N-tert-Butoxycarbonylation of amines using H3PW12O40 as an efficient heterogeneous and recyclable catalyst

Article abstract of DOI:10.1016/j.tetlet.2007.06.064

The commercially available heteropoly acid H₃PW₁₂O₄₀ (0.5 mol %) is a very efficient and environmentally benign catalyst for N-tert-butoxycarbonylation of amines (primary, secondary) with di-tert-butyl dicarbonate at room temperature in short reaction times (<10 min). No competitive side products such as isocyanates, ureas, N,N-di-tert-butoxycarbonyls, O-Boc and oxazolidinones were observed. Chiral α-amino alcohols and esters afforded the corresponding N-Boc derivatives chemoselectively in excellent yields.

Full text of DOI:10.1016/j.tetlet.2007.06.064

Tetrahedron Letters 48 (2007) 5865–5868
N-tert-Butoxycarbonylation of amines using H PW O
3
12 40
as an efficient heterogeneous and recyclable catalyst
*
Akbar Heydari, Roohollah Kazem Shiroodi, Hossein Hamadi,
Maryam Esfandyari and Mehrdad Pourayoubi
Chemistry Department, Tarbiat Modares University, PO Box 14155-4838, Tehran, Iran
Received 22 March 2007; revised 4 June 2007; accepted 13 June 2007
Available online 20 June 2007
This Letter is dedicated to Professor Mehdi Golshani on the occasion of his 70th birthday
3
Abstract—The commercially available heteropoly acid H PW12O40 (0.5 mol %) is a very efficient and environmentally benign cat-
alyst for N-tert-butoxycarbonylation of amines (primary, secondary) with di-tert-butyl dicarbonate at room temperature in short
reaction times (<10 min). No competitive side products such as isocyanates, ureas, N,N-di-tert-butoxycarbonyls, O-Boc and oxazol-
idinones were observed. Chiral a-amino alcohols and esters afforded the corresponding N-Boc derivatives chemoselectively in excel-
lent yields.
Ó 2007 Elsevier Ltd. All rights reserved.
6
1
. Introduction
bonate in the presence of DMAP. Commercially avail-
able di-tert-butyl dicarbonate is an efficient reagent for
clean and rapid introduction of the t-Boc-protecting
group. Although alkylamines are well known to give,
without the assistance of any catalyst, the mono-
As N-tert-butoxycarbonyl amino acids are resistant to
racemization during peptide synthesis, the N-Boc moiety
is one of the most important amine protecting groups.
1
,2
7
a,b
The tert-butoxycarbonyl group is cleaved with
protected derivatives on reaction with (Boc) O,
the
2
CF CO H in 5–10 min at room temperature. Cheaper
analogous reactions of poorly reactive primary and
secondary arylamines, due to their reduced nucleophilic-
3
2
acids such as 3 M HCl in EtOAc or 10% H SO in diox-
2
4
4
,7c
ane or hot formic acid can be considered for large scale
deprotection. N-Boc-protected amino acids can easily
be converted into the free amine and are useful in Merri-
field’s solid phase peptide synthesis. The stability of N-
Boc to catalytic hydrogenation and its resistance towards
basic and nucleophilic attack make carbamates and
benzyl esters ideal orthogonal partners for protection of
ity, proceed sluggishly.
Moreover, the base catalyzed
reactions are often associated with the occurrence of var-
ious side reactions such as biscarbamoylation, or the for-
8
mation of isocyanates and urea. Further, the high
toxicity of DMAP and reagents derived from it, limit
9
their use. Due to the very attractive nature of the
N-Boc group, there have been many attempts to find
alternative methodologies for this reaction, which do
not suffer the drawbacks associated with the classical
procedures.
3
amines during the synthesis of multifunctional targets.
Various reagents and methods have been developed for
4
N-tert-butoxycarbonylation of amines. Most are carried
out in the presence of a base, for example: 4-(dimethyl-
amino)-1-tert-butoxycarbonylpyridinium chloride or
There are limited number of reports on the use of Lewis
acid catalysts to effect the above transformation. These
5
tetrafluoroborate in aq NaOH, tert-butyl-1-chloroalkyl
1
b
10
11
12
carbonates/K CO ,
2
2-tert-butoxycarbonyloxyimino-
include yttria-zirconia, Zn(ClO ) Æ6H O, LiClO4,
2
3
4 2 2
1
b
13
14
15
-phenylacetonitrile/Et N, or di-tert-butyl pyrocar-
ZrCl4, Cu(BF ) ÆXH O, HClO /SiO
2
and Mont-
3
4 2
2
4
1
6
morillonite K10 or KSF. Although these methods cir-
cumvent the problems associated with the formation of
the above mentioned side products, they are plagued by
a number of other serious drawbacks and have limited
applications in large scale applications (e.g., the use of
Keywords: Phosphotungstic acid; Amine protection; Boc-derivatives;
Boc) O.
Corresponding author. Fax: +98 21 88006544;
akbar.heydari@gmx.de
(
2
*
e-mail:
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.064

5866
A. Heydari et al. / Tetrahedron Letters 48 (2007) 5865–5868
H SO at 500 °C to prepare yttria-zirconia; ZrCl is
lyzed conditions. However, under conventional condi-
2
4
4
highly moisture sensitive and liberates HCl fumes;
perchlorate reagents are strong oxidants and explosive
in nature). Moreover, it should be noted that most
Lewis acids cannot be used in this reaction since they
are consumed and deactivated by the amines.1 Even
when the desired reactions proceed, more than stoichio-
metric amounts of the Lewis acids are needed, as the
tions the reaction of 1,2-phenylenediamine with Boc O
2
in MeCN at rt afforded the N,N-di-Boc product in
2
6
95% yield after 24 h. The use of Boc O in the presence
2
of 0.5 equiv of 4-(dimethylamino)pyridine and 1,2-phen-
7
ylendiamine afforded 1,3-di-t-Boc benzimidazolidinone
6
b
in 50% yield and 50% of starting amine was recovered.
In a further study, an a-amino acid ester was converted
into the corresponding N-Boc ester under similar reac-
tion conditions. It is noteworthy that the reaction is
chemoselective in the case of 2-phenylglycinol, N-benzyl-
ethanolamine and ephedrine where the corresponding
N-Boc protected products were obtained as the sole
products, no O-Boc or oxazolidinone derivatives were
observed, even though alcohols are known to react with
1
8
acids are trapped by the basic nitrogen.
Over the past three decades, heteropoly compounds
have been extensively studied as homogeneous and
heterogeneous acid and oxidation catalysts for many
1
9
reactions. They also have found industrial applications
in several processes as oxidants and acid catalysts both
in solid and in solution reactions. Presently, four indus-
trial processes utilize heteropoly compounds, propylene
hydration, methacrolein and olefin oxidation and the
polymerization of tetrahydrofuran.20 Except for metha-
crolein oxidation, these industrial processes are based on
polyoxometallate homogeneous catalysis with high con-
version and selectivity at very low temperature. The use
of heteropoly compounds in acid catalyzed reactions has
opened new possibilities for processes requiring acidities
greater than mineral acids, ion-exchange resins, zeolites,
mixed oxides, H PO /SiO , CF SO H, PTS and
Boc O in the presence of DMAP to give O-Boc-deriva-
2
2
7
tives together with symmetrical carbonates. Another
notable feature of the reaction is that a secondary amine
reacted smoothly to afford the desired product in high
isolated yield. The insolubility of the catalyst (PW) in
CH Cl allows for easy separation of the product by
2
2
simple filtration; PW was reused with only a gradual
decrease in its activity observed. For example, the reac-
tion of (S)-a-methylbenzylamine (1c) and (Boc) O affor-
2
ded the corresponding N-Boc derivative in 88%, 88%
and 87% yields over three cycles (entry c).
3
4
2
3
3
CF COOH, in both heterogeneous and homogeneous
3
systems. Furthermore, when using hetropoly acid
In continuation of this study, p-toluenesulfonamide and
N,N-dimethylhydrazine underwent smooth N-Boc pro-
tection in the presence of PW (0.5 mol % in <10 min)
to give 3r and 3s, respectively, in 90% and 89% yields.
Furthermore, noroxycodone was converted into the cor-
responding N-Boc derivative 3t under similar reaction
conditions in 10 min in 90% isolated yield.
(
HPAs) fewer side reactions occur, which frequently
take place with mineral acids. HPAs are non corrosive
and environmentally benign. Dodecatungstophosphoric
acid, H PW O (PW), is an effective catalyst in the
3
12 40
Keggin series. These HPAs can be reused or recycled,
involve easy work up procedures, possess high structural
OH
N
Boc
O
Boc
S
N
N
Boc
O
O
H
N
H
O
3r
3s
OMe
3
t
and thermal stability and well defined acidic and redox
properties, and have attracted much attention in syn-
In summary, this protocol represents a safer, and experi-
mentally simple procedure for Boc-protection of amines.
2
1
thetic chemistry. Furthermore, H PW O is found
3
12 40
to retain its activity even in the presence of a number
of organic substrates containing N, S or O atoms, that
2. General procedure: preparation of N-Boc amines
2
2
23
24
is, amino acids,
quinoline,
TTF
and crown
2
5
ethers. This prompted us to use this catalyst for the
To a mixture of Boc O (218 mg, 1 mmol) and
2
synthesis of N-Boc protected amines.
H PW O (15 mg, 0.5 mol %) in 4 mL of CH Cl
3
12 40
2
2
was added 1.1 mmol of amine. After stirring for
<10 min at room temperature, the resulting suspension
was filtered and the solid residue washed with CH Cl
Herein we report that H PW O is as an excellent
3
12 40
catalyst for the selective tert-butoxycarbonylation of
various amines and amine derivatives. The products
obtained are summarized in Table 1. The method can
be applied to the conversion of sterically hindered
amines, such as tert-butylamine, as well as the poorly
reactive 4-nitroaniline. With 1,2-phenylenediamine, only
the mono N,t-Boc protected product was obtained in
reasonably good yield (86%) under H PW O cata-
2
2
(10 mL). The filtrate was concentrated on a rotary evap-
orator to afford a crude product, which was purified by
1
flash chromatography (hexane–ethyl acetate). H NMR,
1
3
C NMR and IR spectra were consistent with the
assigned structures and by comparison with those
11
reported in the literature. Compound 3d is commercially
2
8
available; 3t is a known compound. Spectral data for
3
12 40

A. Heydari et al. / Tetrahedron Letters 48 (2007) 5865–5868
3
Table 1. H PW12O40 catalyzed protection of amines Table 1 (continued)
5867
a
Entry
Product
Time (min)
6
Yield (%)
H PW O (0.5 mol%)
3
12 40
Amine
+
Boc O
Amine-Boc
2
Boc
N
CH Cl , , r. t.
2
2
3
n
98
94
1
2
Bn
OH
a
Entry
a
Product
Time (min)
Yield (%)
H
Boc
OH
H
N
N
o
p
5
8
8
3
84
92
Boc
Ph
Boc
N
Boc
N
OH
b
c
94
96
Bn
Ph
H
Ph
Ph
Boc
Boc
O
H
4
8
88
85
N
N
H
q
9
Boc
N
OMe
d
e
a
H
Yields of pure products isolated by column chromatography.
1
selected products: 3l: H NMR (90 MHz, CDCl3):
H
N
d = 1.5 (s, 9H), 3.4 (m, 4H), 3.5–4.0 (m, 5H, NH and
13
6
86
80
CH ), 5.6 (br s, 1H); C NMR (22.5 MHz, CDCl3):
2
2
Boc
7.6 (CH ), 39.7 (C), 60.6 (CH ), 69.6 (CH ), 71.8
3 2 2
1
NH2
(
(
(
CH ), 78.6 (CH ), 156.2 (C@O); 3m: H NMR
2
2
90 MHz, CDCl ): d = 1.5 (s, 9H), 2.4 (br s, 3H), 3.7
3
Boc
N
1
s, 6H), 7.2 (br s, 1H); 3n: H NMR (90 MHz, CDCl ):
d = 1.5 (s, 9H), 2.9 (br s, 1H), 3.4 (d, J = 9 Hz, 2H), 3.7
d, J = 9 Hz, 2H), 4.6 (s, 2H), 7.1–7.5 (br s, 5H);
3
f
H
12
13
(
C
O N
2
NMR (22.5, CDCl ) 28.0 (CH ), 49.3 (C), 52.2 (CH ),
3
3
2
6
1.5 (CH ), 80.4 (CH ), 127.4 (CH), 127.8 (CH), 128.7
2 2
H
N
(CH), 138.4 (C), 156.7 (C@O).
g
3
88
84
Boc
OH
Acknowledgement
Boc
N
This research was supported by the National Research
Council of the Islamic Republic of Iran as a National
Research project under the number 984.
h
H
10
HO C
2
i
j
N
Boc
10
7
85
83
References and notes
N
O
1
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