A protic ionic liquid catalyzed strategy for selective hydrolytic cleavage of tert-butyloxycarbonyl amine (N-Boc)

Article abstract of DOI:10.1039/c4ra13419b

A simple, mild and efficient strategy for selective hydrolytic cleavage of the N-tert-butyloxycarbonyl (Boc) group is devised using a protic ionic liquid as an efficient catalyst. The deprotection reaction proceeded well for N-Boc protected aromatic, heteroaromatic, aliphatic compounds, and chiral amino acid esters and peptides. A wide range of labile protecting groups such as tert-butyl ester, tert-butyl ether, benzyloxycarbonyl (Cbz), TBDMS, O-Boc and S-Boc remained unaffected under the reaction conditions. This journal is

Full text of DOI:10.1039/c4ra13419b

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A protic ionic liquid catalyzed strategy for selective
hydrolytic cleavage of tert-butyloxycarbonyl amine
Cite this: RSC Adv., 2015, 5, 3200
(N-Boc)†
a
Swapan Majumdar, Jhinuk De,a Ankita Chakraborty,a Dipanwita Royb
Received 29th October 2014
Accepted 4th December 2014
*
and Dilip K. Maitib
DOI: 10.1039/c4ra13419b
www.rsc.org/advances
A simple, mild and efficient strategy for selective hydrolytic cleavage of are also reported. However, most of the reported strategies
the N-tert-butyloxycarbonyl (Boc) group is devised using a protic ionic suffer from serious drawbacks such as (i) longer reaction time,
liquid as an efficient catalyst. The deprotection reaction proceeded (ii) high temperature, (iii) low yield of products and (iv)
well for N-Boc protected aromatic, heteroaromatic, aliphatic exploiting expensive catalysts. Moreover, preparations of some
compounds, and chiral amino acid esters and peptides. A wide range of the catalysts are very tedious. Thus, organic synthesis
of labile protecting groups such as tert-butyl ester, tert-butyl ether, professionals of industries and academia seek simple, efficient
benzyloxycarbonyl (Cbz), TBDMS, O-Boc and S-Boc remained unaf- and milder methods for deprotection of this most frequently
fected under the reaction conditions.
used protecting group, which should be selective enough for
preserving the other functionalities in the molecule. G. Wang
et al. (2009) reported8 a special and efficient “green”, catalyst-
free, N-Boc deprotection in supercritical water under pressure.
In their methodology, both aromatic and aliphatic N-Boc
amines can be converted into the corresponding amines in high
yields within 2–16 h, using distilled and deionized water (20 mL
mmolÀ1) at 150 ꢀC. J. Wang and his colleagues (2009) described9
a selective N-Boc deprotection method using boiling water as a
reaction medium. In spite of the potentiality of these green
methods, their major limitation is the use of sophisticated and
costly technology, incompatibility of the deprotection reaction
with ester functionality and longer reaction time. As an inex-
pensive and readily available reagent, imidazolium based protic
ionic liquid has attracted considerable interest due to its less
hazardous nature and efficiency in various organic trans-
formations.10 We have reported earlier an efficient method11a for
the tert-butyloxycarbonylation of amines, amino acids/esters,
alcohols and a green strategy for the selective hydrolytic
cleavage of acetals and ketals11b using protic ionic liquid as an
effective catalyst. In this communication, we disclose the effi-
cacy of a protic ionic liquid as a catalyst for the selective
deprotection of N-Boc group of a wide range of achiral and
chiral compounds.
Due to environmental and economic issues as well as legisla-
tion, chemistry is driven to reduce waste, and reuse and recycle
materials in order to meet the principles of green chemistry.1
Thus the development of an environmentally benign, efficient
and simple methodology for a fundamental organic trans-
formation is in great demand. The protection and deprotection
of functional groups is a common feature to synthesize multi-
functionalized molecules in target oriented syntheses.2 The
choice of a suitable protecting group is oen crucial in the
context of simplifying the procedure, achieving the highest yield
of the desired product, easy workup and separation. The
protection of amines plays pivotal role in the synthetic organic
chemistry. For instance, the N-Boc group is extensively used as a
protecting group of amines in organic synthesis and amino
acids in peptide and nucleoside chemistry. Consequently, a
number of methods were developed for cleavage of the N-Boc
group using strong acids,3 Lewis acids4 and microwave assisted
neutral conditions5 to liberate the parent amine. In some cases,
basic conditions6 such as aq. Na2CO3, Cs2CO3–imidazole and
NaOtBu have been employed. The heterogeneous catalysis
promoted N-Boc deprotection using sulfonic acid resin,7a
montmorillonite K10,7b silica,7c heteropolyacids,7d HY-zeolite7e
In our initial experiments we choose readily available N-Boc
aniline as a model substrate and, the results for development
and optimization of the deprotection studies is displayed in
Table 1. On treatment of the N-Boc aniline (1 mmol) with 1
mmol of Bronsted acid ionic liquid (I or II) in water–dioxane
(1 : 1) at 30 ꢀC, the deprotection did not take place (Table 1,
entry 1). However on rising the temperature to 70–72 ꢀC
aDepartment of Chemistry, Tripura University, Suryamaninagar, 799 022, India.
E-mail: smajumdar@tripurauniv.in; Fax: +91-381-2374802; Tel: +91-381-237-9070
bDepartment of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata 700 009,
India
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra13419b
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Table 1 Standardization of PIL catalyzed N-Boc cleavage of N-Boc aniline
Entry
Solvent
Temp. (ꢀC)
Ionic liquid
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
Dioxane–H2O (1 : 1)
Dioxane–H2O (1 : 1)
Dioxane–H2O (1 : 1)
Water
Dioxane–H2O (1 : 1)
Dioxane–H2O (1 : 1)
Dioxane
30
I or II (100 mol%)
II (100 mol%)
II (10 mol%)
II (10 mol%)
III (100 mol%)
IV (100 mol%)
II (100 mol%)
None
12
1
6
0
92
85
Mixture
0
0
0
0
0
70–72
70–72
70–72
70–72
70–72
80
6
12
12
12
4
Water
Dioxane–H2O (1 : 1)
80
80
None
4
deprotection was smoothly accomplished aer 1 h in 92% yield ionic liquid (II) to afford the desired amines in good to excellent
(Table 1, entry 2). Disappearance of the characteristic infrared yields (Table 2). It can be seen from the results summarized in
absorption peak at 1690 cmÀ1 and 1H NMR signal at d 1.35 of 1a Table 2 that the electron donating substituents such as methyl
conrmed the cleavage of N-Boc group. Usage of catalytic (Table 2, entries 1 and 2), hydroxyl (entry 3), methoxy (entry 4)
amount of II (10 mol%) was slowed down the reaction rate (6 h) accelerate the reaction rate whereas the electron withdrawing
and yield was also marginally dropped to 85% (Table 1, entry 3). substituents uoro (entry 9) and nitro (entry 10) decrease the
Changing the solvent system dioxane–water (1 : 1) to water rate of the reaction. N-Boc imidazole/benzimidazole (entries 6, 7)
results incomplete conversion (Table 1, entry 4), probably due to or N-Boc-2-amino pyridine (entry 8) also took longer reaction
the poor solubility of the precursor. It indicates that homoge- time. The slow reactivity of hetero-aromatic could be explained
neous solution of substrate in water–dioxane is essential for by the fact that the heterocyclic ring nitrogen got protonated by
executing the catalytic cycle of the PIL. Since it was known that protic ionic liquid, which reduced the catalyst concentration. In
imidazolium cation has the capability to activate carbonyl the case of N-Boc protected 4-uoroaniline and 4-nitroaniline
group thus we turned our attention whether this cleavage the deprotection reactions were rather slow, but complete
reaction is compatible to other imidazolium based ionic liquid deprotection could be achieved at 80–82 ꢀC in 72% and 75%
irrespective of their anionic counterparts. To investigate such yields respectively (Table 2, entries 9, 10). This is probably due to
role of imidazolium cation in this cleavage reaction we the solubility problem of the substrates in dioxane–water (1 : 1)
have employed 1-methyl-3-butyl imidazolium bromide (III) and medium.
1-methyl-3-butyl imidazolium hydroxide (IV)12 under the same
The previous method is also applicable for deprotection of
reaction conditions. Unfortunately hydrolytic cleavage was N-Boc protected aliphatic amines, which was working at a little
unsuccessful (Table 1, entries 5, 6). These results revealed the bit higher temperature (80–82 ꢀC). The N-Boc protected hexa-
proton present in ionic liquid II (PIL) is indispensable. Water decyl and octadecyl amines (Table 3, entries 1, 2) proceeded
has also important role with the protic ionic liquid as the efficiently at 80 ꢀC, whereas it was sluggish on use of N-Boc
deprotection reaction did not undergo in anhydrous condition benzylamine and N-Boc dibenzylamines (Table 3, entries 3, 4).
even at 80 ꢀC (Table 1, entry 7). The conversion of N-Boc aniline The N,N-di-Boc protected benzylamine was also cleaved to
to aniline was also unsuccessful without protic ionic liquid benzylamine by protic ionic liquid in water–dioxane (1 : 1)
either in water alone at 80 ꢀC, (Table 1, entry 8, which was rather slowly (entry 5). The equimolar mixture of protected
consistent with the results reported by G. Wang et al.8) or water– aromatic amine (N-Boc aniline) and aliphatic amine (N-Boc
dioxane (Table 1, entry 9).
benzylamine) were treated together with equivalent amount of
ꢀ
Aer the standard condition of the deprotection reaction is protic ionic liquid II in water–dioxane (1 : 1) at 70–72 C, and
set, we have chosen several N-Boc protected aromatic and het- complete conversion of N-Boc aniline to aniline was observed
eroaromatic compounds, which were subjected to deprotection aer 1 h with 90% yield (Table 3, entry 6). This experiment
under the optimized reaction conditions. We were pleased to indicates that the deprotection strategy is highly selective for
observe that N-Boc protected o- and p-toluidine, 4-amino- aromatic Boc-protected amino compounds over aliphatic N-Boc
phenol, 4-methoxyaniline, 1-naphthylamine, imidazole, benz- amines.
imidazole, 2-amino pyridine, 4-uoroaniline and 4-nitroaniline
In contrary to cleavage of both the N-Boc and ester functional
undergo smoothly for deprotection under the catalysis of protic groups on use of supercritical water8 or boiling water9 herein N-
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Table 2 Protic ionic liquid catalyzed deprotection of N-Boc aromatic aminesa
Entry
Substrate
Product
Time (h)
1
Yieldb (%)
98
1
2
3
4
1
2
1
92
82
85
5
2
89
6
7
8
9
3
4
5
5
77
65
55
72c
75c
10
5
a
b
c
Reaction temperature 70–72 ꢀC. Yield reported on the basis of isolated product aer column chromatography. Reaction was carried out at
80–82 ꢀC.
Boc deprotection were proceeds without cleavage of the ester interested to examine the behavior of these O-Boc protected
functionality, tert-butyl ether group and N-benzyloxycarbonyl compounds under the N-Boc deprotection reaction conditions.
(Cbz) group present in amino acid derivatives or other mole- We noticed that only O-Boc protected phenol underwent
cules. To broaden the scope of the deprotection strategy, several deprotection to afford the desired product in 90% yield aer
other acid labile protecting groups such as tetrahydropyranyl, 1.5 h (Table 4, entry 1), whereas alcoholic O-Boc compounds
t
–CO2 Bu and –TBDMS were also addressed in our study. Since were completely inert under the same reaction conditions, even
both phenolic –OH and alcoholic –OH get protected by Boc aer 6 h (Table 4, entries 2, 3). The S-Boc protected benzyl thiol,
group at 70 ꢀC under solvent free conditions11a we were O-TBDMS and tert-butyl ester were also inert against protic ionic
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Table 3 Deprotection of N-Boc group of aliphatic aminesa
Entry
Substrate
Product
Time (h)
1.5
Yieldb (%)
1
2
96
92
1.5
3
4
4.0
5.5
98
80
5
7.0
1.0
74
6
90c
a
Reaction temperature 80–82 ꢀC. b Isolated yield. c Reaction temperature 70–72 ꢀC.
Table 4 Deprotection of O-Boc and other protecting groups
Having in mind the importance of N-Boc protection strategy
in peptide synthesis, feasibility of N-Boc deprotected of
different amino acids or their esters were examined keeping the
Entry Substrate
1
Product
Time (h) Yield (%)
ꢀ
reaction temperature at 80–82 C. The N-Boc protected L-Phe-
OBn, L-Phe-OMe and L-Ser(tBu)-OMe (Table 5, entries 1–3) all
undergo smooth deprotection in water–dioxane to the corre-
sponding amines. Racemization at the a-carbon of the amino
acid derivatives were not observed in any cases. N-Boc protected
amino acids such as Boc-Ala-OH or Boc-Pro-OH both underwent
deprotection to free amino acids in 65% and 92% isolated yield
respectively. In both the cases deprotection proceeds well in
water (no need of dioxane) in shorter reaction time with respect
to corresponding esters. It is noteworthy to mention that N-Cbz
protected amino acid did not respond because no change was
observed on treatment of Cbz-Phe-OH with 100 mol% of PIL (II)
in water–dioxane (1 : 1) for 3 h at 80–82 ꢀC. Thus, it is possible to
deprotect N-Boc group in presence of an orthogonal N-Cbz
group present in the same molecule (Table 5, entry 7).
1.5
6.0
6.0
90
2
3
NR
NR
4
6.0
NR
5
6
6.0
6.0
NR
NR
We are also delighted to observed that Boc protected N-
terminal amino group was selectively deprotected when fully
protected dipeptide BocAsp(OtBu)Ser(tBu)-OtBu (7h)13 was
treated with protic ionic liquid in water–dioxane (1 : 1) for 4 h at
80–82 ꢀC to produced N-deprotected product 8h in 82% yield
7
4.0
93
t
(Scheme 1). In this reaction, peptide bond, CO2 Bu group of side
chain as well as terminal position in aspartic acid residue and
tert-butyl ether in serine residue were retained. This observation
indicated that our method is highly selective for N-Boc group in
a peptide in the presence of other common protecting groups.
The generally accepted mechanism for the deprotection of
the Boc group under anhydrous acidic condition14 involves the
formation of carbon dioxide and isobutylene. In this case, the
rst step is the activation of Boc group by protonation and
subsequent elimination of isobutylene produced unstable
liquid under the similar reaction conditions (Table 4, entries
4–6) to afford the desired thiol, alcohol and acids. Interestingly
the PIL catalyst was efficiently deprotected O-THP protecting
group under the reaction conditions to afford corresponding
aliphatic alcohol in 93% yield (Table 4, entry 7).
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Table 5 Deprotection of N-Boc group present in amino acids and other derivativesa
Entry
Substrate
Product
Time (h)
3.5
Yieldb (%)
72
1
2
3
4
3.0
4.5
1.0
70
75
65c
5
6
1.0
3.0
92c
NR
7
1.0
76
a
Isolated yield. b Reaction temperature 80–82 ꢀC. c Reaction proceed in water.
Scheme 2 Probable mechanism of N-Boc deprotection reaction.
Scheme 1 Chemoselective deprotection of N-Boc group in a peptide.
In conclusion we have demonstrated a simple, mild and
chemoselective Boc-deprotection strategy for N-Boc amines
using imidazolium based protic ionic liquid in water–dioxane
mixture. The present approach proceeded well for aromatic,
heteroaromatic, aliphatic N-Boc substrates as well as N-Boc
amino acid/esters and N-Boc peptides. The acid sensitive and
labile protecting groups such as methyl or tert-butyl ester, tert-
butyl ether, TBDMS survived under the reaction conditions.
Chemoselectivity of the reaction and many sensitive functional
groups tolerance will make the protocol attractive and useful to
the synthetic and medicinal chemists in academia and industry.
carbamic acid which releases carbon dioxide to afford parent
amine. On the other hand, activation of carbonyls by imidazo-
lium cation is well established. In our study we observed that
the N-Boc deprotection was smoothly proceed when protic ionic
liquid was employed and the cleavage reaction was not
successful when imidazolium bromide or hydroxide was
employed. To see whether proton alone could catalyzed the N-
Boc deprotection we have carried out one control experiment
with triethylammoniun triuoroacetate by keeping the other
conditions same (not shown in the tables) but this does not
produce any deprotected product. Thus it is likely to involve
dual activation of carbamate by imidazolium ion and proton
attached in ionic liquid and then nucleophilic attack by water
providing a tetra-coordinated species that can expels tert-BuOH
and carbamic acid. The elimination of carbon dioxide from
carbamic acid provides the parent amine (Scheme 2).
General procedure
To a stirred solution of N-Boc amine (1 mmol) in water–dioxane
(1 : 1, 2 mL), protic ionic liquid II (1 equiv. or 10 mol%) was
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added and then the mixture was heated at 70–72 ꢀC or 80–82 ꢀC
depending upon the nature of substrate as indicated in the
Tables 2–5 until the complete consumption of starting material
(monitored by TLC). Aer completion of the reaction, dioxane
was removed under reduced pressure and the mixture was
diluted with water (5 mL). The mixture was extracted with
diethyl ether or ethyl acetate (3 Â 5 mL), washed with water,
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was then passed through a short
pad silica-gel to afforded parent amines. The aqueous part
containing ionic liquid was recycled. The product was charac-
terized by IR, 1H and 13C NMR spectral data and compare with
authentic samples (ESI).
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Acknowledgements
We are pleased to acknowledge the nancial support from
Department of Science & Technology (DST), Govt. of India (grant
no. SR/S1/OC-49/2010) for this investigation. A.C. is thankful to
Department of Science and Technology, Govt of India for
providing INSPIRE research fellowship. We are also very much
thankful to learned reviewers for their valuable comments and
suggestions, which improved the quality of the work.
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