirmed the structure and purity of com-
pounds 4a–h.
tert-Butyldimethylsilyl 4-Methylbenzyl Ether (3c)
Compound 3c was prepared by Method B and isolated as a colorless
oil. Registry number: 258339-30-9. Spectral data were consistent
with those reported in the literature.23
tert-Butyldimethylsilyl 4-Methoxybenzyl Ether (3d)
Compound 3d was prepared by Method B and isolated as a colorless
oil. Registry number: 256521-85-4. Spectral data were consistent
with those reported in the literature.24
tert-Butyldimethylsilyl 4-Nitrobenzyl Ether (3e)
Compound 3e was prepared by Method B and isolated as a colorless
oil. Registry number: 135605-97-9.
1H NMR (CDCl3): d = 8.20 (d, J = 8.8 Hz, 2 H), 7.48 (d, J = 8.8 Hz,
4-[(tert-Butyldiphenylsilyloxy)methyl]benzaldehyde (4k)
Compound 4k was prepared by Method C and isolated as a colorless
oil. Registry number: 196880-47-4. Spectral data were consistent
with those reported in the literature.28
2 H), 4.83 (s, 2 H), 0.96 (s, 9 H), 0.12 (s, 6 H).
tert-Butyldimethylsilyl 1-Phenylethyl Ether (3f)
Compound 3f was prepared by Method B and isolated as a colorless
oil. Registry number: 92976-56-2. Spectral data were consistent
with those reported in the literature.25
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Benzyl tert-Butyldiphenylsilyl Ether (3g)
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Synthesis 2005, No. 11, 1757–1760 © Thieme Stuttgart · New York