Thioglycoluril as a highly efficient, recyclable and novel organocatalyst for N-Boc protection of amines

Article abstract of DOI:10.1016/j.tetlet.2010.09.096

A simple and efficient protocol for the chemoselective mono-N-Boc protection of various structurally diverse amines with di-tert-butyl dicarbonate using thioglycoluril as the catalyst is described. The catalyst can be readily separated from the reaction products by simple filtration and recovered for reuse. No competitive side reactions, such as formation of isocyanate, urea, oxazolidinone, and N,N-di-Boc derivatives were observed.

Full text of DOI:10.1016/j.tetlet.2010.09.096

Tetrahedron Letters 51 (2010) 6388–6391
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Tetrahedron Letters
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Thioglycoluril as a highly efficient, recyclable and novel organocatalyst
for N-Boc protection of amines
Samad Khaksar a, , Seyed Mohammad Vahdat a, Mahmood Tajbakhsh b, Fatemeh Jahani b, Akbar Heydari c
⇑
a Chemistry Department, Islamic Azad University, Ayatollah Amoli Branch, Amol, Iran
b Chemistry Department, Mazandaran University, Babolsar, Iran
c Chemistry Department, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient protocol for the chemoselective mono-N-Boc protection of various structurally
diverse amines with di-tert-butyl dicarbonate using thioglycoluril as the catalyst is described. The cata-
lyst can be readily separated from the reaction products by simple filtration and recovered for reuse. No
competitive side reactions, such as formation of isocyanate, urea, oxazolidinone, and N,N-di-Boc deriva-
tives were observed.
Received 13 April 2010
Revised 23 August 2010
Accepted 20 September 2010
Available online 21 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
In memory of Shahid Dr. Hasan Abbaspour
Keywords:
Thioglycoluril
Hydrogen bonding
Chemoselective
(Boc)2O
1. Introduction
carbonyl group toward basic and nucleophilic attack and its labile
nature in the presence of acid.5 Traditional methods for Boc protec-
The term ‘organocatalysis’ describes the acceleration of chemi-
cal reactions through the addition of a substoichiometric quantity
of an organic compound.1 Interest in this field has increased as a
result of both the novel approaches of the concept and, more
importantly, by the fact that the efficiency and selectivity of many
organocatalytic reactions meet the standards of established organ-
ic reactions. Nowadays, ureas and thioureas are widely recognized
as very useful templates on which powerful organocatalytic sys-
tems,2 both mono- and bifunctional, can be constructed. However,
the design and development of new, effective, and easily accessible
bifunctional organic catalysts continue to be a major challenge. In
1989, Butler and co-workers reported that the condensation of
thiourea and benzil in butanol yielded an insoluble white solid
now known as thioglycoluril.3 Recently, Wu and co-workers dem-
onstrated that thioglycoluril, as a novel organocatalyst, efficiently
tion involve the reaction of amines with di-tert-butyl dicarbonate
[(Boc)2O] in the presence of 4-(N,N-dimethylamino)pyridine
(DMAP)6 or inorganic bases;7 drawbacks include long reaction
times and the toxicity of the reagents. Furthermore, the base-cata-
lyzed reactions are often associated with the formation of isocya-
nates,8 ureas,6 and N,N-di-Boc derivatives.9 Further, modified
methods have been reported with amines and (Boc)2O in the pres-
ence of Lewis acids, such as ZrCl4,10 LiClO4,11 HClO4,12 Cu(BF4)2Á
xH2O,13 Zn(ClO4)2Á6H2O,14 and La(NO3)3Á6H2O.15 Although these
methods circumvent the problems associated with the formation
of side products, they are plagued by a number of other serious
drawbacks and have limited applications in large scale preparation
(e.g., ZrCl4 is 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.16 Even when the desired reactions proceed, more than
stoichiometric amounts of the Lewis acids are needed, as the acids
are trapped by the basic nitrogen.17 In recent years, several new
promoted selective
a-monobromination of 1,3-diketones and b-
keto esters.4 Bearing in mind the usefulness and efficiency of
organocatalysts, we decided to explore thioglycoluril as a bifunc-
tional organocatalyst for the N-Boc protection of amines.
N-tert-Butoxycarbonylation of amines has received consider-
able attention in synthesis due to the stability of the N-tert-butoxy-
and efficient methods have been developed including the use of
20
HClO4/SiO2,12 Montmorillonite K10 or KSF,18 I2,19 H3PW12O40
,
thiourea,21 HFIP,22 sulfamic acid,23 Amberlyst 15,24 and H2O.25
However, most of these methods still have limitations, such as high
costs and the air-sensitive nature of the catalysts, toxicity and cor-
rosiveness, restrictions for large-scale applications, deprotection of
⇑
Corresponding author. Tel./fax: +98 121 2552136.
E-mail addresses: S.khaksar@iauamol.ac.ir, samadkhaksar@yahoo.com (S. Khak-
sar).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.096

S. Khaksar et al. / Tetrahedron Letters 51 (2010) 6388–6391
6389
Table 1
Table 1 (continued)
Thioglycoluril-catalyzed N-Boc protection of amines
Entry Substrate
Time
(min)
Product
Yield (%)
3a
R1
R1
NH2
H
N
(10 mol%)
Thioglycoluril
Boc
N
N
u
10
80
Boc2
O
+
R2
NH2
R2
Boc
H
NH2
EtOH, 30- 40 C, 5 - 60 min
1
2
3
NH2
H
N
Boc
Boc
v
10
80
50
40
Entry Substrate
Time
(min)
Product
Yield (%)
HS
Cl
3a
HS
NH2
H
N
H
N
H
N
wb
xb
4 h
6 h
Boc
a
8
6
95
94
H
Boc
Boc
NH2
H
N
NH2
OH
H
N
b
Cl
OH
a
Isolated product.
Without catalyst.
H
H
N
b
N
H
H
c
40
60
92
90
Boc
Br
Cl
Br
Cl
other protecting groups,26 difficult product isolation procedures,
lack of generality especially with deactivated (electron-deficient)
amines, and difficulties in recovery of high-boiling solvents. We re-
cently reported that thiourea can catalyze N-Boc protection of var-
ious activated amines in toluene at 60–70 °C.21 Herein we report
thioglycoluril as an excellent organocatalyst for the selective tert-
butoxycarbonylation of various amines and amine derivatives.
The general applicability of the method for the synthesis of a wide
variety of diverse N-Boc-amines is demonstrated (Table 1).
H
N
H
N
d
Boc
H
N
H
N
H
H
Boc
Boc
e
f
30
30
93
95
Cl
Cl
H
N
H
N
In an initial endeavor, one equivalent each of (Boc)2O and ani-
line were stirred at ambient temperature in ethanol. After 4 h, only
50% of the expected product was obtained after work-up and
recrystallization of the crude from ethanol. To improve the yield
and optimize the reaction conditions, the same reaction was car-
ried out in the presence of a catalytic amount of thioglycoluril
(10 mol %) under similar conditions. Surprisingly, a significant
improvement was observed and the yield of the expected product
increased to 95% after stirring the mixture for only 8 min (Table 1,
entry a). This study was extended to a wide range of structurally
diverse amines including open-chain, cyclic, aromatic and hetero-
Br
Br
H
Boc
N
H
N
g
5
95
95
H
H
Boc
N
H
N
H
h
10
Cl
Cl
Boc
i
8
92
N
N
NH2
N
H
N
H
N
Ph
Ph
Ph
Ph
O
j
5
5
90
92
Boc
aromatic, as well as b-amino alcohols and a-amino acid esters all
k
O
N
Boc
N H
of which underwent reaction smoothly with (Boc)2O. The method
can be applied for the conversion of poorly reactive amines, such
as 4-chloroaniline, as well as the sterically hindered tert-butyl-
amine, into the corresponding N-Boc derivatives (entries d and
m). Similarly, with 1,2-phenylenediamine the mono-N-Boc pro-
tected product was obtained in reasonably good yield (entry u).
In addition, an amino acid ester was converted into the corre-
sponding N-Boc ester under similar reaction conditions (entry t).
It is noteworthy that this reaction is chemoselective in the cases
of 2-phenylglycinol and ephedrine, where the N-Boc protected
derivatives were obtained as the sole products (entries q and r)
and neither O-Boc nor oxazolidinone derivatives were observed
(by NMR). In all cases, a remarkable rate acceleration effect was ob-
served as demonstrated by the short reaction times and excellent
yields of the corresponding N-Boc products. TLC was used to mon-
itor the progress of the reactions which in some cases could also be
followed visually, for example, with secondary amines, an exother-
mic reaction took place immediately after the addition of (Boc)2O
to the amine with vigorous effervescence. For primary amines,
commencement of slow effervescence took place with concomitant
formation of the N-Boc derivatives.27
l
5
10
10
10
10
90
95
94
92
90
N
H
N
Boc
H
NH2
N
m
n
o
p
Boc
H
N
H
N
Boc
NH2
N
H
NH2
H
N
N
Boc
N
TMS
H
N
NH2
TMS
O
Boc
O
NH2
Boc
HN
q
15
93
OH
OH
OH H
N
OH H
N
r
15
20
95
95
Boc
O
Boc
H
O
HO
N
H
HO
H
N
H
s
To extend the synthetic potential of this novel method for
chemoselective protection of amines, we also examined its effi-
ciency in reactions with hydroxylamines and hydrazines. As shown
in Table 1, the corresponding mono-N-Boc products were obtained
in good isolated yields (entries o and p).
NH2
O
Boc
N
t
20
95
O
OMe
OMe

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S. Khaksar et al. / Tetrahedron Letters 51 (2010) 6388–6391
TS 1
O
O
O
O
O
S
S
O
thioglycoluril
H
O
O
O
O
H
O
H
O
H
N N
O
N
O
O
N
Ph
Ph
H
N
R1
R2
R1
R1
R2
R2
S
H
CO2
S
+
O
N
N
Boc
N
+
O
H
O
O
O
H
N
H +
N
R2
N
O
R1
O
H
N
O
H
H
O
S
S
O
O
Ph
Ph
H
H
H
N
H
N
N
N
TS 2
Ph
Ph
Scheme 1. Proposed mechanism for the thioglycoluril-catalyzed chemoselective N-tert-butoxycarbonylation of amines.
The mechanistic role of thioglycoluril is illustrated in Scheme
chromatography (hexane–EtOAc). 1H NMR, 13C NMR, and IR spec-
tra were consistent with the assigned structures.11,24 Spectroscopic
data for selected examples are given below. (3a)19 White solid, mp:
130–132 °C; 1H NMR (500.13 MHz, CDCl3): d 1.56 (s, 9H), 6.51 (br s,
1H), 7.06–7.09 (m, 1H), 7.30–7.41 (m, 4H); 13C NMR (125.75 MHz,
CDCl3): d 28.7, 85.5, 115.9, 123.4, 129.3, 138.7, 153.2. (3b) White
solid, mp 142 °C, 1H NMR (500.13 MHz, CDCl3): d 1.57 (s, 9H),
6.69 (br s, 1H, NH), 6.88–7.30 (m, 4H), 8.17 (br s, 1H, OH); 13C
NMR (125.75 MHz, CDCl3): d 28.6, 82.4, 119.0, 121.1, 121.7,
125.8, 126.0, 147.3, 155.3. (3d) White solid, mp: 102–104 °C; 1H
NMR (500.13 MHz, CDCl3): d 1.53 (s, 9H), 6.59 (br s, 1H, NH),
7.23–7.33 (m, 4H); 13C NMR (125.75 MHz, CDCl3): d 28.3, 80.8,
119.7, 127.9, 128.9, 136.9, 152.6. (3q) Solid, mp 130–132 °C, 1H
NMR (500.13 MHz, CDCl3): d 1.47 (s, 9H), 2.69 (br s, 1H, NH),
3.85 (s, 2H), 4.51 (s, 1H), 5.30 (s, 1H), 7.30–7.40 (m, 5H); 13C
NMR (125.75 MHz, CDCl3): d 28.7, 52.2, 67.2, 80.4, 126.9, 128.1,
129.1, 140.1, 156.5.
1.21,25 Hydrogen bond formation between thioglycoluril and the
carbonyl oxygen atoms of (Boc)2O leads to ‘electrophilic activation’
(TS 1) making the carbonyl group more susceptible to nucleophilic
attack. The sulfur atom of thioglycoluril in turn forms a hydrogen
bond with the hydrogen atom of the amine and increases the elec-
tron density at the nitrogen atom (nucleophilic activation). Electro-
static attraction between the carbonyl group and the nitrogen
atom leads to TS 2. Intramolecular nucleophilic attack by the nitro-
gen atom on the carbonyl carbon followed by elimination of CO2,
t-BuOH, and thioglycoluril yields the corresponding carbamate. A
similar mechanism for the activation of carbonyl compounds by
thioglycoluril has been reported.4 Due to the poor solubility of
thioglycoluril in ethanol and CH2Cl2 the catalyst can be separated
easily after completion of the reaction and reused without any de-
crease in its activity. For example, the reaction of aniline (entry a)
and (Boc)2O afforded the corresponding N-Boc product in 95%, 95%,
and 94% isolated yields over three cycles. Although the amount of
catalyst has been optimized to 10 mol %, lower amounts (5 mol %)
also worked but with longer reaction times.
Acknowledgment
In summary, we have described an efficient method for N-tert-
butoxycarbonylation of various electronically and structurally di-
verse amines in good-to-excellent isolated yields. In contrast to
some existing methods using potentially hazardous catalysts/addi-
tives, this new method offers the following advantages: (i) avoids
the use of any base, metal, or Lewis acid catalysts, (ii) short reac-
tion times, (iii) ease of product isolation/non-aqueous work-up,
(iv) high chemoselectivity, (v) no side reactions, and (vi) simple
processing and handling. The recovered thioglycoluril can be
recycled.
This research is supported by the Islamic Azad University, Aya-
tollah Amoli Branch.
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