Catalytic removal of tert-butyldimethylsilyl (TBS) ether by PVP-I

Article abstract of DOI:10.1016/j.tetlet.2019.05.059

A mild, efficient and rapid protocol the deprotection of alcoholic TBDMS ethers using PVP-1 as catalyst in methanol, the procedure of deprotection of various TBDMS ethers were found to be very convenient, easy work-up, high yielding.

Full text of DOI:10.1016/j.tetlet.2019.05.059

Accepted Manuscript
Catalytic Removal of tert-Butyldimethylsilyl (TBS) ether by PVP-I
Guangying Lu, Di Wang, Jiangmeng Ren, Yanxiong Ke, Bu-Bing Zeng
PII:
S0040-4039(19)30513-1
https://doi.org/10.1016/j.tetlet.2019.05.059
TETL 50831
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 April 2019
24 May 2019
28 May 2019
Please cite this article as: Lu, G., Wang, D., Ren, J., Ke, Y., Zeng, B-B., Catalytic Removal of tert-Butyldimethylsilyl
(TBS) ether by PVP-I, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.05.059
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Catalytic Removal of tert-Butyldimethylsilyl
Leave this area blank for abstract info.
Group from Protected Alcohols by PVP-I
Guangying Lua , Di Wanga, Jiangmeng Rena, Yanxiong Keb and Bu-Bing Zenga
0.01 eq. PVP-I
R-OH
R-OTBS
Methanol
30 oC
81 - 96%
R = alkyl, aryl
- high yield
- broad substrate scope
- easy product isolation - mild reaction condition
- simple work-up procedure
Tetrahedron Letters
journal homepage: www.elsevier.com
Catalytic Removal of tert-Butyldimethylsilyl (TBS) ether by PVP-I
Guangying Lua , Di Wanga, Jiangmeng Rena, Yanxiong Keb, and Bu-Bing Zenga,
a . School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China
b .Engineering Research Center of Pharmaceutical Process Chemistry, School of Pharmacy, East China University of Science and Technology, 130 Meilong
Road, Shanghai 200237, P. R. of China
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: 021-64253689; e-mail: zengbb@ecust.edu.cn
 Corresponding author. Tel.: 021-64250622; e-mail: key@ecust.edu.cn
Article history:
Received
A mild, efficient and rapid protocol the deprotection of alcoholic TBDMS ethers using PVP-1 as
catalyst in methanol, the procedure of deprotection of various TBDMS ethers were found to be
very convenient, easy work-up, high yielding.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
PVP-I
Catalytic
Deprotection
TBS ether
The strategies of hydroxyl group protection and deprotection
have become an important issue either in pharmaceutical industry
or in multistep total synthesis of natural products. t-
Butyldimethylsilyl ether has become one of the most practical
silyl proctective group and widely used in organic synthesis
because of its advantages including the tolerance to various
reaction condition such as Grignard reaction, Wittig reaction,
reduction reaction, basic or acidic hydrolysis as well as in

2
Tetrahedron Letters
thermal condition up to 230 ºC, etc., and finally, it can be
report the application of PVP-I as an even more potent, but much
less expensive, catalyst for efficiently desilylation of TBDMS
ethers.
readily removed under various conditions without interruption of
other function groups using designed deprotecting conditions.1 It
is well-known that the cleavage of t-butyldimethylsilyl (TBDMS)
ethers are classically conducted using t-butylammonium fluoride
(TBAF) in anhydrous THF. However, basic fluoride ion led to
the undesired byproduct and the deprotection reaction is sensitive
to water.2 Beside TBAF, chemists applied other fluoride source
such as (Me2N)3S+F2SiMe3 (TAS-F),3 KF/18-crown-6,4
pyridine·HF,5 CsF,6 NH4F·HF,7 etc. in the reaction to cut the C-
Si bonds.
Povidone-iodine (PVP-I) has characteristics of gradual and
sustained release free iodine into solution. Therefore, it was
widely used in the clinical practice instead of free iodine as the
povidone itself is water soluble and nontoxic acting as a carrier of
free iodine in aqueous medium34. Inspired by Keith group and
Szarek groups’ work35 for the removal of the TBDMS ether
catalyzed by I2, a hypothesis was put forward that PVP-I could
catalyze this reaction, the obvious advantage is to avoid use of
venomous, chromatophilous, easy to sublimate molecule iodine
and workup process using sodium hyposulfite solution.
During the last two decades, many efforts have been devoted
to explore novel TBS deprotection methods using various
catalysts, such as AgSTA in MeOH,8 Ce(SO4)2·4H2O in MeOH
The investigation was initiated using TBS protected 2-
(thiophen-2-yl) ethanol (1a) as a model compound to optimize
reaction condition including the catalytic loading amount, solvent
and reaction temperature. As shown in Table 1, the reaction was
conducted using 0.01 eq. of PVP-I in methanol under room
temperature for 3 h, the yield of 1b was 89.5% (Table 1, entry 1).
If the solvent was switched to H2O, DMF, i-Propanol and
Ethanol, the yield of desired product is varied from 22% to
88.7% (Table 1, entries 2-5). In addition, the reaction did not
proceed in THF at all (Table 1, entry 6). The loading amount of
catalyst was also investigated and found that either increasing or
decreasing the amount of catalyst used in the reaction all slightly
cut down the production yield to around 86% (Table 1, entries 7
and 8). Lower the reaction temperature leaded yield drop down
and increasing the reaction temperature to 40 °C seemed to have
no contribution to the production of 1b (Table 1, entries 9 and
10). Therefore, the optimal condition for the deprotection of
TBDMS ethers using PVP-I was obtained with a loading of 1%
eq. of PVP-I in MeOH at room temperature for 3 h.
o
under microwave condition(130 C) or conventional heating(60
11a
11b
oC),9 SmCl3 in MeOH,10 Fe(OTs)3
or FeCl3
in MeOH,
CuSO4·5H2O in MeOH,12 CuBr2 in dry MeCN,13 AlCl3·5H2O in
MeOH or isopropanol,14 ZrCl4 in isopropanol,15 Bi(OTf)3 in
MeCN or MeOH,16 Hf(OTf)4,17 NaAuCl4·2H2O in MeOH,18
NiCl2 in methanol-dichloromethane (2:5),19 InCl3 in aqueous
MeCN,20 LiOAc·2H2O in DMF-H2O (50:1),21 NaCN in aqueous
EtOH (15:1),22 Selectfluor® in MeCN under microwave
condition,23 SnO2 in MeOH,24 KHF2 in MeOH,25
Phosphomolybdic acid.26 Some organic compounds and ionic
liquid were also found to catalyze the desilyation of tert-
butyldimethylsilyl ethers, for instance, P(MeNCH2CH2)3N in
MeCN,27 ATPB in methanol-dichloromethane (2:5),28 NIS in
MeOH,29 CEC in MeOH,30 HS-cellulose sulphate in MeOH.31
CBr4 in MeOH,32 and dicationic or tailor-made ionic liquid.33
However, most of these reported procedures have difficulties
such as preparation of catalyst, longer reaction time, harsh
reaction condition, use of expensive and corrosive reagents as
well as cumbersome work-up procedures. In this study, we
Table 1 Screening of PVP-I catalyzed TBS deprotection.a
TBDMS ether on all the examined substrates could be easily
cleaved with excellent yield, and it seems to be better than that of
the classic deprotection method using TBAF (Table 2, entries 2-
13, 15, 17, 19-23). Piperitol derivatives bearing Br or I on the
benzene ring also give good results (Table 2, entries 8-10). After
that, some unsaturated alcohols were achieved using optimal
reaction condition with yields (Table 2, entries 11-16). Stereo-
hindrance TBDMS ether were smoothly disconnected to afford
secondary hydroxyl group with high yields up to 96% (Table 2,
entries 13, 14 & 19-23). Unlike the use of basic TBAF, TBS and
THP as protective groups for hydroxyl group could be removed
simultaneously using this reported catalytic condition (Table 2,
entry 24). Importantly, the work-up procedures were very simply
without quench operation using sodium sulfite, after the
completion of the reaction, the concentrated residual was directly
purified to produce the desired compounds. The results presented
in Table 2 reveal that TBDMS ethers are cleanly and efficiently
removed using PVP-I, meanwhile, the yields of desilylation using
excess TBAF in anhydrous THF were listed in Table 2, the
advantages between these two protocols are easy to see by
comparing the detailed data and operations.
OTBS
OH
S
S
PVP-I
Solvent
1a
1b
Entry
1
2
3
4
5
6
7
PVP-I
Solvent
MeOH
EtOH
DMF
i-PrOH
H2O
T (ºC)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
15
Yield (%)b
89.5
88.7
67.6
70.4
22.5
N.R.
86.6
86.1
81
0.01 eq.
0.01 eq.
0.01 eq.
0.01 eq.
0.01 eq.
0.01 eq.
THF
0.005 eq.
0.02 eq.
0.01 eq.
0.01 eq.
MeOH
MeOH
MeOH
MeOH
MeOH
8
9
10
11
40
r.t.
90.1
N.R.
c
-
a Reagents and condition: TBDMS ether (1.0 mmol), solvent
b
(2.0 mL), 3 h. Yield was determined by HPLC using biphenyl
as internal standard. 0.01 eq. of PVP was used. N.R. = No
c
Reaction
With the optimum reaction condition in hand, the scope of
substrates bearing TBDMS ether was investigated under optimal
condition. The result was shown in Table 2, it can be seen that
Table 2 Deprotection reaction under the optimal condition.
PVP-I (0.01 eq.)
ROTBS
ROH
MeOH, 30 °C
Yield(%)b
Using PVP-I
Entry
Substrate
Product
Using TBAF

3
S
S
91
95
90
91
1
2
OTBS
OH
O
O
OTBS
OTBS
N
H
N
H
O2N
O2N
O
O
90
90
81
89
OH
OTBS
3
4
F3C
N
H
F3C
N
H
O
O
F3C
OTBS
F3C
OH
OH
N
H
N
H
CF3
NO2
CF3
O
O2N
N
H
H
N
95
50
5
O2N
OTBS
NO2
O
OTBS
OH
90
81
85
76
6
7
NBoc
NHAc
NBoc
NHAc
OTBS
OH
O
O
OTBS
OH
OH
93
93
86
89
90
81
8
9
O
O
O
O
Br
Br
I
OTBS
OTBS
O
O
I
OH
O
O
10
O
O
Br
Br
O
O
OTBS
OH
93
90
82
92
88
80
11
12
13
O
O
OTBS
OH
OTBS
OH
OTBS
OH
89
85
91
84
14
15
OTBS
OH

4
Tetrahedron Letters
90
90
91
87
16
17
( )5
( )5
OTBS
OTBS
OH
OH
OTBS
OH
88
93
90
90
18
19
S
S
OTBS
OH
OTBS
OH
90
80
20
COOMe
COOMe
O
O
96
85
21
22
HO
TBSO
OTBS
Cl
OH
( )5
85
86
88
87
91
31
34
0f
Cl
I
( )5
OTBS
OH
( )5
OH
23
24
I
( )5
OTBS
OTHP
OH
OH
OH
( )5
OTBS
OTBS
( )5
OH
( )5
OH
( )5
86
89
25
26
( )5
OTBS
OH
( )5
a Reagents and condition: 1a (1.0 mmol), PVP-I (0.01 eq.), methanol (2.0 mL), 1h. b isolated Yields. c 3.0 eq. of TBAF. d 4.0 eq. of
TBAF. e 6.0 eq. of TBAF, f THP group could not be removed by TBAF.
The removal of TBDMS ethers on the primary or secondary
alcohol had no selectivity. However, current method showed
selectivity between different silyl ethers. As shown in Scheme 1,
TBS group would be selectively removed under optimized
condition in the presence of TIPS and TBDPS. Based on the
reported literature,24,34,35
a possible mechanism could be
described as the following: PVP-I could provide acidic
atmosphere. Therefore, the oxygen atom of O-Si bond could be
protonated and transferred into free hydroxyl group.

5
11. (a) Bothwell, J. M.; Angeles, V. V.; Carolan, J. P.; Olson, M. E.;
OTBS
OH
Mohan, R. S. Tetrahedron Lett. 2010, 51, 1056-1058; (b) Yang,
Y.-Q.; Cui, J.-R.; Zhu, L.-G.; Sun, Y.-P.; Wu, Y. K. Synlett 2006,
1260-1262.
12. González-Calderón, D.; Benítez-Puebla, L. J.; González-González,
C. A.; Assad-Hernández, S.; Fuentes-Benítez, A.; Cuevas-Yáñez,
E.; Corona-Becerril, D.; González-Romero, C. Tetrahedron Lett.
2013, 54, 5130-5132.
PVP-I, MeOH
30 C, 90 mins
13. Bhatt, S.; Nayak, S. K. Tetrahedron Lett. 2006, 47, 8395-8399.
14. González-Calderón, D.; Benίtez-Puebla, L. J.; Gonzalez-Gonzalez,
C. A.; Garcia-Eleno, M. A.; Fuentes-Benitez, A.; Cuevas-Yanez,
E.; Corona-Becerril, D.; González-Romero, C. Synth. Commun.
2014, 44, 1258-1265.
OTIPS
OTIPS
27a
27b 85%
15. Sharma, G. V. M.; Srinivas, B.; Krishna, P. R. Lett. Org. Chem.
2005, 2, 57-60.
OTBS
OH
16. (a) Barnych, B.; Vatèle, J.-M. Synlett 2011, 2048-2052; (b)
PVP-I, MeOH
Firouzabadi, H.; Mohammadpoor-Baltork, I.; Kolagar, S. Synth.
Commun. 2001, 31, 905-909.
17. Zheng, X.-A.; Kong, R.; Huang, H.-S.; Wei, J.-Y.; Chen. J. Z.;
Gong, S.-S. Synthesis, 2019, 51, 944-952.
30 C, 90 mins
18. Zhang, Q.; Kang, X. Q.; Long, L.; Zhu, L. J.; Chai, Y. H.
Synthesis 2015, 47, 55-64.
19. Khan, A. T.; Islam, S.; Choudhury, L. H.; Ghosh, S. Tetrahedron
Lett. 2004, 45, 9617-9621.
20. Yadav, J. S.; Subba, B. V.; Reddy, B. V. S.; Madan, C New J.
Chem. 2000, 24, 853-854.
OTBDPS
28a
OTBDPS
28b 70%
21. Wang, B.; Sun, H.-X.; Sun, Z.-H. J. Org. Chem. 2009, 74, 1781-
1784.
22. Qiao, X._J.; Hou, X.; Fang, W.-H.; Bao, X.-F.; Chen, G.-L. J.
Braz. Chem. Soc. 2016, 27, 899-904.
Scheme 1. Chemoselective deprotection of TBS ethers in the
presence of TIPS and TBDPS.
In conclusion, a catalytic TBDMS ether desilylation was
developed using catalytic amount of non-hazardous PVP-I
instead of molecule iodine with short reaction time at room
temperature. This newly developed catalytic method has the
advantages of high yield compared with the traditional strategy
using excess anhydrous TBAF. The work-up process is also
simplifier than other methods like use of iodine. In addition, this
method is especially suitable for those base-sensitive compounds.
Further exploration of PVP-I catalytic system to protect or
deprotect other functional groups was still going on in our
laboratory.
23. Shah, S. T. A.; Singh, S.; Guiry, P. J. J. Org. Chem. 2009, 74,
2179-2182.
24. Bhure, M. H.; Kumar, I.; Natu, A. D.; Rode, C. V. Synth. Commun.
2008, 38, 346-353.
25. Lakshman, M. K.; Tine, F. A.; Khandaker, T. A.; Basava, V.;
Agyemang, N. B.; Benavidez, M. S. A.; Gasi, M.; Guerrera, L.;
Zajc, B. Synlett 2017, 28, 381-385.
26. (a) Huang, H.-S.; Kong, R.; Zheng, X.-A.; Chen, W.-J.; Han, S.-B.;
Zeng, D.-Y.; Gong, S.-S.; Sun, Q. Synlett 2018, 29, 2437-2443; (b)
Kumar, G. D. K.; Baskaran, S. J. Org. Chem. 2005, 70, 4520-4523.
27. Yu, Z. K.; Verkade, J. G. J. Org. Chem. 2000, 65, 2065-2068.
28. Khan, A. T.; Ghosh, S.; Choudhury, L. H. Eur. J. Org. Chem.
2004, 2198-2204.
29. Karimi, B.; Zamani, A.; Zareyee. D. Tetrahedron Lett. 2004, 45,
9139-9141.
Acknowledgments
30. Yeom, C.-E.; Kim, Y. J.; Lee, S. Y.; Shin, Y. J.; Kim, B. M.
Tetrahedron 2005, 61, 12227-12237.
31. Shekar, S. S.; Penthala, N. R.; Calahan, J. L. Org. Biomol. Chem.
2018, 16, 6057-6062.
32. Chen, M.-Y.; Lu, K.-C.; Lee, A. S.-Y.; Lin, C.-C. Tetrahedron
Lett. 2002, 43, 2777-2780.
This work was financially supported by Science and
Technology
Commission
of
Shanghai
Municipality
(14DZ1900102) and the Fundamental Research Funds for the
Central University (WY1113007).
33. (a) Jadhav, A. H.; Kim, H. Tetrahedron Lett. 2012, 53, 5338-5342;
(b) Jadhav, V. H.; Lee, S. B.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-
H.; Kim, D. W. Tetrahedron Lett. 2012, 53, 2051-2053.
34. Kanagalingam, J.; Feliciano, R.; Hah, J. H.; Labib, H.; Le, T. A.;
Lin, J. C. Int. J. Clin. Pract., 2015, 69, 1247-1256.
35. (a) Lipshutz, B. H.; Keith, J. Tetrahedron Lett., 1998, 39, 2495-
2498; b) Vaino, A. R.; Szarek, W. A. J. Chem. Soc. Chem.
Commun., 1996, 2351-2352.
References and notes
1.
Wuts, P. G. M.; Greene, T. W. Greene’s protective groups in
organic synthesis: Fourth edition. 2007, John Wiley & Sons, Inc.:
New Jersey.
2.
3.
4.
Clark, J. H. Chem. Rev., 1980, 80, 429-452.
Middleton, W. J. Org. Syn. 1986, 64, 221.
Liotta, C. L.; Harris, H. P. J. Am. Chem. Soc., 1974, 96, 2250-
2252.
Supplementary Material
5.
6.
7.
Nicolaou, K. C.; Webber, S. E. Synthesis, 1986, 453-461.
Cirillo, P. F.; Panek, J. S. J. Org. Chem., 1990, 55, 6071-6073.
Seki, M.; Kondo, K.; Kuroda, T.; Yamanaka, T.; Iwasaki, T.
Synlett, 1995, 609-611.
Jadhav, A. H.; Chinnappan, A.; Patil, R. H.; Chung, W.-J.; Kim, H.
Chem. Eng. J. 2014, 236, 300-305.
González-Calderón, D.; González-Calderón, C. A.; Fuentes-
Benítez, A.; Cuevas-Yáñez, E.; Corona-Becerril, D.; González-
Romero, C. Helv. Chim. Acta, 2014, 97, 965-972.
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
8.
9.
10. Gopinath, P.; Nilaya, S.; Muraleedharan, K. M. Org. Lett. 2011,
13, 1932-1935.
Click here to remove instruction text...

6
Tetrahedron
Highlights
A PVP-I catalyzed OTBS deprotection method was
developed with simple work-up process
OTBS and OTHP could be removed
simultaneously.
Chemoselective deprotection of TBS ethers in the
presence of TIPS and TBDPS