Chemoselective deprotection of aryl tert-butyldimethylsilyl ethers promoted by phosphates

Article abstract of DOI:10.1080/00397911.2010.523859

A facile protocol to the chemoselective deprotection of aryl t-butyldimethylsilyl (TBDMS) ethers using Na₃PO₄ ? 12H₂O as promoter is described. From aryl TBDMS ethers to the corresponding phenols, the TBDMS group could be cleaved in the presence of 0.5 equivalent of Na₃PO₄ ? 12H₂O in dimethylformamide at room temperature with good to excellent yields in the presence of other common protecting and functional groups. K₃PO ₄ ? 3H₂O was also found to be useful for the selective deprotection reaction. This is, to our knowledge, the first report on chemoselective deprotection of aryl TBDMS ethers using phosphates. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.523859

This article was downloaded by: [University of Guelph]
On: 18 June 2012, At: 01:38
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Chemoselective Deprotection of Aryl
tert-Butyldimethylsilyl Ethers Promoted
by Phosphates
Lin Yan a b , Fangli Zhao b , Yin Gan a , Jin Zhao a & Zhiyong Jiang a
a Provincial Key Laboratory of Natural Medicine and Immuno-
engineering, Henan University, Jinming Campus Kaifeng, Henan,
China
b Pharmaceutical College, Henan University, Jinming Campus
Kaifeng, Henan, China
Available online: 18 Jul 2011
To cite this article: Lin Yan, Fangli Zhao, Yin Gan, Jin Zhao & Zhiyong Jiang (2012): Chemoselective
Deprotection of Aryl tert-Butyldimethylsilyl Ethers Promoted by Phosphates, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:2, 285-291
To link to this article: http://dx.doi.org/10.1080/00397911.2010.523859
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,

demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 42: 285–291, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.523859
CHEMOSELECTIVE DEPROTECTION OF ARYL
TERT-BUTYLDIMETHYLSILYL ETHERS PROMOTED
BY PHOSPHATES
Lin Yan,1,2 Fangli Zhao,2 Yin Gan,1 Jin Zhao,1 and
Zhiyong Jiang1
1Provincial Key Laboratory of Natural Medicine and Immuno-engineering,
Henan University, Jinming Campus Kaifeng, Henan, China
2Pharmaceutical College, Henan University, Jinming Campus Kaifeng,
Henan, China
GRAPHICAL ABSTRACT
Abstract A facile protocol to the chemoselective deprotection of aryl t-butyldimethylsilyl
(TBDMS) ethers using Na3PO4 ꢀ 12H2O as promoter is described. From aryl TBDMS ethers
to the corresponding phenols, the TBDMS group could be cleaved in the presence of 0.5
equivalent of Na3PO4 ꢀ 12H2O in dimethylformamide at room temperature with good to excel-
lent yields in the presence of other common protecting and functional groups. K3PO4 ꢀ 3H2O
was also found to be useful for the selective deprotection reaction. This is, to our knowledge,
the first report on chemoselective deprotection of aryl TBDMS ethers using phosphates.
Keywords 4-Desmethyllepipodophyllotoxin; K3PO4 ꢀ 3 H2O; Na3PO4 ꢀ 12 H2O; selective
deprotection; t-butyldimethylsilyl (TBDMS)
INTRODUCTION
Sequential protection and deprotection of the various functionalities are often
required in the chemical manipulation of complex polyfunctional molecules. The
protection of hydroxy group as tert-butyldimethylsilyl (TBDMS) ethers has been
recognized as one of the most useful protection strategies because of its easy
installation and general stability to basic and mild acidic reagents.[1] Although
tetrabutylammonium fluoride (TBAF) is the most popular reagent for cleavage of
Received August 18, 2010.
Address correspondence to Zhiyong Jiang, Provincial Key Laboratory of Natural Medicine and
Immuno-engineering, Henan University, Jinming Campus Kaifeng, Henan, China. E-mail: chmjzy@
henu.edu.cn
285

286
L. YAN ET AL.
TBDMS ethers, the selectivity is often poor and side reactions are common due to
the highly basic and nucleophilic fluoride ion.[2] It is known that many biologically
significant natural products such as vancomycin and teicoplanian contain both
phenol and alcohol functional groups, and therefore the differential deprotection
of alkyl and aryl silyl ethers is of considerable interest.[3] Thus it is important to
develop a series of mild and convenient protocols to selectively deprotect TBDMS
ethers. The cleavage of alkyl TBDMS ethers has been extensively studied, leading
to a wide array of deprotection methods,[1] but there are relatively few options
available for the removal of aryl TBDMS protecting groups. From the various
established protocols, acid-catalyzed deprotection of aryl TBDMS ethers is done
with camphorsulfonic acid in the presence of secondary alcoholic TBDMS ethers.[4]
Bhatt and Nayak[5] reported using a copper(II) bromide catalytic version but selec-
tivity was moderate. Under basic reaction conditions, fluorides (TBAF and KF),[1d,6]
alkoxides (KOH, NaOH, and LiOH),[7] carbonates (K2CO3 and Cs2CO3),[8] acetates
(LiOAc),[9] and organic base (tetramethyl guanidine, TMG,[10a] and triethylamine
N-oxide[10b]) were published. Herein, we report a new protocol for the selective
cleavage of aryl TBDMS ethers promoted by phosphates, Na3PO4 ꢀ 12H2O, and
K3PO4 ꢀ 3H2O, which are cheap and mild bases able to do the reaction at room
temperature. To the best of our knowledge, this is the first report using phosphates
for deprotection of aryl TBDMS ethers.
RESULTS AND DISCUSSION
The p-methylphenyl TBDMS ether was subjected to desilylation with 0.5
equivalent of Na3PO4 ꢀ 12H2O in various solvents at room temperature but the
deprotection did not proceed (Table 1, entries 1ꢁ4). However, p-methylphenol
Table 1. Solvent effect investigations on deprotection of p-methylbenzyl
TBDMS ether using Na3PO4 ꢀ 12H2Oa
Entry Equiv. of base
Solvent
Reaction time (h) Yield (%)b
1
2
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.5
0.5
THF
CH2Cl2
24
24
24
24
24
24
NRc
NRc
NRc
Trace
41
3
Dioxane
Acetone
EtOH
4
5
6
H2O
DMF
27
97
7
1.8
8
DMF
DMF=H2O (10:1)
DMF=H2O (2:1)
18
14
24
85
95
9
10
12
aReactions were conducted under 0.5 equiv. Na3PO4 ꢀ 12H2O in
different solvents (2 ml) at room temperature (0.5-mmol scale).
bIsolated yield.
c NR, no reaction.

SELECTIVE DEPROTECTION OF ARYL TBDMS ETHERS
287
was obtained with 41% yield using the protic solvent ethanol (Table 1, entry 5). The
reaction also worked in water but in poorer yield (Table 1, entry 6). The optimal
solvent, the highly polar aprotic solvent dimethylformamide (DMF), gave the depro-
tected phenol in 97% yield within 1.8 h (Table 1, entry 7). When the amount of
Na3PO4 ꢀ 12H2O was decreased to 10 mol%, the reaction completed in 18 h with good
yield (Table 1, entry 8). This demonstrates that Na3PO4 ꢀ 12H2O acts as catalyst in
the desilylation. Mixed solvents with different DMF and water ratios were investi-
gated. However, this did not significantly improve the reaction (Table 1, entries 9
and 10). Weighing both efficacy and the cost factor of the phosphate salts, the reac-
tion condition was fixed at 0.5 equivalent of Na3PO4 ꢀ 12H2O in DMF (Table 1).
Next, a variety of substrates including aryl and alkyl TBDMS ethers were
examined. As shown in Table 2, all aryl TBDMS ethers could be cleaved smoothly
under the established reaction condition. The substrates containing electron-
withdrawing groups on the aromatic ring (Table 2, entries 1–3) were remarkably
faster than those containing electron-donating groups (Table 2, entries 7 and 8).
However, the allyl TBDMS ether gave poor deprotected product (Table 2, entry
9), and benzyl and alkyl TBDMS ethers did not reaction even at 100 ꢂC in DMF
(Table 2, entries 10–13).
To establish the chemoselectivity of this protocol, the aryl TBDMS ethers
containing other common utilized functional groups were allowed to cleave in
DMF in the presence of 0.5 equivalent of Na3PO4 ꢀ 12H2O at room temperature.
Results are summarized in Table 3. The aryl TBDMS ethers could be deprotected
cleanly to give the corresponding phenols in good to excellent yields, with TBDMS-
protected alcohols (Table 3, entries 1ꢁ5), TBDPS-protected alcohols (Table 3, entry
6), carboxylic esters (Table 3, entries 7ꢁ11), and carbonates (Table 3, entries 12ꢁ13).
To investigate the influence of phosphate on other protecting groups, examples of
Table 2. Deprotection of aryl and alkyl TBDMS ethers to phenols and alcohols using Na3PO4 ꢀ 12H2Oa
Entry
Substrates
Products
Reaction time (h)
Yield (%)b
1
2
4-ClC6H4OTBDMS
4-CHOC6H4OTBDMS
2-CHOC6H4OTBDMS
C6H5OTBDMS
4-ClC6H4OH
4-CHOC6H4OH
2-CHOC6H4OH
C6H5OH
0.3
0.8
1.0
1.5
1.5
2.5
2.0
4.0
24
98
94
3
93
87
4
5
4-t-BuC6H4OTBDMS
2-CH3C6H4OTBDMS
3-NH2C6H4OTBDMS
4-CH3OC6H4OTBDMS
4-t-BuC6H4OH
2-CH3C6H4OH
3-NH2C6H4OH
4-CH3OC6H4OH
90
83
6
7
92
95
8
9c
10c
11c
12c
13c
C6H5CH CHCH2OTBDMS
C6H5CH CHCH2OH
C6H5CH2OH
36
=
=
C6H5CH2OTBDMS
C6H5CH2CH2OTBDMS
n-C8H17OTBDMS
18
24
Trace
NRd
NRd
NRd
—
—
—
24
48
Cyclo-C6H11OTBDMS
aReactions were conducted under 0.5 equiv. Na3PO4 ꢀ 12H2O in DMF at room temperature (0.5-mmol
scale, 2 ml DMF).
bIsolated yield.
cReactions were conducted at 100 ꢂC.
dNR, no reaction.

288
L. YAN ET AL.
Table 3. Chemoselective deprotection of various aryl TBDMS-protected ethers using Na3PO4 ꢀ 12H2Oa
Entry
Substrates
Products
Time (h)
Yield (%)b
1
2
3
4
1.6
94
90
90
84
1.5
1.8
2.0
5
3.5
87
6
7
12
76
92
86
91
92
2.0
2.0
2.5
1.5
8
9
10
11
2.5
90
12
13
14
15
1.5
1.8
2.0
3.2
90
94
95
80
aReactions were conducted under 0.5 equiv. Na3PO4 ꢀ 12H2O in DMF at room temperature (0.5-mmol
scale, 2 ml DMF).
bIsolated yield.
tetrahydropyranyl (THP)–protected alcohol (Table 3, entry 14) and sulfonate (Table 3,
entry 15) remain unreacted under these conditions.
Next, a more basic K3PO4 ꢀ 3H2O was investigated. Solvent screening gave the
best reaction condition as 0.5 equivalent of K3PO4 ꢀ 3H2O in DMF–H2O (10:1, v=v)
at room temperature. Although the reactions were slower than with
Na3PO4 ꢀ 12H2O, the chemoselectivity is similarly good (Table 4).
In recent years, the analogs of enantiopure podophyllotoxin and 40-
desmethylepipodophyllotoxin have drawn interest for the development of etoposide
(VP-16) and teniposide (VM-26) as anticancer drugs.[11] However, the lactone

SELECTIVE DEPROTECTION OF ARYL TBDMS ETHERS
289
Table 4. Deprotection of various aryl TBDMS-protected ethers using
K3PO4 ꢀ 3H2O in DMF-H2O (10:1, v=v)a
Entry
Silyl ethers
Reaction time (h)
Yield (%)b
1
2
3
4
5
4-ClC6H4OTBDMS
2-CHOC6H4OTBDMS
4-MeC6H4OTBDMS
3-NH2C6H4OTBDMS
4-MeOC6H4OTBDMS
0.5
1.5
3.5
4.3
7.0
96
95
92
83
92
6
7
3.2
7.0
93
92
8
9
4.3
92
3.5
90
aReactions were conducted under 0.5 equiv. K3PO4 ꢀ 3H2O in DMF–H2O
(10:1, v=v) at room temperature (0.5-mmol scale, 2 ml DMF).
bIsolated yield.
functional group is often racemized in the presence of bases. Using our established
method, we found that TBDMS-protected 40-desmethylepipodophyllotoxin 1 could
be deprotected with 0.5 equivalent of Na3PO4 ꢀ 12H2O in DMF at room temperature
to achieve the aryl TBDMS-deprotected product 2 with 67% yield (Scheme 1). Under
the same reaction condition with K3PO4 ꢀ 3H2O, only 43% yield was obtained.
In summary, we have developed a mild and efficient protocol for the deprotec-
tion of aryl TBDMS ethers. The protecting group TBDMS could be cleaved
from aryl TBDMS ethers efficiently using 0.5 equivalent of Na3PO4 ꢀ 12H2O or
K3PO4 ꢀ 3H2O at room temperature to give the corresponding phenols in good to
excellent yields. The reaction conditions allow selective deprotection of aryl TBDMS
ethers in the presence of alkyl TBDMS ethers, alkyl TBDPS ethers, and other
commonly utilized protecting groups and functional groups. This is the first report
to selectively deprotect aryl TBDMS ethers using phosphates, which we have
Scheme 1. Selective deprotected of TBDMS-protected 40-desmethylepipodophyllotoxin in the presence of
0.5 equivalent of Na3PO4 ꢀ 12H2O in DMF at room temperature.

290
L. YAN ET AL.
demonstrated to be suitable for a wide range of substrates and able to tolerate
existing protecting groups.
RESULTS AND DISCUSSION
All chemicals were purchased at highest commercial quality and used without
any further purification. All reactions were monitored by thin-layer chromatography
1
(TLC). H and 13C NMR spectra were obtained with a Bruker AC-P500-Hz spec-
trometer. Chemical shifts are given in parts per million (ppm) from Me4Si in CDCl3
and coupling constants (J) were reported in hertz (Hz). Mass spectra were taken on a
Bruker Esquire 3000 Plus 01073 (ESI) and HP5989B (EI). Infrared (IR) spectra were
taken on a Nicolet Nexus 470, 350–7400 cmꢁ1. Melt points were taken on Yanaco
melting-point apparatus. All silyl ethers were prepared according to the standard
procedure.[1]
Representative Procedure
A mixture of TBDMS-protected 40-desmethylepipodophyllotoxin 1 (0.5 mmol)
and Na3PO4 ꢀ 12H2O (0.25 mmol) in DMF (2.0 ml) was stirred at room temperature
until the reaction was finished as indicated by TLC. Then, the reaction mixture
was diluted with brine (15 ml), extracted with Et2O (5 ꢃ 5 ml), and dried over anhy-
drous Na2SO4. The solvent was removed in a vacuum. The residue was purified by
flash column chromatography over silica gel using ethyl hexane=acetate (5:1) as elu-
ent. Finally, the desired product 2 was obtained with 67% yield.
Characterization Data
4,4’-Bis-O-(dimethyl-tert-butylsilyl)-4’-O-demethylepipodophyllotoxin 1.
1
White solid; mp 161.8–163.5 ꢂC; H NMR (500 MHz, CDCl3, ppm): d 0.04 (s, 6H),
0.09 (s, 6H), 0.87 (s, 9H), 0.94 (s, 9H), 2.82–2.85 (m, 1H), 3.38 (dd, 1H, J ¼ 5.3,
27.5 Hz), 3.66 (s, 6H), 4.24 (d, 2H, J ¼ 4.9 Hz), 4.57 (t, 1H, J ¼ 5.3 Hz), 4.86
(d, 2H, J ¼ 2.9 Hz), 5.96 (d, 2H, J ¼ 1.5 Hz), 6.20 (s, 2H), 6.51 (s, 1H), 6.75 (s, 1H).
13C NMR (125 MHz, CDCl3, ppm): d ꢁ4.3 (two peaks), ꢁ3.8, ꢁ3.1, 0.2, 1.3, 18.5,
18.9, 26.1, 26.2, 39.5, 40.8, 44.1, 56.3, 68.0, 68.1, 101.6, 108.9, 109.6, 110.9, 132.1,
132.6, 132.7, 134.1, 147.0, 148.2, 151.2, 175.5. LRMS (ESI): 651.2 (M þ Naþ). IR
(KBr): 2955, 2929, 2895, 2857, 1778, 1586, 1512, 1484, 1335, 1253, 1129, 837,
780 cmꢁ1
.
4-O-(Dimethyl-tert-butylsilyl)-4’-O-demethylepipodophyllotoxin 2.
1
White solid; mp 213.9–215.1 ꢂC; H NMR (500 MHz, CDCl3, ppm): d 0.13 (s, 6H),
0.87 (s, 9H), 2.83–2.86 (m, 1H), 3.40 (dd, 1H, J ¼ 5.3, 27.5 Hz), 3.76 (s, 6H), 4.25
(t, 1H, J ¼ 4.6 Hz), 4.59 (d, 1H, J ¼ 5.3 Hz), 4.87 (d, 2H, J ¼ 2.9 Hz), 5.97 (d, 2H,
J ¼ 3.2 Hz), 6.26 (s, 2H), 6.51 (s, 1H), 6.76 (s, 1H). 13C NMR (125 MHz, CDCl3,
ppm): d ꢁ3.9, ꢁ3.1, 0.2, 18.5, 26.2, 39.5, 40.6, 44.1, 56.8, 68.0, 68.1, 101.6, 108.4,
109.7, 110.8, 131.3, 132.1, 132.4, 146.6, 147.0, 148.3, 175.6. LRMS (EI, m=z): 514
(mþ, 15.68%). IR (KBr): 3534, 2928, 2856, 1782, 1582, 1510, 1484, 1328, 1249,
1126, 838, 783 cmꢁ1
.

SELECTIVE DEPROTECTION OF ARYL TBDMS ETHERS
291
ACKNOWLEDGMENT
This work was supported by international cooperation grants from Henan
Province (104300510062).
REFERENCES
1. (a) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis,
4th ed; John Wiley & Sons: Hoboken, NY, 2007; (b) Crouch, R. D. Selective mono-
deprotection of bis-silyl ethers. Tetrahedron 2004, 60, 5833–5871; (c) Kocienski, P. J. Pro-
tecting Groups; Georg Thieme Verlag: New York, 1994; (d) Corey, E. J.; Venkateswarlu, A.
Protection of hydroxyl groups as tert-butyldimethylsilyl derivatives. J. Am. Chem. Soc.
1972, 94, 6190–6191.
2. (a) Corey, E. J.; Snider, B. B. A total synthesis of (ꢄ)-fumagillin. J. Am. Chem. Soc. 1972,
94, 2549–2550; (b) Hayami, J.-I.; Ono, N.; Kaji, A. Quaternary ammonium fluoride: A
reagent for proton abstraction. Tetrahedron Lett. 1968, 9, 1385–1386.
3. Evans, D. A.; Dinsmore, C. J.; Ratz, A. M.; Evrard, D. A.; Barrow, J. C. Synthesis
and conformational properties of the m(4-6)(5-7) bicyclic tetrapeptide common to the
vancomycin antibiotics. J. Am. Chem. Soc. 1997, 119, 3417–3418.
4. Angle, S. R.; Wada, T. An approach to the narciclasine alkaloids via a quinone methide–
initiated cyclization reaction. Tetrahedron Lett. 1997, 38, 7955–7958.
5. Bhatt, S.; Nayak, S. K. A facile and catalytic method for selective deprotection of tert-
butyldimethylsilyl ethers with copper(II) bromide. Tetrahedron Lett. 2006, 47, 8395–8399.
6. (a) Blass, B. E.; Harris, C. L.; Portlock, D. E. A facile, selective KF=Al2O3-mediated method
for the deprotection of aryl silyl ethers and preparation of aryl SEM ethers. Tetrahedron
Lett. 2001, 42, 1611–1613; (b) Schmittling, E. A.; Sawyer, J. S. Selective desilylation of
tert-butyldimethylsilyl ethers of phenols using potassium fluoride–alumina and ultasound.
Tetrahedron Lett. 1991, 32, 7207–7210; (c) Collington, E. W.; Finch, H.; Smith, I. J. Selective
deprotection of alcoholic and phenoilc silyl ethers. Tetrahedron Lett. 1985, 26, 681–684.
7. (a) Ankala, S. V.; Fenteany, G. Selective deprotection of either alkyl or aryl silyl ethers
from aryl, alkyl bis-silyl ethers. Tetrahedron Lett. 2002, 43, 4729–4732; (b) Crouch,
R. D.; Stieff, M.; Frie, J. L.; Cadwallader, A. B.; Bevis, D. C. Selective deprotection of
silyl-protected phenols using solid NaOH and a phase transfer catalyst. Tetrahedron Lett.
1999, 40, 3133–3136; (c) Jiang, Z.; Wang, Y.-G. A mild, efficient, and selective cleavage of
aryl tert-butyldimethylsilyl ethers using KOH in ethanol. Chem. Lett. 2003, 32, 568–569.
8. (a) Wilson, N. S.; Keay, B. A. Mild base-mediated desilylation of various phenolic silyl
ethers. Tetrahedron Lett. 1997, 38, 187–190; (b) Jiang, Z.; Wang, Y.-G. A mild, efficient,
and selective deprotection of t-butyldimethylsilyl-protected phenols using cesium carbon-
ate. Tetrahedron Lett. 2003, 44, 3859–3861; (c) Prakash, C.; Saleh, S.; Blair, I. A. Selective
removal of phenolic and alcoholic silyl ethers. Tetrahedron Lett. 1994, 35, 7565–7568.
9. Wang, B.; Sun, H.-X.; Sun, Z.-H. LiOAc-catalyzed chemoselective deprotection of aryl
silyl ethers under mild conditons. J. Org. Chem. 2009, 74, 1781–1784.
10. (a) Oyama, K.-I.; Kondo, T. A novel and convenient chemoselective deprotection method
for both silyl and acetyl groups on acidic hydroxyl groups such as phenol and carboxylic
acid by using a nitrogen organic base, 1,1,3,3-tetramethylguanidine. Org. Lett. 2003, 5,
209–212; (b) Zubaidha, P. K.; Bhosale, S. V.; Hashmi, A. M. A facile and selective
deprotection of tert-butyldimethylsilyl ethers of phenols using triethylamine N-oxide.
Tetrahedron Lett. 2002, 43, 7277–7279.
11. Lee, K. H. Antineoplastic Agents for Chinese Traditional Medicine and Their Analogs, 1:
Human Medical Agents from Plants; A. D. Kinghorn and M. Balandrin (Eds.); American
Chemical Society: Washington, DC, 1993; pp. 170–190.