Facile method for trimethylsilylation of alcohols using hexamethyldisilazane and ammonium thiocyanate under neutral conditions

Article abstract of DOI:10.1080/00397910701227440

A highly efficient method for trimethylsilylation of primary, secondary, tertiary, allylic, and a variety of sugar-derived alcohols using hexamethyldisilazane in the presence of a catalytic amount of ammonium thiocyanate under neutral conditions is reported. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701227440

This article was downloaded by: [University of Chicago Library]
On: 19 November 2014, At: 03:14
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
Facile Method for Trimethylsilylation of
Alcohols using Hexamethyldisilazane and
Ammonium Thiocyanate under Neutral
Conditions
a
a
a
Vrushali H. Jadhav , K. S. Ajish Kumar , Vinod D. Chaudhari & Dilip D.
a
Dhavale
a
Garware Research Centre, Department of Chemistry , University of Pune ,
Pune, India
Published online: 13 Apr 2007.
To cite this article: Vrushali H. Jadhav , K. S. Ajish Kumar , Vinod D. Chaudhari & Dilip D. Dhavale (2007)
Facile Method for Trimethylsilylation of Alcohols using Hexamethyldisilazane and Ammonium Thiocyanate
under Neutral Conditions, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 37:8, 1363-1370, DOI: 10.1080/00397910701227440
To link to this article: http://dx.doi.org/10.1080/00397910701227440
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
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. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

w
Synthetic Communications , 37: 1363–1370, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701227440
Facile Method for Trimethylsilylation of
Alcohols using Hexamethyldisilazane and
Ammonium Thiocyanate under Neutral
Conditions
Vrushali H. Jadhav, K. S. Ajish Kumar, Vinod D. Chaudhari,
and Dilip D. Dhavale
Garware Research Centre, Department of Chemistry, University of Pune,
Pune, India
Abstract: A highly efficient method for trimethylsilylation of primary, secondary,
tertiary, allylic, and a variety of sugar-derived alcohols using hexamethyldisilazane
in the presence of a catalytic amount of ammonium thiocyanate under neutral con-
ditions is reported.
Keywords: alcohols, ammonium thiocyanate, 1,1,1,3,3,3-hexamethyldisilazane,
trimethylsilylation
The protection–deprotection steps of active protic functional groups are fre-
quently required in multistep synthesis to prevent their interference while
modifying other functional groups in the same molecule. Because hydroxyl
functionality is a largely encountered functional group in many natural
products, its protection under different conditions is in demand.
Among the various types of protecting groups, trimethylsilyl protection of
hydroxyl functionality is most popular and widely used in organic synthesis
[1]
because of its easy removal under mild reaction conditions. A number of
methods are available for trimethylsilyl protection of hydroxyl groups that
include the use of trimethylsilyl halides or trimethylsilyltriflate in the
Received September 22, 2006
Address correspondence to Dilip D. Dhavale, Garware Research Centre, Depart-
ment of Chemistry, University of Pune, Pune 411 007, India. E-mail: ddd@chem.
unipune.ernet.in
1
363

1
364
V. H. Jadhav et al.
[
2]
[3]
presence of lithium sulphide (Li S) and/or different bases. Allylsilanes in
2
[4]
[5]
conjunction with p-toluenesulphonic acid,
iodine,
trifloromethane–
[
6]
[7]
sulphonic acid, and scandium triflate (Sc(OTf)3) are also reported to
give trimethylsilyl derivatives. In these methods, the use of acid or base as
a catalyst is always associated with the formation of by-products and
requires careful use of the catalyst to get an optimum yield without
affecting other sensitive functionalities. This problem has partially been
overcome by substituting a cheap, stable, and commercially available
1,1,1,3,3,3-hexamethyl-disilazane (HMDS) for trimethylchlorosilane
(
activation in the form of additives. Recently, activators such as iodine
TMSCl). The very low reactivity of HMDS, as a silylating agent, requires
[8]
[
9]
[10]
.
(
I ), coppersulphate pentahydrate (CuSO 5H O),
and lithiumperchlo-
have been used in such type of reactions.
While working in the field of carbohydrate chemistry and its utility for
2
4
2
[
11]
rate (LiClO4)
[
12]
the synthesis of azasugars,
of a secondary hydroxyl functionality, at C-3 of pyrrolidine derivative
Table 1, entry q), which failed with variety of protecting groups
we came across a difficulty in the protection
(
(benzyl(Bn), p-methoxybenzyl (PMB), tertiary-butyl-dimethyl-silyl (TBDMS),
trimethylsilyl (TMS)) under different reaction conditions.
[13]
Our surveil-
lance with different reagents resulted in a new method for the protection
of hydroxyl functionality using HMDS in association with a catalytic
amount of ammonium thiocyanate as a catalyst. (The use of ammonium
thiocyanate as a reagent is well known in the metal complex and
pesticide industry; however, to the best of our knowledge, no report is
available on its application in organic synthesis.) Thus, the reaction of
different alcohols (1 mmol) with HMDS (0.6 mmol) in the presence of
catalytic amount of ammonium thiocyanate (0.05 mmol) in dry dichloro-
methane afforded excellent yields of corresponding trimethylsilyl ethers
(
Eq. (1)).
HMDSð0:6 eqÞ;NH4SCNð0:05 eqÞ
ROH
!
ROTMS
CH2Cl2
R ¼ aliphatic=benzylic=sugar=steroid=terpenoid
(1)
As shown in Table 1, the trimethylsilylation reaction was found to be suc-
cessful with primary, secondary, tertiary, benzylic, and propargylic
hydroxyl groups (Table 1, entries a–f, h, i, r). Trimethylsilylation with con-
formationally locked and relatively hindered hydroxyl groups was found to
be sluggish albeit high yielding (Table 1, entries j, k, l). The functional
groups such as nitrile, chloride, and acetonide were found to be persistent
under the reaction conditions. In the case of sugar substrates, primary,
secondary, and allylic alcohols afforded high yields of the products
(Table 2, entries m–p). Our attempts to protect different phenols (with
electron-withdrawing and donating substituents) and quinols (Table 1,

Trimethylsilylation of Alcohols
1365
Table 1. Trimethylsilylation of various alcohols using HMDS and catalytic amount
of ammonium thiocyanate
Temp. Yield
(8C)
Entry Substrate (1)
Product (2)
Time
(%)
a
b
c
d
e
10 min
10 min
10 min
10 min
10 min
0
99
97
93
98
97
0
0
0
0
f
10 min
10 min
10 min
0
0
0
98
97
98
g
h
i
j
10 min
10 h
0
95
0 to rt 95
k
l
6 h
8 h
0 to rt 95
0 to rt 98
entries s–u) did not afford the product, and starting material was recovered
under a variety of reaction conditions: temperature, time, solvents, and stoi-
chiometry of reagents.
The trimethylsilylation of hydroxyl group using HMDS in combination
with I was reported recently via an ionic pathway. In the present investi-
2
gation, we presume that the ammonium thiocyanate is acting as an activator
(initiator) to HMDS giving hexamethyldisilazonium species (A) in which
Si-N bond is polarized (Fig. 1). In the next step, nucleophilic attack of
hydroxyl group on silicon, facilitated by oxophilicity of the silicon, affords

1
366
V. H. Jadhav et al.
Table 2. Trimethylsilylation of sugar substrates and tertiary alcohol using HMDS and
ammonium thiocyanate
Temp. Yield
(%)
Entry
m
Substrate (1)
Product (2)
Time
(8C)
5 min
0
91
n
8 min
0
90
o
p
10 min
10 min
0
0
85
90
q
r
20 min 0 to rt
25 min 0 to rt
88
92
s
t
No reaction
No reaction
No reaction
u
trimethylsilylated product and trimethylsilylammonium ion (B), which further
reacts with the second molecule of alcohol to give the oxonium intermediate
(
C) and ammonia (g). Subsequently, HMDS abstracts the proton from the
oxonium intermediate (C) to regenerate the activated species (A) that
continues the cycle. The driving force for the reaction is believed to be the
evolution of ammonia gas as confirmed by testing with turmeric paper and
conc. HCl.

Trimethylsilylation of Alcohols
1367
Figure 1. Catalytic cycle.
CONCLUSION
In conclusion, our protocol demonstrates the use of ammonium thiocyanate as
an effective catalyst for the trimethylsilylation of alcohols using HMDS under
neutral reaction conditions affords high yields in short reaction time. The
reaction is environmentally benign with atom economy of HMDS.
GENERAL PROCEDURE
To a solution of alcohol (1 mmol) in dry dichloromethane, HMDS (0.6 mmol)
was added followed by a catalytic amount of ammonium thiocyanate
(
0.05 mmol) at 08C. The reaction mixture was stirred and monitored by
thin-layer chromatography (TLC). After completion of the reaction, water
3 mL) was added, and the reaction mixture was extracted with dichloro-
(
methane (3 ꢀ 5 mL). Evaporation of the solvent gave product (ꢀ95% trimethyl-
1
silyl derivatives as evident from the H NMR spectra of the crude product) that
was purified by column chromatography on neutral alumina using n-hexane as
an eluent. In some cases, loss in the yield of the product was observed
because of the highly volatile nature of the trimethylsilyl derivatives.
Data
1
Spectroscopic data of 2d: H NMR (300 MHz, CDCl ) d 0.1 (s, 9H), 1.97
3
1
3
(
(
m, 2H), 3.64 (t, J ¼ 5.7 Hz, 2H), 3.72 (t, J ¼ 6.3 Hz, 2H); C NMR
75 MHz, CDCl ) d20.5 (s), 35.2, 41.7, 58.8.
3

1
368
V. H. Jadhav et al.
1
Spectroscopic data of 2e: H NMR (300 MHz, CDCl ) d 0.14 (s, 9H), 2.53
3
1
3
(
d 20.6 (s), 21.6, 57.8, 117.9.
t, J ¼ 6.3 Hz, 2H), 3.78 (t, J ¼ 6.3 Hz, 2H); C NMR (75 MHz, CDCl3)
1
Spectroscopic data of 2l: H NMR (300 MHz, CDCl ) d 0.10 (s, 9H), 0.79
3
13
(s, 3H), 0.96 (s, 3H), 1.01 (s, 3H), 0.90–1.80 (m, 7H) 3.22 (s, 1H); C NMR
(75 MHz, CDCl ) d0.6 (s), 19.9, 21.1, 25.5, 26.3, 30.5, 39.3, 40.9, 48.4, 49.4, 85.3.
3
1
Spectroscopic data of 2m: H NMR (300 MHz, CDCl ) d 0.01 (s, 9H), 1.20
3
(
s, 3H), 1.27 (s, 3H), 1.33 (s, 3H), 1.40 (s, 3H), 3.47 (d, J ¼ 10.5 Hz, 1H), 3.57
(
dd, J ¼ 6.6, 12.9 Hz, 2H), 3.77 (dd, J ¼ 2.1, 12.9 Hz, 1H), 4.08 (bd,
J ¼ 7.8 Hz, 1H), 4.24 (d, J ¼ 2.4 Hz, 1H), 4.45 (dd, J ¼ 2.7, 8.1 Hz, 1H);
1
3
C NMR (75 MHz, CDCl ) d 0.1 (s), 23.8, 24.4, 24.8, 26.1, 61.2, 64.5,
3
69.8, 71.1, 71.3, 103, 108.5, 109.0.
1
Spectroscopic data of 2n: H NMR (300 MHz, CDCl ) d 0.10 (s, 9H), 1.32
3
(
s, 3H), 1.36 (s, 3H), 1.41 (s, 3H), 1.46 (s, 3H), 3.96 (dd, J ¼ 6.0, 8.4 Hz,
1
H), 4.06 (dd, J ¼ 8.1 Hz, 1H), 4.07 (dd, J ¼ 2.7, 8.1 Hz, 1H), 4.22 (dd,
J ¼ 1.5, 6.0 Hz, 1H), 4.23 (d, J ¼ 2.7 Hz, 1H), 4.35 (d, J ¼ 3.6 Hz, 1H),
1
3
5
2
.89 (d, J ¼ 3.6 Hz, 1H); C NMR (75 MHz, CDCl ) d 2 0.0 (s), 25.4,
3
6.3, 26.8, 26.9, 67.4, 72.3, 75.2, 81.8, 85.5, 105.2, 108.7, 111.7.
1
Spectroscopic data of 2o: H NMR (300 MHz, CDCl ) d 0.09 (s, 9H), 0.11
3
(
s, 9H), 1.29 (s, 3H), 1.48 (s, 3H), 3.53 (dd, J ¼ 6.9, 10.5 Hz, 1H), 3.83
dd, J ¼ 1.8, 10.5 Hz, 1H), 4.03 (d, J ¼ 2.7 Hz, 1H), 4.08 (m, 2H), 4.54
d, J ¼ 3.9 Hz, 1H), 4.57 (d, J ¼ 11.7 Hz, 1H), 4.65 (d, J ¼ 11.7 Hz, 1H),
(
(
1
3
5
2
1
.86 (d, J ¼ 3.9 Hz, 1H); C NMR (75 MHz, CDCl ) d 2 0.4 (s), 0.9 (s),
3
6.3, 26.8, 65.5, 70.8, 72.0, 80.4, 81.4, 82.0, 105.2, 111.6, 127.1, 127.2,
27.6, 128.3, 137.6.
1
Spectroscopic data of 2p: H NMR (300 MHz, CDCl ) d 0.1 (s, 9H),
3
1
.32 (s, 3H), 1.49 (s, 3H), 3.85 (d, J ¼ 3 Hz, 1H), 4.15 (t, J ¼ 6 Hz, 1H),
.56 (d, J ¼ 12.4 Hz, 1H), 4.63 (m, J ¼ 3, 5.4, 12 Hz, 4H), 5.94
4
1
3
(
m, J ¼ 3.6 Hz, 3H); C NMR (75 MHz, CDCl ) d 0.02 (s), 26.2, 26.7,
3
6
1
2.7, 72.1, 80.5, 82.7, 83.2, 104.6, 111.4, 124.6, 127.5 (s), 127.7, 128.3 (s),
34.1, 137.2.
1
Spectroscopic data of 2q: HNMR (300 MHz, CDCl ) d 0.10 (s, 9H), 0.22
3
(
s, 9H), 1.25 (t, J ¼ 7.1 Hz, 3H), 2.38 (dd, J ¼ 10.9, 6.3 Hz, 1H), 2.47
d, J ¼ 5.7 Hz, 2H), 2.73 (dd, J ¼ 11.8, 5.7 Hz, 1H), 2.80 (dd, J ¼ 10.9,
(
1
.9 Hz, 1H), 3.14 (d, J ¼ 13.1 Hz, 1H), 3.61–3.65 (m, 1H), 3.89
(
d, J ¼ 13.1 Hz, 1H), 3.98 (dd, J ¼ 7.1, 4.6 Hz, 1H), 3.99 (q, J ¼ 7.1 Hz,
1
3
2
H), 4.27 (ABq, J ¼ 11.8 Hz, 2H), 7.05–7.23 (m, 10H); C NMR (75 MHz,
CDCl ) d 0.13 (s), 14.1, 36.6, 56.3, 58.3, 60.3, 66.9, 71.4, 80.9, 83.5, 126.8,
3
1
27.5, 127.6 (s), 128.1 (s), 128.2 (s), 128.6 (s), 138.0, 138.8, 171.9.

Trimethylsilylation of Alcohols
1369
1
Spectroscopic data of 2r: H NMR (300 MHz, CDCl ) d 0.15 (s, 9H), 1.63
3
(
(
(
s, 6H), 7.25 (d, J ¼ 6.6 Hz, 1H), 7.34 (t, J ¼ 7.2 Hz, 2H), 7.48
1
3
d, J ¼ 7.5 Hz, 2H); C NMR (75 MHz, CDCl ) d 2.5 (s), 32.5(s), 124.5
3
s), 126.1, 127.7 (s).
ACKNOWLEDGMENT
We are thankful to the Department of Science and Technology (SP/S1/G-32/
2
000), New Delhi, for financial support. V. H. J. and A. K. S. are thankful to
Council of Scientific and Industrial Research-University Grants Commission
CSIR-UGC), New Delhi, for fellowships.
(
REFERENCES
1
2
3
. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.;
Wiley: New York, 1999; p. 116.
. Olah, G A.; Gupta, B. G. B.; Narang, S. C.; Malhotra, R. J. Org. Chem. 1979, 44,
4
272.
. (a) Lolonde, M.; Chan, T. H. Synthesis 1985, 817; (b) West, R. J. Am. Chem. Soc.
958, 80, 3246; (c) House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. D. J. Org.
Chem. 1969, 34, 2324; (d) Corey, E. J.; Snider, B. B. J. Am. Chem. Soc. 1972, 94,
549; (e) Brook, M. A. Silicon in Organic, Organometalic, and Polymer
1
2
Chemistry; Wiley: New York, 2000; (f) D’ Sa, B. A.; Mc Leod, D.;
Verkade, J. G. J. Org. Chem. 1997, 62, 5057; (g) D’ Sa, B. A.; Verkade, J. G.
J. Am. Chem. Soc. 1996, 118, 12832.
4. (a) Morita, T.; Okamoto, Y.; Sakurai, H. Tetrahedron Lett. 1980, 21, 835;
(b) Vesoglu, T.; Mitscher, L. A. Tetrahedron Lett. 1981, 22, 1299.
. Hosomi, A.; Sakurai, H. Chem. Lett. 1981, 85, 880.
5
6. Olah, G. A.; Husain, A.; Gupta, B. G. B.; Salem, G. F.; Narang, S. C. J. Org. Chem.
1981, 46, 5212.
7
8
. Suzuki, T.; Watahiki, T.; Oriyama, T. Tetrahedron Lett. 2000, 41, 8903.
. (a) Firouzabadi, H.; Iranpoor, N.; Amani, K.; Nowrouzi, F. J. Chem. Soc., Perkin
Trans. 1 2002, 2601; (b) Zhang, Z. H.; Li, T. S.; Yang, F.; Fu, C. G. Synth.
Commun. 1998, 28, 3105; (c) Langer, S. H.; Connel, S.; Wender, J. J. Org.
Chem. 1958, 23, 50; (d) Gauttret, P.; El-Ghamarti, S.; Legrand, A.; Coutrier, D.;
Rigo, B. Synth. Commun. 1996, 26, 707; (e) Cossy, J.; Pale, P. Tetrahedron
Lett. 1987, 28, 6039; (f) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.;
Constantino, U. Synth. Commun. 1999, 29, 541; (g) Zuercher, K.; Hadorn, H.
Dtsch. Lebensm-Rundsh. 1975, 71, 68; (h) Patents applied for, e.g., European
Patent Application. 81.200771.4. Bruynes; Jurriens; EP0043630A2; filing date:
July 3, 1981; (i) Harrp, D. N.; Steliou, K.; Chan, T. H. J. Am. Chem. Soc. 1978,
100, 1222; (j) Firouzabadi, H.; Karimi, B. Synth. Commun. 1993, 23, 1633;
(
k) Firouzabadi, H.; Sardarian, A. R.; Khayat, Z.; Karimi, B.;
Tangestaninejad, S. Synth. Commun. 1997, 27, 2709; (l) Goldschmidt, A. G. T.
German Patent. 2 758884; filing date: December 30, 1977; (m) Kumar, P.;
Pais, G. C. G.; Keshavaraja, A. J. Chem. Res. Synop. 1996, 376; (n) Bruynes, C. A.;
Jurriens, T. K. J. Org. Chem. 1982, 47, 3966; (o) Bandgar, B. P.; Wadgaonkar, P. P.

1
370
V. H. Jadhav et al.
Synth. Commun. 1997, 27, 2069; (p) Tillu, V. H.; Jadhav, V. H.; Borate, H. B.;
Wakharkar, R. D. Arkivoc 2004, xiv, 83.
. Karimi, B.; Golshani, B. J. Org. Chem. 2000, 65, 7228.
9
1
1
1
0. Akhlaghinia, B.; Tavakoli, S. Synthesis 2005, 11, 1775.
1. Azizi, N.; Saidi, M. Organometallics 2004, 23, 1457.
2. (a) Dhavale, D. D.; Markad, S. D.; Karanjule, N. S.; Prakashareddi, J. J. Org.
Chem. 2004, 69, 4760; (b) Karanjule, N. S.; Markad, S. D.; Sharma, T.;
Sabarwal, S. G.; Puranik, V. G.; Dhavale, D. D. J. Org. Chem. 2005, 70, 1356.
3. Chaudhari, V. D.; Ajish Kumar, K. S.; Dhavale, D. D. Tetrahedron 2006, 62, 4349.
1