A new protocol for selective deprotection of N-tert-butoxycarbonyl protective group (t-Boc) with Sn(OTf)2

Article abstract of DOI:10.1081/SCC-120015775

A simple and efficient method for the selective removal of N-Boc group by employing tin(II) trifluoromethanesulfonate [Sn(OTf)₂] in CH₂Cl₂ or solvent-free conditions was developed. The scope of this procedure is explored for the deprotection of a variety of amines, including amino acid derivatives.

Full text of DOI:10.1081/SCC-120015775

This article was downloaded by: [University of California, San Diego]
On: 05 June 2015, At: 14:22
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
A New Protocol for Selective Deprotection of N -
tert -Butoxycarbonyl Protective Group ( t -Boc) with
Sn(OTf)2
a
a
a
D. Subhas Bose , K. Kiran Kumar & A. V. Narsimha Reddy
a
Organic Chemistry Division III , Fine Chemicals Laboratory , Indian Institute of Chemical
Technology , Hyderabad, India
Published online: 17 Aug 2006.
To cite this article: D. Subhas Bose , K. Kiran Kumar & A. V. Narsimha Reddy (2003) A New Protocol for Selective Deprotection
of N - tert -Butoxycarbonyl Protective Group ( t -Boc) with Sn(OTf) , Synthetic Communications: An International Journal for
2
Rapid Communication of Synthetic Organic Chemistry, 33:3, 445-450, DOI: 10.1081/SCC-120015775
To link to this article: http://dx.doi.org/10.1081/SCC-120015775
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

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 3, pp. 445–450, 2003
A New Protocol for Selective Deprotection of
N-tert-Butoxycarbonyl Protective Group
#
(t-Boc) with Sn(OTf )2
D. Subhas Bose,* K. Kiran Kumar, and A. V. Narsimha Reddy
Organic Chemistry Division III, Fine Chemicals Laboratory,
Indian Institute of Chemical Technology, Hyderabad, India
ABSTRACT
A simple and efficient method for the selective removal of N-Boc
group by employing tin(II) trifluoromethanesulfonate [Sn(OTf )
CH Cl or solvent-free conditions was developed. The scope of this
2
] in
2
2
procedure is explored for the deprotection of a variety of amines,
including amino acid derivatives.
Key Words: N-tert-butoxycarbonyl group; Deprotection; Tin(II)-
trifluoromethane sulfonate; Solvent-free.
#
IICT Communication No. 4372.
*
Correspondence: D. Subhas Bose, Organic Chemistry Division III, Fine
Chemicals Laboratory, Indian Institute of Chemical Technology, Hyderabad,
5
00 007, India; E-mail: dsb@iict.ap.nic.in.
4
45
DOI: 10.1081/SCC-120015775
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
4
46
Bose, Kumar, and Reddy
The need of developing selective and mild methods for the protection
and deprotection of functional groups with hi ghselectivity, is still one
of the most important manipulations in organic synthesis. The tert-
butoxycarbonyl (t-Boc) group is extensively used as a convenient group
for the protection of amine and amide NH groups due to its stability to
basic and mildly acidic conditions and its ease of removal under specific
[1]
conditions. Classically, removal of the t-Boc group can be accom-
plished by the action of acid trifluoroacetic acid (TFA) either neat or
[
in combination withCH Cl . Deprotection withot he r mineral acids
2]
2
2
[3]
has been reported. In some instances Lewis acids have been used,
[
4]
e.g., BF ꢀOEt . Less frequently, non-acidic conditions have been
3
2
[5]
developed. In some cases, suchas withelectron richsubstrates,
thermolytic conditions can be used.
During the course of our investigations directed towards the total
[
6]
[
7]
synthesis of natural products containing a proline-ring system, we had
the opportunity to examine the selective removal of a t-Boc group.
Toward this end, we were particularly interested in the nature of
tin(II)trifluoromethanesulfonate Sn(OTf )2. Literature reports have
demonstrated that this reagent is widely used primarily for the generation
[
8]
of tin(II) enolates for stereoselective Aldol and Michael reactions. In this
article, we describe our findings on the utility of this reagent for the
selective deprotection of N-Boc derivatives under mild conditions (Sch. 1).
In order to study the generality of the present method we examined
the deprotection of different substrates. The results are illustrated in
Table 1. A variety of N-Boc derivatives were cleanly deprotected in
CH Cl at room temperature in 2 h. This method overcomes many of
2
2
the disadvantages associated with Lewis acids developed so far, e.g.,
some of them are restricted to sec-N-Boc amines, require longer reaction
times or reflux temperatures. The salient features of our method are that
the reaction proceeds efficiently in high yield at room temperature within
a short period of time, side products formation is minimized, and the
work-up procedure is easy. Notably, esters (tert-butyl or methyl), ether
linkages, base-sensitive groups present in the molecule, were found to be
Scheme 1.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Deprotection of (t-Boc) with Sn(OTf )2
447
Table 1. Removal of Boc group from different N-Boc derivatives.
a
b
Entry
1
Substrate 1
Product 2
Yield (%)
9
0
8
8
2
3
92
91
4
87
5
6
92
89
7
95
a
1
All products gave satisfactory analytical and H NMR spectroscopic data.
[9]
b
Yields of pure isolated products.
resistant under the conditions employed. N-Boc derivatives bearing ‘‘a’’
stereogenic centers afford the corresponding amines with full retention of
configuration (specific rotation measurement was performed after recon-
[
9]
version to the starting N-Boc derivative). Finally, removal of t-Boc in
the presence of N-Cbz was achieved with a high degree of selectivity.
To reduce the employment of ecologically suspected solvents, we
have also carried out the similar cleavage of 1a under solvent-free con-

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
4
48
Bose, Kumar, and Reddy
ditions. For example, neutral Al O used as solid support at room tem-
2
3
perature for 4 hgave t he corresponding amine 2a in almost quantitative
yield (88%). Among various mineral supports examined, suchas alu-
mina, clay, silica, etc., alumina was found to give the best results.
PROCEDURE (I)
To a solution of N-Boc derivative (1a) (0.458 g, 2.0 mmol) in anhy-
drous CH Cl (10 mL) in a 25 mL round-bottomed flask equipped witha
2
2
magnetic stirrer under N atmosphere, was added Sn(OTf ) (832 mg,
2
2
ꢁ
2
.0 mmol) in portions at 0 C. The suspension was stirred at room tem-
perature for 2 h. After completion of the reaction (monitored by TLC;
eluent: EtOAc:hexane, 9:1 v/v), it was neutralized with aqueous NaHCO3
solution and the product was extracted with EtOAc (2 ꢂ 15 mL). The
organic phase was separated, dried (Na SO ), the mixture filtered and
2
4
the solvent was removed in vacuo to afford the crude product which was
purified by column chromatography (ethyl acetate/hexane, 9:1 v/v) to
afford 2a (0.116 g), in 90% yield.
PROCEDURE (II)
Solvent-free conditions: neutral alumina (2.0 g) is added to substrate
(1a) (0.458 g, 2.0 mmol), and Sn(OTf ) (832 mg, 2.0 mmol) that is dis-
2
solved in a minimum amount of dichloromethane (2–3 mL). After evap-
[
10]
oration of the solvent,
vortex mixer and the reaction mixture is kept at room temperature for
h. The product is extracted into ethyl acetate (2 ꢂ 5 mL). The combined
organic phases were washed with aqueous NaHCO , brine, dried
the dry powder is mixed thoroughly using a
4
3
(Na SO ) and the solvent was removed in vacuo to afford the crude
2 4
product 2a (0.113 g) in 88% yield.
In summary, this method offers considerable advantages for use in
organic synthesis in view of its simplicity, excellent yield, short reaction
period, and mild conditions involved.
ACKNOWLEDGMENT
One of the authors (K.K.K) thanks CSIR, New Delhi for financial
support in the form of research fellowship.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Deprotection of (t-Boc) with Sn(OTf )2
REFERENCES
. (a) Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic
449
1
Synthesis, 2nd Ed.; John Wiley & Sons: New York, 1991; (b)
Kocienski, P.J. Protecting Groups; Georg Thieme Verlag: Stuttgart,
1994.
2
3
. (a) Schwyzer, R.; Costopanagiotis, A.; Sieber, P. Helv. Chim. Acta
1963, 46, 870; (b) Sakai, N.; Ohfune, Y.J. J. Am. Chem. Soc. 1992,
114, 998.
. (a) Stahl, G.L.; Walter, R.; Smith, C.W. J. Org. Chem. 1978, 43,
285; (b) Houghten, R.A.; Beckman, A.; Ostresh, J.M. Int. J. Pept.
2
Protein Res. 1986, 27, 653; (c) Yamashiro, D.; Blake, J.; Li, C.H.
J. Am. Chem. Soc. 1972, 94, 2855; (d) Shaikh, N.S.; Gajare, A.S.;
Deshpande, V.H.; Bedekar, A.V. Tetrahedron Lett. 2000, 41, 385.
. (a) Bose, D.S.; Lakshminarayana, V. Synthesis 1999, 66; (b) Nigam,
S.C.; Mann, A.; Taddei, M.; Wermuth, C.-G. Synth. Commun. 1989,
4
5
19, 3139.
. (a) Hwu, J.R.; Jain, M.T.; Tsay, S.-Ch.; Hakimelahi, G.H.
Tetrahedron Lett. 1996, 37, 2035; (b) Wei, Z.-Y.; Knaus, E.E.
Tetrahedron Lett. 1994, 35, 847; (c) Boeckman, R.K., Jr.; Potenza,
J.C. Tetrahedron Lett. 1985, 26, 1411.
6. Rawal, V.H.; Cava, M.P. Tetrahedron Lett. 1985, 26, 6141.
7. Thurston, D.E.; Bose, D.S. Chem. Rev. 1994, 94, 433.
8. Paquette, L.A. Encyclopedia of Reagents for Organic Synthesis; Joh n
Wiley & Sons: Chichester, 1995; Vol. 7, 4907.
9
. Selected analytical data: compounds 1a, 1b, 2a, 2f isolated as amine
ꢁ
1
hydrochloride salts. 1a: [ꢀ] ¼ À45.0 (c 0.53, CHCl3), H NMR
D
(
(
(
(
CDCl ) ꢁ 1.45 (s, 9H), 1.85–2.05 (m. 4H), 3.38–3.60 (m, 2H), 3.75
3
ꢁ
1
s, 3H), 4.16–4.36 (m, 1H). 1b: [ꢀ] ¼ À49.5 (c 3.4, CHCl ), H NMR
D
3
CDCl ) ꢁ 1.45 (s, 9H), 1.50 (s, 9H), 1.81–1.98 (m, 3H), 2.15–2.30
3
m, 2H), 3.38–3.58 (m, 2H), 4.10 (dd, 1H, J ¼ 3.4, 8.9). Anal. calcd.
for C H NO : C, 61.7; H, 9.6; N, 5.1. Found: C, 61.5; H, 9.6; N,
1
5.2. 2a: m.p. 68–70 C (lit.
H O), lit.
4
26
4
ꢁ
[11]
ꢁ
m.p. 69–71 C); [ꢀ] ¼ À31.0 (c 0.5,
D
[11]
ꢁ
ꢁ
[12]
[ꢀ] ¼ À33 Æ 2 (c 0.5, H O). 2b: m.p. 108–109 C
2
D
2
[
13]
ꢁ
(
lit.
m.p. 109–111 C); [ꢀ] ¼ À30.0 (c 1.2, EtOH), lit.
D
ꢁ
[
1
ꢀ] ¼ À31.0 (c 2.0, EtOH), Anal. calcd. for C H NO: C, 69.6; H,
D
9
17
ꢁ
[11]
1.0; N, 9.0. Found: C, 69.0; H, 10.6; N, 8.7. 2c: m.p. 58–59 C (lit.
ꢁ
1
m.p. 57–60 C); 1d: [ꢀ] ¼ þ13.5 (c 1.0, CHCl ). H NMR (CDCl ) ꢁ
D
3
3
1
1
.45 (s, 9H), 3.54–3.70 (m, 2H), 3.95–4.01 (m, 2H), 4.72–4.88 (bs,
H), 5.12–5.31 (m, 2H), 5.75–5.94 (m, 1H), 7.22–7.35 (m, 5H). 2d:
[
ꢀ] ¼ þ 24.5 (c 1.0, CHCl3). Anal. calcd. for C H NO;
D
11 15

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
4
50
Bose, Kumar, and Reddy
C, 74.5; H, 8.5; N, 7.9. Found: C, 75.0; H, 8.2; N, 7.5. 1f:
ꢁ
1
[
1
ꢀ] ¼ þ 9.0 (c 1.0, CHCl ), H NMR (CDCl ): ꢁ 1.44 (s, 9H),
D
3
3
.50–1.81 (m, 6H), 3.11–3.27 (m, 2H), 3.75 (s, 3H), 4.18–4.31
(
5
1
m, 1H), 4.78 (bs, 1H, exchangeable with D O), 5.05 (bs, 1H),
2
ꢁ
.08 (s, 2H), 7.22 (s, 5H). 2f: m.p. 116–118 C (lit. m.p.
ꢁ
17–118 C); Anal. calcd. for C H N O : C, 61.2; H, 7.5; N, 9.5.
2
1
5
22
4
ꢁ
Found: C, 61.5; H, 7.8; N, 9.2. [ꢀ] ¼ þ14.5 (c 1.0, H O), lit.
D
2
ꢁ
[
ꢀ] ¼ þ15.5 (c 2.0, H O), Coggins, J.; Demayo, R.; Benoiton,
3
D
2
1
N.L. Can. J. Chem. 1970, 48, 385. 1g: H NMR (CDCl ): ꢁ 1.65
(
8
s, 9H) 6.53 (d, 1H), 7.12–7.33 (m, 2H), 7.46–7. 48–57 (m, 2H),
[11]
ꢁ ꢁ
.10 (d, 1H). 2g: m.p. 53–55 C (lit. m.p. 52–54 C).
10. To dissolve the starting substrate, CH Cl can be replaced withany
2 2
solvent, e.g., THF and CH CN. During the reaction, carbon dioxide
3
gas evolution was observed [positive Ba(OH) test].
2
11. Aldrich Catalogue Handbook of Fine Chemicals, 1999–2000.
12. Csandy, G.; Medzihradszky, K. Org. Prep. Proced. Int. 1988,
20, 180.
Received in the USA February 22, 2002