Aluminium chloride hexahydrate (AlCl3.6H2o): An efficient, facile, mild, and highly chemoselective catalytic deprotection of tert-butyldimethylsilyl (tbs) ethers

Article abstract of DOI:10.1080/00397911.2013.851243

tert-Butyldimethylsilyl (TBS) phenyl / alkyl ethers were cleaved to the corresponding efficiently parent hydroxyl compounds in good yields using catalytic amounts of AlCl₃.6H₂O by conventional or microwave-assisted heating in methanol or isopropanol solution. Intramolecular and competitive experiments demonstrated the chemoselective deprotection of TBS ethers in the presence of triisopropylsilyl and tert-butyldiphenylsilyl ethers.

Full text of DOI:10.1080/00397911.2013.851243

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Aluminium Chloride Hexahydrate (AlCl3
·
6H O): An Efficient, Facile, Mild,
2
And Highly Chemoselective Catalytic
Deprotection of Tert-Butyldimethylsilyl
(
TBS) Ethers
a
a
Davir González-Calderón , Luis J. Benitez-Puebla , Carlos A.
Click for updates
a
b
Gonzalez-Gonzalez , Marco A. Garcia-Eleno , Aydeé Fuentes-
a
b
b
Benitez , Erick Cuevas-Yañez , David Corona-Becerril & Carlos
a
González-Romero
a
Departamento de Química Orgánica, Facultad de Química ,
Universidad Autónoma del Estado de México , Toluca , Estado de
México , Mexico
b
Centro Conjunto de Investigación en Química Sustentable UAEM-
UNAM , Toluca , Estado de México , Mexico
Accepted author version posted online: 02 Dec 2013.Published
online: 28 Mar 2014.
To cite this article: Davir González-Calderón , Luis J. Benitez-Puebla , Carlos A. Gonzalez-Gonzalez ,
Marco A. Garcia-Eleno , Aydeé Fuentes-Benitez , Erick Cuevas-Yañez , David Corona-Becerril & Carlos
González-Romero (2014) Aluminium Chloride Hexahydrate (AlCl · 6H O): An Efficient, Facile, Mild,
3
2
And Highly Chemoselective Catalytic Deprotection of Tert-Butyldimethylsilyl (TBS) Ethers, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:9, 1258-1265, DOI: 10.1080/00397911.2013.851243
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Synthetic Communications , 44: 1258–1265, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2013.851243
ALUMINIUM CHLORIDE HEXAHYDRATE (AlCl • 6H O):AN
3
2
EFFICIENT, FACILE, MILD, AND HIGHLY CHEMOSELECTIVE
CATALYTIC DEPROTECTION OFTERT-
BUTYLDIMETHYLSILYL (TBS) ETHERS
1
1
Davir González-Calderón, Luis J. Benitez-Puebla,
1
2
Carlos A. Gonzalez-Gonzalez, Marco A. Garcia-Eleno,
1
2
Aydeé Fuentes-Benitez, Erick Cuevas-Yañez,
2
1
David Corona-Becerril, and Carlos González-Romero
1
Departamento de Química Orgánica, Facultad de Química, Universidad
Autónoma del Estado de México, Toluca, Estado de México, Mexico
2
Centro Conjunto de Investigación en Química Sustentable UAEM-UNAM,
Toluca, Estado de México, Mexico
GRAPHICAL ABSTRACT
Abstract tert-Butyldimethylsilyl (TBS) phenyl / alkyl ethers were cleaved to the correspond-
ing efficiently parent hydroxyl compounds in good yields using catalytic amounts of AlCl3•
6
H O by conventional or microwave-assisted heating in methanol or isopropanol solution.
2
Intramolecular and competitive experiments demonstrated the chemoselective deprotection
of TBS ethers in the presence of triisopropylsilyl and tert-butyldiphenylsilyl ethers.
Received August 13, 2013.
Address correspondence to Davir González-Calderón or Carlos González-Romero, Departmento
de Química Orgánica, Facultad de Química, Universidad Autónoma del Estado México, Paseo Colón/
Pasco Tollocan s/n, Toluca, Estado de México, 50120, Mexico. E–mail: cgonzalezr@uaemex.mx;
qfb_dgonzalez@yahoo.com.mx
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
1
258

ALUMINIUM CHLORIDE HEXAHYDRATE
1259
Keywords Alcohols; aluminium chloride; deprotection; hexahydrate; protective groups;
silyl ethers
INTRODUCTION
Protection and deprotection strategies of functional groups have become very
common features used in multistep organic syntheses. In this context, the tert-butyldi-
methylsilyl (TBS), triisopropylsilyl (TIPS), and tert-butyldiphenylsilyl (TBDPS) moie-
ties are among the most important hydroxyl protecting groups because they are easily
and efficiently installed and are stable to a useful variety of reagents and reaction con-
ditions.[ A wide variety of protocols for silyl ether removal have been reported.
1]
[1,2]
A convenient method for removing silyl ethers should be mild, facile, and
selective to approach compounds in good yields by readily available, nontoxic, and
preferably catalytic reagents. Unfortunately, many reported methods do not meet
[
3]
[4]
these expectations: some protocols require excess amounts or strong reagents
[
5]
[6]
and cumbersome experimental procedures. Others procedures are mild, selec-
tive, or both for cleavage of silyl ethers, but unfortunately the use of uncommon
reagents (Na PO •12H O, TBPA SbCl , selectfluor, Fe(OTs) •6H O ) hin-
[
7]
[8]
[
8f]
+•
− [8g]
[8h]
[8i]
3
4
2
6
3
2
der their use. However, none of these methods describe in an alternative to con-
ventional or microwave-assisted heating and do not describe in the same protocol a
selective cleavage of TBS alky ethers in the presence of TIPS aryl ethers as well as
a cleavage of TBS-protected alcohols and phenols in the presence of TBDPS aryl
and alkyl ethers.
The study of aluminum-based inorganic reagents for deprotection of silyl ethers
[
9]
[10]
is highly limited; only the use of alumina has been explored. AlCl /MnO system
3
2
has been described for the direct conversion of TBS ethers to their corresponding
carbonyl compounds in good yields as well as their unavailability in the regeneration
of their parent hydroxyl compounds.
RESULTS AND DISCUSSION
During one of our current research programs, we observed that the bis-TBS
ether 1a was rapidly cleaved upon microwave heating of a methanol solution contain-
ing AlCl •6H O. This communication describes our detailed studies of the use of this
3
2
methodology for the deprotection of silylated alcohols.
Optimization studies for this cleavage process were carried out on compound 1a.
Complete silyl group removal occurred within 15min, upon microwave heating at 100
°
C of methanol or iso-propanol solutions containing 5 mol% AlCl •6H O (Table 1).
3 2
At room temperature silyl group loss was slow, but it occurred at an acceptable rate at
0 °C (conventional heating) and was complete within 12 h. Under microwave condi-
5
tions, silyl group loss was very inefficient in tert-butanol, anhydrous acetonitrile, or
aqueous acetone (1:9), and occurred in trace amounts or failed completely in anhy-
drous THF, 10% aqueous THF, dichloromethane, or anhydrous acetone. Finally, the
use of anhydrous AlCl in methanol or iso-propanol was considerably less efficient
3
(
<50% yields) for this deprotection (microwave heating) than that observed for the
hexahydrate.

1
260
D. GONZÁLEZ-CALDERÓN ET AL.
Table 1. Effects of distinct solvents on MW-catalyzed desyl-
ation of TBS ether (1a)
Entry
Solvent
Yield (%)a,b
1
2
3
4
5
6
7
8
9
MeOH
i-PrOH
t-BuOH
THF anh.
95
95
35
NR
Trace
NR
15
Trace
25
THF–H O (9:1)
2
DCM
MeCN anh.
Acetone
Acetone–H O (9:1)
2
aYields refer to chromatographically pure isolated com-
pounds.
bIn some cases no reaction occurred (NR) or product yields
were very poor and ca. 80–98% of starting material was recov-
ered.
The optimized conditions, under microwave and conventional heating condi-
tions (12 h), were then used to study the deprotection of a series compounds con-
taining silylated alcohols and/or phenols, in both methanol and isopropanol solution
(
1
Table 2). Both TBS ethers of alcohols (entries 1 and 3) and phenols (entries 13 and
9) are very efficiently cleaved in methanol under microwave or conventional heat-
ing conditions. TBS alkyl ethers were also cleaved in very good yields in isopropanol
solution (entries 2 and 4), but TBS aryl ethers were less efficiently deprotected in this
solvent (entries 14 and 20). The TIPS alkyl and aryl ethers were cleaved in acceptable
yields (entries 5, 9, 15, and 21) in methanol. In isopropanol solution, TIPS alkyl ethers
were hydrolyzed with poor efficiency (entries 6 and 10) while TIPS aryl ethers were
cleaved in trace amounts or not at all (entries 16 and 22). TBDPS alkyl and aryl ethers
were essentially inert in both solvents.
These data clearly suggest that selective deprotection of TBS alkyl ethers
should be possible by modulating the type of solvent. Table 3 shows the high che-
moselective deprotection of TBS alkyl ethers in the presence of TIPS phenyl ethers
in isopropanol (entries 1 and 2). Moreover, both methanol and isopropanol allowed
chemoselective deprotection of TBS alkyl ethers in the presence of TBDPS phenyl
ethers (entries 3 and 4).
Lastly, we have also carried out a series of intra- and intermolecular competi-
tion experiments (Table 4), which show that TBS alkyl/aryl ethers are very selectively
cleaved in the presence of TBDPS alkyl/aryl ethers in both solvents.

ALUMINIUM CHLORIDE HEXAHYDRATE
1261
Table 2. Deprotection of silyl ethers using 5 mmol% AlCl3•6H2O by MW-assisted
or conventional heating
Yield (%)b,c
Entry
Silyl ether
Solvent
Alcohola
MWd
∆e
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
2a
2a
3a
3a
4a
4a
4b
4b
5a
5a
5b
5b
6a
6a
6b
6b
6c
6c
7a
7a
7b
7b
7c
7c
MeOH
i-PrOH
MeOH
i-PrOH
MeOH
i-PrOH
MeOH
i-PrOH
MeOH
i-PrOH
MeOH
i-PrOH
MeOH
i-PrOH
MeOH
i-PrOH
MeOH
i-PrOH
MeOH
i-PrOH
MeOH
i-PrOH
MeOH
i-PrOH
2
2
3
3
4
4
4
4
5
5
5
5
6
6
6
6
6
6
7
7
7
7
7
7
93
94
98
95
60
95
92
96
96
67
33
25
Trace
NR
72
Trace
NR
75
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
35
42
Trace
NR
90
55
60
Trace
NR
NR
92
64
43
NR
NR
95
66
57
NR
Trace
NR
95
58
39
Trace
NR
NR
NR
NR
NR
aConfirmed by comparison with MS, 1H NMR, and 13C NMR with authentic
samples.
b
Yields refer to chromatographically pure isolated compounds.
c
In some cases no reaction occurred (NR) or product yields were very poor and ca.
8
0–98% of starting material was recovered.
d
1
00ºC, 15min.
e50ºC, 12h.

1
262
D. GONZÁLEZ-CALDERÓN ET AL.
Table 3. Intramolecular chemoselectivity deprotection of TBS alkyl ethers in
the presence of TIPS and TBDPS phenyl ethers
Yield (%)b
Entry
Substrate
Solvent
Producta
MWc
∆d
1e
2e
3
8a
9a
8c
i-PrOH
i-PrOH
MeOH
i-PrOH
MeOH
i-PrOH
8b
9b
8d
8d
9d
9d
90
97
94
93
93
94
90
94
96
93
96
95
4
9c
a
Confirmed by comparison with H NMR and 13C NMR with authentic sample.
1
b
c
Yields refer to chromatographically pure isolated compounds.
1
00ºC, 15min.
d
e
5
0ºC, 12h.
Clearly the use of methanol is not possible in these cases.
A plausible mechanism for the AlCl ·6H O-catalyzed deprotection of silyl ethers
3
2
is shown in Scheme 1. Thus, complexation of the silyl ether oxygen with metal weak-
ens the silyl ether bond while the bond formation between oxygen of the hydration
molecule and silicon atom allows the formation of protonated hydroxyl silyl ether.
Then, gain and loss of a proton produces the free silanol. The alcohol is produced and
the catalytic species is regenerated by rehydration.
CONCLUSION
In conclusion, we report that catalytic AlCl •6H O in isopropanol solution
3
2
selectively cleaves TBS alky ethers in the presence of TIPS aryl ethers. Furthermore,
TBS alkyl and aryl ethers are removed in the presence of TBDPS aryl and alkyl ethers
in either methanol or isopropanol. In addition to its selectivity, this methodology is

ALUMINIUM CHLORIDE HEXAHYDRATE
1263
Table 4. Chemoselective deprotection of TBS alkyl and phenyl ethers in the presence of
TBDPS alkyl and phenyl ethers by intramolecular and competition experiments
Yield (%)b
Entry
1
Substrate
Solvent
Producta
∆c
MWd
10a
MeOH
i-PrOH
MeOH
i-PrOH
10
10
11
11
93
88
95
93
96
85
93
90
2
11a
Competition Experiments:
3
4
12a+14
13a+15
MeOH
MeOH
12 (90)+14
13 (92)+15
(94)
(95)
12 (92)+14 (96)
13 (93)+15 (93)
a
b
c
Confirmed by comparison with H NMR and 13C NMR with authentic samples.
1
Yields refer to chromatographically pure isolated compounds.
5
0ºC, 12h.
d
e
1
00ºC, 15min.
Clearly the use of isopropanol is not possible in these cases.
noteworthy because aluminum chloride hexahydrate is inexpensive, is easily handled,
and has very low toxicity.
EXPERIMENTAL
General Microwave Irradiation Procedure
A 10-mL reaction vessel was charged with a magnetic stir bar, 0.4 mmol
of TBS ether, and 5 mol% AlCl ·6H O in 2 mL of MeOH or i-PrOH. A septum
3
2
cap was affixed; the vessel was placed in the microwave cavity of an Anton-Paar
microwave equipment. The stirring reaction mixture was irradiated at 100ºC for
1
5min. After cooling to room temperature, thin-layer chromatography (TLC)

1
264
D. GONZÁLEZ-CALDERÓN ET AL.
Scheme 1. Proposed plausible mechanism for the cleavage of silyl ethers.
indicated the disappearance of starting material. The solvent was removed under
reduced pressure. Column chromatography afforded the pure alcohol. All products
were spectrally identical with authentic alcohols.
General Conventional Heating Procedure
A 10-mL round-bottom flask was equipped with a magnetic stir bar and a
reflux condenser. Then 0.4 mmol of TBS ether and 5 mol% AlCl ·6H O in 2 mL
3
2
of MeOH or i-PrOH were added. The reaction mixture was stirred at 50 °C for 12
h. After cooling to room temperature, TLC indicated the disappearance of starting
material. The solvent was removed under reduced pressure. Column chromatogra-
phy afforded the pure alcohol. All products were spectrally identical with authentic
alcohols.
ACKNOWLEDGMENTS
The authors thank the referee and Joseph M. Muchowski (visiting professor,
UNAM) for valuable comments and suggestions, and M. N. Zavala-Segovia, L.
Triana-Cruz (CCIQS UAEMéx–UNAM), and E. Díaz-Torres (UNAM) for technical
support.
FUNDING
Financial support from UAEMéx (Project No. 2441) and CONACyT (post-
graduate scholarship) is gratefully acknowledged.

ALUMINIUM CHLORIDE HEXAHYDRATE
1265
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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