An expeditious, efficient green methodology for the Boc protection of amines and silyl protection of alcohols over tungstophosphoric acid-doped mesoporous silica

Article abstract of DOI:10.1016/j.tetlet.2010.05.080

An efficient, chemoselective and eco-friendly protocol for the protection of amines as N-tert-butylcarbamate using (Boc)₂O and protection of alcohols as silyl ether using HMDS over tungstophosphoric acid/SBA15 has been developed. Solventless condition, easy work-up, short reaction time, excellent yields and reusability of the catalyst are the striking features of this methodology which can be considered to be one of the better methods for the protection of amines and alcohols.

Full text of DOI:10.1016/j.tetlet.2010.05.080

Tetrahedron Letters 51 (2010) 3855–3858
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Tetrahedron Letters
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An expeditious, efficient green methodology for the Boc protection of
amines and silyl protection of alcohols over tungstophosphoric acid-doped
mesoporous silica
Bikash Karmakar a, Julie Banerji b,
*
a Gobardanga Hindu College, Department of Chemistry, Khantura, 24 parganas (North) 743 273, India
b Centre of Advances Studies on Natural products including Organic Synthesis, Department of Chemistry, University of Calcutta, 92, A.P.C. Road, Kolkata 700 009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, chemoselective and eco-friendly protocol for the protection of amines as N-tert-butylcarba-
mate using (Boc)2O and protection of alcohols as silyl ether using HMDS over tungstophosphoric acid/
SBA15 has been developed. Solventless condition, easy work-up, short reaction time, excellent yields
and reusability of the catalyst are the striking features of this methodology which can be considered
to be one of the better methods for the protection of amines and alcohols.
Received 12 April 2010
Revised 16 May 2010
Accepted 19 May 2010
Available online 24 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
N-Boc
Amines
Silyl ether
Alcohols
Mesoporous
Reusable
1. Introduction
Trimethysilylation of labile hydroxyl groups is another important
strategy for the protection of alcohols.6 These functional organosilyl
In synthetic organic chemistry, protection and deprotection of
functional groups constitute a crucial strategy. Protection of
amines as N-tert-butylcarbamate is an important technique in
multistep organic synthesis.1 Among different methods, the N-
tert-butoxycarbonyl (N-Boc) protection has been widely used for
the amino acids during peptide synthesis due to their resistance to-
wards racemization.2 Boc-protected aryl amines are important
intermediates in organic synthesis. The N-Boc strategy has priority
over others because they are stable towards base and nucleophiles
as well as catalytic hydrogenation.3 Moreover, due to their facile
removal by reagents such as CF3COOH, formic acid, 3(N) HCl in
ethyl acetate or 10% H2SO4 in dioxane, the amine can be easily
regenerated. Among the different available groups for N-Boc
protection such as Boc2O, BocONH2, BocN3, BocON@N(CN)Ph and
1-(tert-butoxycarbonyl)benzotriazole,4 the di-tert-butoxypyrocar-
bonate is the most popular because of its commercial availability,
low cost and stability and efficiency. However, there are several
drawbacks behind the classical N-Boc protection technique. The te-
dious work-up takes time and side products are generated. More-
over, the catalysts used to promote the reaction are most of the
time very costly and non-recoverable.5
ethers are stable under various conditions, soluble in non-polar
solvents, have high thermal stability and are easy to remove under
acid or base hydrolytic conditions.7 They also help to increase the
volatility for analysis in gas-chromatography and mass spectrome-
try.8 A wide variety of reagents and methods have been employed
for the introduction of trimethylsilyl group such as trimethylchloro
silane,9 hexamethyldisiloxane,10 allylsilanes, trimethylsilyl triflate,11
trimethylsilyl azide,12 bis-(trimethylsilyl)trifluoroacetamide,13 N-tri-
methylsilyl-2-oxazolidinone,14 N-(trimethylsilyl)imidazoles15 and
ketene methyltrialkylsilyl acetals.16 However, some of them require
O
R'
R'
R
12-TPA/SBA 15
Solventless, rt
(Boc)2O
NH
N
+
O
R
Scheme 1. Protection of amines as N-tert-butylcarbamate.
R'
O
R'
OH
12-TPA/SBA 15
Solventless, 50 oC
Si
HMDS
+
R
R
* Corresponding author. Tel.: +91 33 2350 8386; fax: +91 33 2351 9755.
E-mail address: juliebanerji47@gmail.com (J. Banerji).
Scheme 2. Protection of alcohols as trimethylsilylether.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.080

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B. Karmakar, J. Banerji / Tetrahedron Letters 51 (2010) 3855–3858
Table 1
hazardous conditions. Use of hexamethyldisilazane (HMDS) as a
silylating agent removes some of these difficulties as it is stable,
inexpensive, nearly neutral, easily handled and products can be
recovered from excess HMDS by simple techniques. The only
byproduct is ammonia which can be easily removed. However, the
main drawback is the poor silylating capacity of HMDS which is a
deterrent in its application.
We now report a rapid and efficient solventless technique for
the Boc protection of amines and silyl protection of alcohols over
tungstophosphoric acid-supported ordered mesoporous silica
SBA15 (Schemes 1 and 2). To the best of our knowledge there
has been no report available on these protections over our catalyst
in the literature. We have been working on the applications of
mesoporous materials as catalyst in developing new synthetic
methodologies.17 The large surface area, strong Lewis acidic char-
acter and reusable nature of TPA/SBA15 catalyst have been
exploited here by us leading to high chemoselectivity and excellent
yields of the products.
Optimization of conditions for the N-Boc protection of anilinea
Entry
Solvent
Catalyst (TPA wt%)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
CH3CN
CH3OH
Toluene
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
TPA/SBA15 (20)
TPA/SBA15 (20)
TPA/SBA15 (20)
TPA/SBA15 (20)
TPA/SBA15 (20)
TPA/SBA15 (10)
TPA/SBA15 (15)
TPA/SBA15 (30)
SBA15
15
10
10
30
5
30
15
5
85
90
94
80
97
88
92
94
<20
87
180
30
10
TPA
a
Reaction conditions: Aniline (1.0 mmol), (Boc)2O (1.0 mmol), catalyst 50 mg, rt.
Isolated yield after purification.
b
addition of bases, take longer reaction time and are expensive. More-
over, removalof the amine salts, formed as byproducts, often involve
Table 2
Protection of amines as N-tert-butylcarbamate over TPA/SBA15a
Entry
Amine
Product
Time (min)
5
Yieldb (%)
97
1
NH2
CH3
NH2
NHBoc
CH3
NHBoc
2
3
4
5
6
7
8
8
7
95
96
97
94
95
93
90
NH2
H3C
NHBoc
H3C
NO2
NH2
NO2
NHBoc
6
5
Br
NH2
Br
NHBoc
MeO
MeO
5
NHBoc
NH2
MeO
NH2
NHBoc
5
MeO
COOH
COOH
15
NHBoc
CN
NH2
CN
9
10
2
95
98
NHBoc
NH2
NH2
NHBoc
10
11
12
13
3
2
2
98
98
97
NH2
NHBoc
NH
NBoc
NBoc
NBoc
NHBoc
NH
14
15
O
3
2
97
98
O
NH
NH2
a
Reaction conditions: Amine (1.0 mmol), (Boc)2O (1.0 mmol), catalyst 50 mg, solventless, rt.
Isolated yield after purification.
b

B. Karmakar, J. Banerji / Tetrahedron Letters 51 (2010) 3855–3858
3857
might be due to its better texture and homogeneous distribution
of acidic sites in the silica. The corresponding 10 wt% and 30 wt%
loaded catalysts were comparably less effective. This might be
due to the less number of acidic sites and agglomeration of TPA
molecules in the silica matrix, respectively. In this connection it
seems noteworthy to mention that unloaded SBA15 could not gen-
erate satisfactory yield (Table 1, entry 9). Even TPA itself was not
so efficient because it took longer period to complete the reaction
(Table 1, entry 10).
Finally we decided to continue with the standard conditions
and to explore the scope and limitations of the method. A wide
range of aromatic and aliphatic amines (primary as well as second-
ary) were protected as their di-tert butylcarbamate with excellent
reactivity (Table 2). There was not much difference in reactivity
with variation of functional groups. All the reactions were com-
pleted within 2–10 min in high yields (90–98%). Only anthranilic
acid (Table 2, entry 8) took longer time to complete the reaction
which might be due to steric inhibition. Aliphatic amines showed
tremendous reactivity towards (Boc)2O (entries 10–15) and
2. Results and discussion
The catalysts were prepared in four different wt% (10, 15, 20
and 30) of the TPA loadings over mesoporous SBA15.18 The cata-
lysts were characterized by Scanning Electron Microscopy (SEM),
Transmission Electron Microscopy (TEM), X-ray diffraction (XRD)
and Fluorescence emission spectroscopy. Initially we started with
the standardization of reaction conditions. Aniline (93 mg,
1.0 mmol) was treated with (Boc)2O (260 mg,1.0 mmol) in the
presence of TPA/SBA15 (50 mg) in various solvents such as dichlo-
romethane, acetonitrile, methanol and toluene (Table 1, entries 1–
4) at room temperature. In most of the cases the desired product
was obtained in moderate to good yields. Toluene and acetonitrile
did not prove to be the best solvents due to their inherent basic
character thus reducing the catalytic activity. The best result was
achieved in the absence of any solvent when it furnished the N-
Boc aniline in highest yield in shortest reaction time. Furthermore,
it was also evident that 20 wt% TPA/SBA15 was the best catalyst
among different TPA loaded SBA15 (Table 1, entries 5–8) which
Table 3
Protection of alcohols as silyl ether over TPA/SBA15a
Entry
1
Alcohol
Product
Time (min)
1
Yieldb (%)
98
OH
OH
OSiMe3
OSiMe3
OMe
OMe
2
2
97
OH
OSiMe3
3
4
5
6
2
2
1
1
98
98
97
98
OMe
H3C
O2N
Cl
OMe
H3C
O2N
Cl
OH
OSiMe3
OSiMe3
OSiMe3
OH
OH
OH
OSiMe3
7
8
9
2
3
2
95
96
95
OH
OSiMe3
O
O
OH
OSiMe3
Me
Me
OH
OH
OH
OSiMe3
10
11
2
2
97
95
OSiMe3
OSiMe3
12
13
3
2
93
96
HS
HS
OH
OSiMe3
OSiMe3
H2N
H2N
OH
14
15
3
88
82
OSiMe3
CH3
OH
CH3
15
a
Reaction conditions: Alcohol (1.0 mmol), HMDS (0.7 mmol), catalyst 50 mg, solventless, 50 °C.
Isolated yield after purification.
b

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B. Karmakar, J. Banerji / Tetrahedron Letters 51 (2010) 3855–3858
100
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.080.
75
50
25
0
Aniline+(Boc)2O
References and notes
PhCH2OH+HMDS
1. (a) Satori, G.; Ballini, R.; Bigi, F.; Bosica, G.; Maggi, R.; Righi, P. Chem. Rev. 2004,
104, 199; (b) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,
2nd ed.; Wiley: New York, 2000. p 503 and references cited therein; (c) Xiuo, X.
Y.; Ngu, K.; Choa, C.; Patel, D. V. J. Org. Chem. 1997, 62, 6968; (d) Caroino, L. A.
Acc. Chem. Res. 1973, 6, 191.
2. (a) Gross, E.; Meienhofer, J.. In The Peptides; Academic Press: New York, 1981;
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Am. Chem. Soc. 1963, 85, 2149.
3. Houben-Weyl, Wuensch E., 4th ed.. In Methods of Organic Chemistry; Muller, E.,
Bayer, O., Meerwein, H., Zieglar, K., Eds.; George Thieme Verlag: Stuttgart,
Germany, 1974; Vol. 15/1, p 46.
4. (a) Tarbell, D. S.; Yamamoto, Y.; Pope, B. M. Proc. Natl. Acad. Sci. U.S.A. 1972, 69,
730; (b) Itoh, M.; Hagiwara, D.; Kamiya, T. Bull. Chem. Soc. Jpn. 1977, 50, 718; (c)
Harris, R. B.; Wilson, I. B. Tetrahedron Lett. 1983, 24, 231; (d) Hansen, J. B.;
Nielsen, M. C.; Ehrbar, U.; Buchradt, O. Synthesis 1982, 404; (e) Katritzsky, A. R.;
Fali, C. N.; Li, J.; Ager, D. J.; Prakash, I. Synth. Commun. 1997, 27, 1623.
5. Jia, X.; Huang, Q.; Li, J.; Li, S.; Yang, Q. Synlett 2007, 806. and references cited
therein.
6. (a) Lalonde, E.; Chem, T. H. Synthesis 1985, 817; (b) Suzuki, T.; Watahiki, T.;
Oriyama, T. Tetrahedron Lett. 2000, 41, 8903.
7. (a) Cooper, B. E. Chem. Ind. 1978, 794. and references cited therein; (b)
Shirakawa, E.; Hironaka, K.; Otsuka, H.; Hayashi, T. Chem. Commun. 2006, 3927.
8. Tullberg, I.; Peetra, I. B.; Smith, B. E. J. Chromatogr. 1976, 120, 103.
9. Lissel, M.; Weiffen, J. Synth. Commun. 1981, 11, 545.
10. Pinnick, H. W.; Bal, B. S.; Lajis, N. H. Tetrahedron Lett. 1978, 19, 4261.
11. (a) Morita, T.; Okamaoto, Y.; Sakutai, H. Tetrahedron Lett. 1980, 21, 835; (b)
Olah, G. A.; Gupta, B. G. B.; Salem, G. F.; Narang, S. C. J. Org. Chem. 1981, 46,
5212.
Run1
Run2
Run3
Run4
Run5
Figure 1. Reusability study of the reactions (in % isolated yield) at optimized
conditions.
reacted at a faster rate than aromatic amines (entries 1–9) which is
obviously due to their higher basicity.
This catalyst was then used for the protection of alcohols as
their silyl ethers with HMDS under similar conditions. O-silylation
of benzyl alcohol was chosen as the probe reaction. However, the
reaction was not as efficient as the N-Boc protection of amines
under the prescribed conditions. Therefore the reaction tempera-
ture was raised to 50 °C keeping other conditions same. In this con-
dition benzyl alcohol was O-silylated in a minute to furnish the
product in excellent yield (98%). Then the protocol was followed
using a series of primary, secondary and tertiary alcohols for gen-
eralization and the results are shown in Table 3. Regardless of the
nature of the substituent attached to them, all the primary and sec-
ondary benzylic alcohols produced excellent yields in a very short
time (Table 3, entries 1–9). The method also worked well with allyl
and propargyl alcohols (entries 10 and 11). Some aliphatic alcohols
containing amino and mercapto functionalities were regioselec-
tively O-silylated (entries 12 and 13). However the reaction with
sterically hindered menthol and 1-methylcyclohexanol was slug-
gish and the yields were also moderate (entries 14 and 15).
From the context of green approach, the reusability study of the
catalyst was performed with the N-Boc protection of aniline and
O-silyl protection of benzyl alcohol. After completion of the reaction
(by TLC), the reaction mixture was diluted with dichloromethane
and centrifuged to separate the catalyst. It was washed well with
acetone and then dried at 100 °C before being further used. It was
observed that on successive five runs with the TPA/SBA15 catalyst
for both the reactions the reactivity remained almost unchanged
(Fig. 1).
12. Sinou, D.; Emziane, M. Synthesis 1986, 1945.
13. Chirakul, P.; Hampton, P. D.; Duelser, E. N. Tetrahedron Lett. 1998, 39, 5473.
14. Aizapurua, J. M.; Palomo, C. Bull. Soc. Chim. Fr. 1982, 265.
15. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
16. Kita, Y.; Haruta, J.; Segawa, J.; Tamura, Y. Tetrahedron Lett. 1979, 44, 4311.
17. (a) Karmakar, B.; Nayak, A.; Chowdhury, B.; Banerji, J. Arkivoc 2009, XII, 209; (b)
Postole, G.; Chowdhury, B.; Karmakar, B.; Pinki, K.; Banerji, J.; Auroux, A. J.
Catal. 2010, 269, 110; (c) Karmakar, B.; Chowdhury, B.; Banerji, J. Catal.
Commun. 2010, 11, 601.
18. Preparation of the catalyst: The mesoporous silica support SBA15 was
synthesized by following the method reported by Zhao et al.19
Tungstophosphoric acid was immobilized over SBA15 matrix by an incipient
wet impregnation method. 1.0 mg SBA15 was taken in 20 mL absolute ethanol.
Different loadings of TPA (10, 15, 20 and 30 wt%) was added to it and stirred for
14 h at room temperature. The solution was dried at 60 °C for 2 h and calcined
at 550 °C for 4 h in aerial atmosphere to furnish
a white powder.
Characterization data of the catalyst (SEM, TEM, XRD and Fluorescence
spectra) are available as Supplementary data.
19. Zhao, D.; Feng, J.; Huo, Q.; Melosh, N.; Fredrickson, G. H.; Chmelka, F.; Stucky,
G. D. Science 1998, 279, 548.
20. General procedure for the protection of amines:
A mixture of aliphatic or
aromatic amine (1.0 mmol) and (Boc)2O (1.0 mmol) was stirred in solventless
condition in the presence of 50 mg of the TPA/SBA15 catalyst at room
temperature. After completion, the reaction mixture was diluted with 5 mL
dichloromethane and centrifuged to separate the catalyst for reuse. The filtrate
was crystallized to furnish the pure solid in most of the cases.
3. Conclusion
In summary, we have developed an efficient methodology for
the N-Boc protection of amines and O-silyl protection of alcohols
producing remarkable high yields under very mild conditions.20
The solventless technique, extremely expeditious and reusability
of the catalyst have made our protocol not only environmentally
benign but also one of the better methods for the protection of
amines and alcohols in organic synthesis.
General procedure for the protection of alcohols: A mixture of alcohol (1.0 mmol)
and HMDS (1.0 mmol) was stirred in solventless condition in the presence of
50 mg of the TPA/SBA15 catalyst followed by heating at 50 °C. After
completion, the reaction mixture was diluted with 5 mL dichloromethane
and centrifuged to separate the catalyst for reuse. The filtrate was concentrated
under reduced pressure to furnish the pure product. In some cases it was
further purified by column chromatography using 60–120 silica gel and ethyl
acetate/hexane (4–6%) as eluant.
All the products were characterized with 1H NMR and IR spectrometry and
were compared with the authentic data in the literature.
Acknowledgement
B. K. thanks minor research project scheme under UGC, New
Delhi for providing financial assistance.