Environmentally benign N-Boc protection under solvent- and catalyst-free conditions

Article abstract of DOI:10.1055/s-2007-970755

A practical and highly efficient method for the protection of amines to their corresponding N-Boc derivatives is reported. In the absence of any solvent and catalyst, the present strategy works well for a series of electron-deficient and electron-rich aromatic amines as well as some sterically hindered substrates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-970755

8
06
LETTER
Environmentally Benign N-Boc Protection under Solvent- and Catalyst-Free
Conditions
E
X
nvironmentally B
u
enign
N
-Boc
e
Protectio ns hun Jia,* Qing Huang, Jian Li, Shaoyu Li, Qiushi Yang
Department of Chemistry, Shanghai University, Shanghai 200444, P. R. of China
Fax +86(21)66132797; E-mail: xsjia@mail.shu.edu.cn
Received 8 December 2006
and catalyst (Scheme 1). To the best of our knowledge,
this is the first example of the N-Boc protection of amines
without the presence of any solvent or catalyst.
Abstract: A practical and highly efficient method for the protection
of amines to their corresponding N-Boc derivatives is reported. In
the absence of any solvent and catalyst, the present strategy works
well for a series of electron-deficient and electron-rich aromatic
amines as well as some sterically hindered substrates.
Our initial experiments were carried out using aniline as a
model substrate. At room temperature, when one mmol of
Key words: N-Boc protection, environmentally benign, solvent- aniline was added to one mmol of Boc O under solvent-
2
free, catalyst-free
and catalyst-free conditions, there was an evolution of
heat and quick bubbling. To our delight, this model reac-
tion finished within 30 minutes and the corresponding
Functional group protection and deprotection strategies mono N-Boc derivative was afforded in 95% yield. This is
are important in target molecule synthesis. The protection noteworthy as in the work of Adapa et al, the reaction be-
of amines is one of the most fundamental and useful trans- tween aniline and Boc O was quite sluggish and only 60%
2
formations in organic synthesis, especially in peptide syn- of the desired N-Boc product could be isolated after 48
1
8
thesis. Many mild and selective methods for the hours. Our results indicated that the transformation of
protection of amine groups have been developed for many aniline to the corresponding N-Boc derivative could be
different organic transformations. Among them, the com- achieved in high efficiency without any catalyst or sol-
mercially available di-tert-butyl dicarbonate (Boc O) has vent.
become an efficient reagent for the clean and rapid intro-
2
2
duction of the tert-butoxycarbonyl (Boc or t-Boc) protect-
ing group at the amine functionality. Due to the stability
of N-tert-butylcarbamates towards catalytic hydrogenoly-
sis and extreme resistance to bases and nucleophiles, as
well as easy conversion into the parent amines under mild
R
R
solvent-free
NH
+
Boc2O
N Boc
R1
r.t., 2 min to 8 h
R1
8
7–99%
1
b
Scheme 1
acidic conditions, this protection of amines is used fre-
3
quently. Various base-mediated methods for the N-Boc
protection of amines have been developed, for example Encouraged by these experimental results, a series of
4
DMAP, NaOH, K CO , Et N, NaHCO and Me NOH.
structurally diverse aromatic and aliphatic amines were
2
3
3
3
4
However, these methodologies suffer from a variety of treated with Boc O under catalyst- and solvent-free con-
2
8
drawbacks such as long reaction times, high toxicity ditions. Various amines underwent smooth conversion
(
DMAP), special syntheses of the tert-butyloxycarbony- into the corresponding mono N-Boc products in excellent
lation reagents, basic conditions and the use of solvents. yields (Table 1). No side-products were observed. More-
Several Lewis acids such as yttria-zirconia, Zn(ClO ) , over, behavior of the present strategy is dependent on the
4
2
LiClO Cu(BF ) La(NO ) and ZrCl have also been ex- type of substrate amine used. Generally, aliphatic amines
4
,
4 2,
3 3
4
tensively investigated in order to achieve such transfor- reacted faster, while the aromatic analogues needed pro-
5
mations. However, the Lewis acid catalyzed Boc- longed reaction times. Substituent groups on the aromatic
protection of amines is quite restricted as the strong affin- rings dramatically affected the conversion rate of amines.
ity of many Lewis acids for amino groups does not allow Electron-donating groups such as methyl and methoxy
6
regeneration of the Lewis acids. Moreover, most Lewis groups add to the nucleophilicity of the aromatic amines
acids are decomposed or deactivated by the amines and and help with the conversion into the corresponding N-
7
their amine derivatives. Even when the desired reactions Boc products (Table 1, entries 10 and 11). In contrast, the
proceed, greater than stoichiometric amounts of Lewis presence of electron-withdrawing substituent groups,
acid are needed because the acids are trapped by nitrogen. such as chloride and nitro, decreased the nucleophilicity
Herein we wish to report a novel and highly practical of the aromatic amines and the corresponding conversion
strategy for N-Boc protection in the absence of solvent became quite sluggish (Table 1, entries 12 and 13). In par-
ticular, when a nitro group was present in the aromatic
ring, the transformation to its N-Boc product did not occur
at room temperature even with a prolonged reaction time.
In this case, an elevated reaction temperature made a sig-
SYNLETT 2007, No. 5, pp 0806–0808
Advanced online publication: 08.03.2007
DOI: 10.1055/s-2007-970755; Art ID: W25006ST
1
6.
0
3.
2
0
0
7
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Environmentally Benign N-Boc Protection
807
Table 1 N-Boc Protection of Amines Under Solvent- and Catalyst-
Free Conditons
nificant improvement (Table 1, entry 13). Following liter-
ature precedent, we also tried adding a catalytic amount
a
9
of iodine in the protection of 4-nitroaniline, but only trace
amounts of the protected product were formed (10%) after
48 hours. In view of the importance of peptide synthesis,
we also tried to protect ethyl 2-aminoacetate using our
conditions and the result was quite satisfactory (Table 1,
entry 7).
Entry
1
Amine
Time
2 min
Yield (%)b
97
NH2
2
3
4 min
2 min
95
94
NH2
It is of note that this method also shows good chemoselec-
tivity. In the presence of a hydroxy group, only the mono
N-Boc products were isolated and no O-Boc protection
N
H
1
could be observed from the H NMR (Table 1, entries 5
4
NH2
7 min
98
and 14). However, when o-phenylenediamine was used as
the substrate with one equivalent of Boc O, the mono N-
2
Boc protected product was isolated as the major product
in 70% yield and the corresponding N,N¢-di-Boc deriva-
tive was also afforded as a side-product (30%). The N,N¢-
di-Boc derivative was formed exclusively when the
5
6
HO
N
15 min
4 min
92
92
NH2
NH
amount of the Boc O was increased to two equivalents.
2
7
8
9
O
5 min
8 min
99
94
95
We have developed a practical and highly efficient meth-
H2N
od for the protection of amines with Boc O. This new pro-
2
OEt
NH2
tocol allows for the efficient conversion of both aliphatic
and aromatic amines into their corresponding mono N-
Boc protected derivatives without the occurance of bis-
Boc protection. The advantages including solvent- and
catalyst-free conditions, operation at room temperature,
excellent chemoselectivity, high yields and environmen-
tally benign conditions make this present method superior
to existing methods. We believe that our method will find
its use in organic synthesis, especially in large-scale
industrial preparation.
NH2
30 min
1
1
1
1
0
1
2
3
NH2
40 min
50 min
6 h
96
95
96
87c
MeO
Me
NH2
Acknowledgment
NH2
We thank the National Natural Science Foundation of China (No:
2
0472048 and 20572068) for financial support.
Cl
NH2
8 h
References and Notes
O2N
(1) (a) Kocienski, P. J. Protecting Groups; Georg Thieme
Verlag: New York, 2000. (b) Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis, 3rd ed.; John Wiley
1
1
1
4
5
6
NH2
5 h
5 h
7 h
91
&
Sons: New York, 1999. (c) Brar, A.; Vankar, Y.
OH
Tetrahedron Lett. 2006, 47, 9035. (d) Navath, R. S.;
Pabbisetty, K. B.; Hu, L. Tetrahedron Lett. 2006, 47, 389.
2) Xiao, X.; Ngu, K.; Choa, C.; Patel, D. V. J. Org. Chem.
97d
94
NH2
(
(
1997, 62, 6968.
NH2
NH2
3) (a) Ravinder, K.; Reddy, A. V.; Krishnaiah, P.; Ramesh, P.;
Ramakrishna, S.; Laatsch, H.; Venkateswarlu, Y.
Tetrahedron Lett. 2005, 46, 5475. (b) Agami, C.; Couty, F.
Tetrahedron 2002, 58, 2701.
(4) (a) Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. Engl.
1
984, 23, 296. (b) Grehn, L.; Ragnarsson, U. Angew. Chem.,
a
Unless otherwise stated, all reactions were carried out using amine
Int. Ed. Engl. 1985, 24, 510. (c) Basel, Y.; Hassner, A. J.
Org. Soc. 2000, 65, 6368. (d) Handy, S. T.; Sabatini, J. J.;
Zhang, Y.; Vulfova, I. Tetrahedron Lett. 2004, 45, 5057.
(e) Lutz, C.; Lutz, V.; Knochel, P. Tetrahedron 1998, 54,
9
(
1 mmol) and Boc O (1 mmol) at room temperature.
2
b
Isolated yields.
c
The mixture was heated to 110 °C with five equivalents of Boc O.
2
d
Both amino groups were protected.
6385. (f) Khalil, E. M.; Subasinghe, N. L.; Johnson, R. L.
Tetrahedron Lett. 1996, 37, 3441. (g) Itoh, M.; Hagiwara,
D.; Kamiya, T. Tetrahedron Lett. 1975, 4393. (h) Einhorn,
Synlett 2007, No. 5, 806–808 © Thieme Stuttgart · New York

8
08
X. Jia et al.
LETTER
(6) Niimi, L.; Serita, K. J.; Hiraoka, S.; Yokozawa, T.
Tetrahedron Lett. 2000, 41, 7075.
(7) Kobayashi, S.; Araki, M.; Yasuda, M. Tetrahedron Lett.
1995, 36, 5773.
J.; Einhorn, C.; Luche, J. L. Synlett 1991, 37. (i) Guibe-
Jampel, E.; Wakselman, M. Chem. Commun. 1971, 267.
j) Sikchi, S. A.; Hultin, P. G. J. Org. Chem. 2006, 71, 5888.
(
(
5) (a) Reddy, M. S.; Narender, M.; Nageswar, Y. V. D.; Rama
Rao, K. Synlett 2006, 1110. (b) Bartoli, G.; Basco, M.;
Locatelli, M.; Marcantoni, E.; Massaccesi, M. Synlett 2004,
(8) General Procedure: To Boc O (1 mmol) that was being
2
magnetically stirred in oven-dried glassware at r.t. was
added the amine (1 mmol). Rapid heat evolution and
bubbling was then observed. The mixture was stirred until
completion of the reaction. The product was purified using
silica gel column chromatography eluting with hexane–
EtOAc (5:1) to afford the corresponding N-Boc protected
product. All of the products are known and were
1
2
794. (c) Heydari, A.; Hosseini, S. E. Adv. Synth. Catal.
005, 347, 1929. (d) Sharma, G. V. M.; Reddy, J. J.;
Lakshmi, P. S.; Radha Krishna, P. Tetrahedron Lett. 2004,
5, 6963. (e) Pandey, R. K.; Ragade, S. P.; Upadhyay, R. K.;
Dongare, M. K.; Kumar, P. ARKIVOC 2002, (vii), 28.
f) Chankeshwara, S. V.; Chakraborti, A. K. Tetrahedron
4
(
Lett. 2006, 47, 1087. (g) Suryakiran, N.; Prabhakar, P.;
Reddy, S. T.; Rajesh, K.; Venkateswarlu, Y. Tetrahedron
Lett. 2006, 47, 8039.
characterized by comparison of their spectral data with those
of authentic samples.
(9) Varala, R.; Nuvula, S.; Adapa, S. R. J. Org. Chem. 2006, 71,
8283.
Synlett 2007, No. 5, 806–808 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.