A Lewis acid-mediated protocol for the protection of aryl amines as their Boc-derivatives

Article abstract of DOI:10.1055/s-2004-829059

A new protocol of protection of poorly reactive aryl amines and functionalized amines with Boc₂O in the presence of Zn(ClO ₄)₂·6H₂O as the catalyst is reported. The catalytic action of Zn(ClO₄)₂·6H₂O is specific for the activation of the pyrocarbonates, thus acid sensitive functionalities and stereochemical configurations of the starting materials remain unaltered in the protection process.

Full text of DOI:10.1055/s-2004-829059

1794
LETTER
A Lewis Acid-Mediated Protocol for the Protection of Aryl Amines as their
Boc-Derivatives
A
Convenient
P
rot
i
ocol fo
u
r
the Protect
s
ion of
A
m
e
ines as thei
p
r
B
oc-Deriva
p
tives e Bartoli,*a Marcella Bosco,a Manuela Locatelli,a Enrico Marcantoni,b Massimo Massaccesi,a
Paolo Melchiorre,a Letizia Sambri*a
a
Dipartimento di Chimica Organica ‘A. Mangini’, v.le Risorgimento 4, 40136 Bologna, Italy
Fax +39(051)2093654; E-mail: giuseppe.bartoli@unibo.it; E-mail: letizia.sambri@unibo.it
b
Dipartimento Scienze Chimiche, Università di Camerino, via S.Agostino 1, 62032 Camerino (Macerata), Italy
Received 30 March 2004
In the last few years, we were interested in the use of an-
Abstract: A new protocol of protection of poorly reactive aryl
amines and functionalized amines with Boc2O in the presence of
Zn(ClO4)2·6H2O as the catalyst is reported. The catalytic action of
Zn(ClO4)2·6H2O is specific for the activation of the pyrocarbonates,
hydrous metallic perchlorates as Lewis acid promoters in
various organic transformations.7 LiClO4 and Mg(ClO4)2
showed increased efficiency if hot-dried under vacuum
thus acid sensitive functionalities and stereochemical configura- before use. Owing to the potential hazards connected with
the heating of such salts,8 we focused our attention to
tions of the starting materials remain unaltered in the protection
process.
more efficient perchlorates, active even in the presence of
Key words: protection, Lewis acid, zinc perchlorate, aryl amines,
Boc-derivatives
water. In fact, Zn(ClO4)2·6H2O was recently found to be-
have as a powerful catalyst in the acylation of alcohols9
and in the synthesis of N-substituted b-enamino esters.10
It has been recently reported that perchlorate salts activate
bidentate compounds such as anhydrides by forming a cy-
clic complex.11 It may be expected that an analogous acti-
vation can be exerted on pyrocarbonates, such as Boc2O.
The development of mild and selective methods for the
protection and deprotection of functional groups contin-
ues to be an important tool in the synthetic chemistry of
polyfunctional molecules.1
As a part of our research program devoted to the develop-
ment of new Lewis acid systems, we report here that
Zn(ClO4)2·6H2O can act as a powerful catalyst for the pro-
tection of aryl amines as mono-Boc-derivatives. More-
over, Zn(ClO4)2·6H2O showed to be able to promote the
reaction of various functionalized alkyl amines with
Boc2O to give the N-Boc protected derivative.
Protection of amino groups is often required during the
synthesis of peptides, amino acids and other natural prod-
ucts. Among the various amine protecting groups, the t-
butoxycarbonyl (Boc) is one of the most used, owing to its
stability towards nucleophiles and strong basic conditions
and because of its easy removal.1
Various reagents and methodologies have been developed
over the years to introduce this group using Boc2O. Most
of them are carried out in the presence of a base (DMAP,2
aq NaOH,1,3 NaHMDS4). Although alkyl amines are
known to give the mono-protected derivative by reaction
with Boc2O without the assistance of any catalyst, the
analogous reaction of primary and secondary aryl amines
proceeds sluggishly, owing to their reduced nucleophilic-
ity.4,5 Moreover, when an aryl amine is able to react, var-
ious side reactions, such as biscarbamoylation or the
formation of isocyanates or ureas, can occur.2a,4
Preliminary experiments were carried out on aniline 1a in
order to find the best reaction conditions. The reactions
were carried out in various solvents with 1 equivalent of
Boc2O, and monitored by GC-MS. The results reported in
Table 1 refer to the conversion after 4.5 hours. Although
the differences are not remarkable, dichloromethane
proved to be the best solvent. Moreover, an increased
amount of the catalyst, from 2–10 mol%, does not im-
prove conversion percentages.12
Afterwards, the methodology of protection was applied to
various substrates, varying the catalyst amounts from 2–
5% and using a slight excess of Boc2O (1.3 equiv). The
best-obtained results are reported in Table 2.13 The choice
of the solvent was determined by the peculiar solubility of
the substrates. In some cases, if the products did not solid-
ify during the course of the reaction and the mixture could
On the other hand, methods using a Lewis acid catalyst to
perform this protection are still scarce. For example, a re-
cently reported methodology employs an yttrium–zirconi-
um based strong Lewis acid catalyst, whose preparation
is, however, quite elaborate.6
We report here the first example of a protection method- be continuously stirred, the protection reaction was car-
ology that employs a simple and mild Lewis acid as the ried out under solvent free conditions.
catalyst, which is specific for the activation of Boc2O.
In the cases of low reactive substrates, such as nitroaniline
and 3-aminobenzoic acid (Table 2, entries 4 and 9), the
best results were obtained increasing the reaction temper-
ature, which, in any case, cannot get over 50 °C to avoid
the Boc2O decomposition.
SYNLETT 2004, No. 10, pp 1794–1798
Advanced online publication: 01.07.2004
DOI: 10.1055/s-2004-829059; Art ID: G09904ST
© Georg Thieme Verlag Stuttgart · New York
0
9
.0
8
.2
0
0
4

LETTER
A Convenient Protocol for the Protection of Amines as their Boc-Derivatives
1795
Although an excess of Boc2O is often used to complete the
protection reaction, we generally obtained high yields
with a slight excess of di-t-butyl dicarbonate (1.3 equiv).
Moreover, it is important to highlight that any side reac-
tion, such as biscarbamoylation or the formation of isocy-
anates or ureas, was never observed, as verified by GC-
MS and 1H NMR analysis of the crude of the reactions.
Table 1 Protection of Aniline as the Boc-Derivative under Various
Conditions
H
Zn(ClO4)2·6H2O
Ph
N
Boc
Ph NH2
1a
Boc2O (1 equiv)
solvent, r.t., 4.5 h
2a
Entry
Cat. (mol%)
Solventa
THF
Yields (%)b
Reaction rates and yields are governed by the nucleophi-
licity of the amines. In particular, activated anilines give
the Boc-derivatives in very good yields (Table 2, entry 2,
3, and 5). On the other hand, deactivated substrates give
the protected derivative with acceptable results consider-
ing their low reactivity (Table 2, entries 4, 9). Also sec-
ondary aryl amines, such as N-methyl aniline, can be
protected in high yields (Table 2, entry 13).
1
2
3
4
5
6
7
–
50
65
70
72
75
78
78
2
THF
2
Et2O
2
t-BuOH
CH2Cl2
CH2Cl2
CH2Cl2
2
5
The protection reaction is chemoselective: the amine is
exclusively protected in the presence of amide, acid, in-
dole and thiol groups.
10
a The amount of the solvent was 1.5 mL/mmol of substrate.
b Conversion determined by GC-MS analysis after 4.5 h.
Table 2 Protection of Aryl Amines as Boc-Derivativesa
Boc
Zn(ClO4)2·6H2O
Ar
N
R
Ar NHR
Boc2O (1.3 equiv)
solvent (1.5 mL/mmol)
2
1
Entry
1
Product
Cat. (mol%)
5
Solvent
CH2Cl2
Time (h)
12
Yields (%)b
92
Ph-NH-Boc
2a
2
3
4
5
p-MeO-Ph-NH-Boc
5
5
5
5
t-BuOH
t-BuOH
CH2Cl2
CH2Cl2
6
10
14
48
99
2b
m-MeO-Ph-NH-Boc
99
2c
p-NO2-Ph-NH-Boc
50c,d
94
2d
NH-Boc
2e
6
5
t-BuOH
72
95
H
N
O
NH-Boc
2f
2g
2h
7
8
2
2
–
–
89
9
86
90
NH-Boc
NH-Boc
NC
HS
Synlett 2004, No. 10, 1794–1798 © Thieme Stuttgart · New York

1796
G. Bartoli et al.
LETTER
Table 2 Protection of Aryl Amines as Boc-Derivativesa (continued)
Boc
Zn(ClO4)2·6H2O
Ar
N
R
Ar NHR
Boc2O (1.3 equiv)
solvent (1.5 mL/mmol)
2
1
Entry
9
Product
Cat. (mol%)
5
Solvent
Time (h)
41
Yields (%)b
68e,f
t-BuOH
HOOC
NH-Boc
2i
10
11
5
5
CH2Cl2
164
21
94
Boc-HN
H
N
(CH2)2COOEt
O
COOEt
2l
t-BuOH
90
Boc-HN
N
H
2m
12
13
5
2
CH2Cl2
168
30
83
89
N
S
NH-Boc
2n
–
N
Ph
Boc
2p
a Unless otherwise mentioned, reactions were carried out with Boc2O (1.3 equiv) in the presence of Zn(ClO4)2·6H2O (2–5 mol%) in the appro-
priate solvent (1.5 mL/mmol of substrate) at r.t.
b Yields of pure products isolated by column chromatography.
c Reaction carried out at reflux.
d Starting material was also recovered (42%).
e Reaction was carried out at 50 °C.
f Starting material was also recovered (23%).
The methodology has been extended to benzylic and func- base such as Et3N or pyridine does not increase the yields
tionalized alkyl amines.
(Table 3, entries 10, 11).
The reaction works well with primary and secondary ben- In conclusion, Zn(ClO4)2·6H2O shows a powerful catalyt-
zyl amines (Table 3, entries 1–4). Also in these cases a ic activity in promoting the protection of aryl amines as
complete chemoselectivity towards the amino group was Boc-derivatives. The present method is the first example
observed: alcohols, acetals and acids remain unaffected employing a cheap and easy available Lewis acid as cata-
during the reaction. Moreover, some general consider- lyst to perform such protection. Our methodology works
ations can be outlined. Stereogenic centers do not undergo with various aromatic amines under mild conditions and
racemization or epimerization, (Table 2, entry 8 and the protecting agent is used only in a small excess.
Table 3, entries 3–6) as confirmed by the comparison of
the experimental [a]D with literature data. The methodol-
ogy works also with amino acids which give the N-pro-
Moreover, this protocol appears to be competitive and in
some cases superior to previously reported procedures
that work under basic conditions. In particular, with acti-
vated m-methoxy aniline 2c (Table 2, entry3) our results
tected derivatives in good yields, provided that the aminic
and the carboxylic function are distant each other
are superior to those obtained with NaHDMS procedure4
(Table 2, entry 7, Table 3, entry 8). With a- and b-amino
(99% vs. 88% yields). In the case of N-Boc-2,4,6-trimeth-
acids, in fact, a maximum of 43% yields is attained
ylaniline (2e, Table 2, entry 5) we obtained excellent
(Table 3, entry 9). Very likely, under these reaction con-
yields in 10 hours at room temperature, while other proce-
ditions, the amino acid exists almost completely in the
dures failed4 or required long times2a or very hard reaction
zwitterionic form, so that the aminic group is unreactive
conditions (60 h at 82%).2c
towards Boc2O. Even the addition of a relatively weak
Synlett 2004, No. 10, 1794–1798 © Thieme Stuttgart · New York

LETTER
A Convenient Protocol for the Protection of Amines as their Boc-Derivatives
1797
Table 3 Protection of Amines as Boc-Derivativesa
Acknowledgment
R1
R2
R1
R2
Zn(ClO4)2·6H2O, 2 mol%
This work was carried out in the framework of the National Project
‘Stereoselezione in Sintesi Organica. Metodologie e Applicazioni’
supported by MIUR, Rome, by the University of Bologna, in the
framework of ‘Progetto di Finanziamento Pluriennale, Ateneo di
Bologna’, and by National project FIRB ‘Progettazione, preparazio-
ne e valutazione biologica e farmacologica di nuove molecole orga-
niche quali potenziali farmaci’.
NH
N Boc
Boc2O (1.3 equiv)
solvent, r.t.
3
4
Entry
1
Product
Solvent
–
Time (h) Yields (%)b
PhCH2-NH-Boc
5.5
5.5
92
93
4a
2
3
4
5
–
Boc
References
Ph
N
Ph
(1) (a) Greene, T. W.; Wuts, P. G. M. In Protective Group in
Organic Synthesis, 3rd ed.; John Wiley and Sons: New
York, 1999. (b) Kocienski, P. J. In Protecting Groups;
George Thieme Verlag: Stuttgart-New York, 2000.
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(b) Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. Engl.
1985, 510. (c) Knölker, H.-J.; Braxmeier, T. Tetrahedron
Lett. 1996, 37, 5861.
4b
–
2.5
43
6
97
Ph
NH-Boc
4c
CH2Cl2
CH2Cl2
87c
94c
Ph
OH
(3) For examples see: (a) Lutz, C.; Lutz, V.; Knochel, P.
Tetrahedron 1998, 54, 6385. (b) Bailey, S. W.;
NH-Boc
4d
Chandrasekaran, R. Y.; Ayling, J. E. J. Org. Chem. 1992, 57,
4470.
OH
(4) Kelly, T. A.; McNeil, D. W. Tetrahedron Lett. 1994, 35,
9003.
(5) Darnbrough, S.; Mervic, M.; Condon, S. M.; Burns, C. J.
Synth. Commun. 2001, 31, 3273.
Ph
NH-Boc
4e
(6) Pandey, R. K.; Ragade, S. P.; Upadhyay, R. K.; Dongare, M.
K.; Kumar, P. Arkivoc 2002, 28.
6
–
16
90
OCH3
OCH3
Boc-HN
Boc-HN
(7) (a) Bartoli, G.; Bosco, M.; Marcantoni, E.; Massaccesi, M.;
Rinaldi, S.; Sambri, L. Tetrahedron Lett. 2002, 34, 6331.
(b) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.;
Massaccesi, M.; Rinaldi, S.; Sambri, L. Synlett 2003, 39.
(8) (a) Schumacher, J. C. Perchlorates - Their Properties,
Manufacture and Uses; ACS Monograph Series, Reinhold:
New York, 1960. (b) Long, J. Chem. Health Saf. 2002, 9, 12.
(9) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.;
Massaccesi, M.; Sambri, L. Eur. J. Org. Chem. 2003, 4611.
(10) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.;
Melchiorre, P.; Sambri, L. Synlett 2004, 239.
4f
7
8
t-BuOH
t-BuOH
26
50
68c,d
43c,d
COOH
10
4g
COOH
Ph
NH-Boc
4h
9
10
11
t-BuOH
t-BuOH
t-BuOH
20
20
20
41c,d
33c,d,e
7c,d,f
(11) Chakraborti, A. K.; Sharma, L.; Gulhane, R.; Shivani,
Tetrahedron 2003, 59, 7661.
COOH
NH-Boc
(12) The reaction was also carried out by changing the Zn(II)
counterion of the potentially explosive Zn(ClO4)2·6H2O
using Zn(OAc)2. We obtained worse results, only a 60%
conversion after 4.5 h in CH2Cl2 at r.t. was detected.
(13) Representative Experimental Procedure. Synthesis of
tert-Butyl N-Phenylcarbamate (2a): To a round-bottom
flask were added Zn(ClO4)2·6H2O (28 mg, 0.075 mmol),
CH2Cl2 (2.25 mL), aniline (0.14 g, 1.50 mmol) and Boc2O
(0.43 g, 1.95 mmol, 1.3 equiv). The reaction mixture was
stirred at r.t. for 12 h. After addition of 5 mL of CH2Cl2, the
solution was washed with H2O. The organic layer was dried
over MgSO4 and concentrated at reduced pressure. The
crude product was purified by column chromatography on
silica gel. Compounds 2a, 2b, 2i, 2m, 4a, 4d and 4i are
commercial products; 2c,4 2d14, 2e,4 2p15, 4c16, 4e17, 4g18 and
4h19 are known compounds. Spectroscopic data for selected
examples follow. tert-Butyl N-[4-(Acetylamino)phenyl]
Carbamate (2f): 1H NMR (300 MHz, CDCl3): d = 1.51 (s,
9 H, t-Bu), 2.15 (s, 3 H, CH3), 6.50 (br s, 1 H, NH), 7.20 (br
s, 1 H, NH), 7.26–7.35 (m, 2 H, Ph), 7.40–7.45 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): d = 23.7 (CH3), 26.9 (CH3),
79.8 (C), 116.3 (CH), 118.8 (CH), 133.3 (C), 134.3 (C),
152.7 (C), 168.4 (C). tert-Butyl N-(3-Sulfanylphenyl)
Carbamate (2h): 1H NMR (300 MHz, CDCl3): d = 1.51
4i
COOH
NH-Boc
4i
COOH
NH-Boc
4i
a Unless otherwise mentioned, reactions were carried out with Boc2O
(1.3 equiv) in the presence of Zn(ClO4)2·6H2O (2 mol%) in the appro-
priate solvent (1.5 mL/mmol of substrate) at r.t.
b Yields of pure products isolated by column chromatography.
c Reaction was carried out with 5 mol% of catalyst.
d Reaction was carried out at 50 °C.
e In the presence of 1 equiv of Et3N.
f In the presence of 1 equiv of pyridine.
Synlett 2004, No. 10, 1794–1798 © Thieme Stuttgart · New York

1798
G. Bartoli et al.
LETTER
128.2 (CH), 141.8 (C), 152.3 (C), 166.5 (C), 172.0 (C),
(s, 9 H, t-Bu), 3.46 (s, 1 H, SH), 6.60 (br s, 1 H, NH), 6.90–
6.95 (m, 1 H, Ph), 7.00–7.05 (m, 1 H, Ph), 7.05–7.10 (m, 1
H, Ph), 7.40 (br s, 1 H, Ph). 13C NMR (75 MHz, CDCl3):
d = 28.3 (CH3), 80.7 (C), 115.5 (CH), 118.7 (CH), 123.6
(CH), 129.4 (CH), 131.8 (C), 138.9 (C), 152.5 (C). Diethyl
(2S)-2-(4-[(tert-Butoxycarbonyl)amino] Benzoylamino)
Pentanedioate (2l): [a]D = 13 (c 1.05, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 1.22 (t, 3 H, JHH = 7.1 Hz, CH3), 1.30
(t, 3 H, JHH = 7.2 Hz, CH3), 1.52 (s, 9 H, t-Bu), 2.05–2.60 (m,
4 H, 2 CH2), 4.10–4.20 (m, 2 H, CH2), 4.20–4.30 (m, 2 H,
CH2), 4.75–4.80 (m, 1 H, CH), 6.80 (br s, 1 H, NH), 7.0 (br
d, 1 H, JHH = 7.2 Hz, NH), 7.40–7.45 (m, 2 H, Ph), 7.75–7.80
(m, 2 H, Ph). 13C NMR (75 MHz, CDCl3): d = 14.0 (CH3),
14.1 (CH3), 27.1 (CH2), 28.2 (CH3), 30.5 (CH2), 52.3 (CH),
60.7 (CH2), 61.6 (CH2), 80.9 (C), 117.2 (CH), 127.6 (C),
173.2 (C).
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Synlett 2004, No. 10, 1794–1798 © Thieme Stuttgart · New York