View Article Online / Journal Homepage / Table of Contents for this issue

COMMUNICATION www.rsc.org/chemcomm | ChemComm

Boiling water-catalyzed neutral and selective N-Boc deprotectionw

Jia Wang, Yan-Liang Liang and Jin Qu*
Received (in College Park, MD, USA) 26th May 2009, Accepted 8th July 2009
First published as an Advance Article on the web 31st July 2009
DOI: 10.1039/b910239f

A general protocol for removing Boc groups from various types research was carried out to understand the role water played
of nitrogen is reported and a preliminary investigation of the in the reaction. We found that water acts as a dual acid/base
Published on 31 July 2009. Downloaded by GlaxoSmithKline on 3/12/2025 10:46:02 PM.

reaction mechanism indicates that water acts as a dual acid/base catalyst rather than an acid catalyst, as suggested by Jia et al.13
catalyst at elevated temperature. Thus we are responsible to present these findings.
The N-Boc group on aromatic heterocycles such as imidazole,
Water is the main solvent for life processes and there is growing pyrazole, benzimidazole and benzotriazole could be removed
interest in using it as a ‘‘green’’ solvent for organic transformations.1 in quantitative yields within 10 min (entries 1–4, Table 1).
However, reports about using water as a catalyst to promote N-Boc-indole gave free indole in quantitative yield under the
organic reactions are very limited. An early report from same conditions, but complete reaction took 4 h (entry 5). For
Breslow’s research group pointed out that the Diels–Alder indole’s electron-deficient analogs such as N-Boc-7-azaindole
reaction can be remarkably accelerated in water owing to the and N-Boc-3-acetylindole, the reaction could be completed in
hydrophobic interaction between water and nonpolar moieties.2 1 h and 2 h, respectively (entries 6 and 7).
As an emerging area, supercritical water (liquid water above For the representative N-Boc aromatic amines examined, no
374 1C) and subcritical water (liquid water between 150 1C and obvious electronic substitution effect on the phenyl ring was
374 1C) under high pressure was applied to promote the observed. It appears that the substrates bearing hydrogen
traditionally acid-catalyzed reactions.3 Recently, several reports bond-forming functional groups (–OH, –OMe, –Ac, –NO2,
showed that water could catalyze reactions by forming hydro- –NMe2), which could enhance the solubility of the substrates
gen bonds with substrates.4 A most surprising result came from in water, react faster (entries 5–12, Table 2) than those
Prof. Jamison’s research group, who discovered that the substrates without such functional groups (entries 1–4). As
cascade epoxide-opening yielding ladder polyether could be reported previously,6 the reaction rate of epoxide hydrolysis
efficiently promoted by water.5 Our group reported that the was relevant to the amount of water that served as reaction
generalized ring-opening reactions of epoxides and aziridines by medium. We tested this point again by measuring the reaction
nucleophiles may also be carried out in hot water (60–100 1C) rates of two substrates with different solubilities in water
without additional catalyst.6
The tert-butoxycarbonyl (Boc) group is one of the most Table 1 Deprotection of N-Boc aromatic heterocyclesa
widely used amino protecting groups. The most common Entry Substrate Time Yield (%)
method for its removal is treating the N-Boc substrates in
TFA–CH2Cl2 (1 : 1),7,8 but because of the toxicity and cost
1 10 min 99
issues,9 large scale N-Boc deprotections still use mineral acids
such as sulfuric acid,10 hydrochloric acid11 and phosphoric
acid.12 Neutralization and the production of waste salt are 2 10 min 99
inevitable; thus, a more environmentally benign method is still
desired. We found that boiling water could efficiently catalyze
3 10 min 99
the deprotection of N-Boc groups, which meet all requirements
for a green chemical process. After our work was essentially
completed, Prof. Jia’s research group reported a catalyst-free
N-Boc deprotection in subcritical water under pressure.13 4 5 min 99
Several N-Boc aromatic amines and two N-Boc amino acids
were deprotected in good to excellent yields. Our work included
a much greater variation of substrates, and the utilization of 5 4h 99
manageable boiling water rather than subcritical water makes
the present method safe and practical. The possibility of
6 1h 99
selective deprotection of N-Boc groups could be realized
in molecules containing two kinds of N-Boc. Furthermore,

7 2h 99
State key Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin 300071, China. E-mail: qujin@nankai.edu.cn;
Fax: +86-22-23499254; Tel: +86-22-23499247 a
All reactions were conducted with 1 mmol of substrate in 10 mL of
w Electronic supplementary information (ESI) available: Experimental water at 100 1C.
details and analytical data. See DOI: 10.1039/b910239f

5144 | Chem. Commun., 2009, 5144–5146 This journal is 

c The Royal Society of Chemistry 2009
 View Article Online

Table 2 Deprotection of N-Boc aromatic aminesa Table 3 Deprotection of N-Boc aliphatic amines and amidesa

Entry Substrate Time/h Yield (%) Entry Substrate Product Time Yield (%)

1b 10 99 1 13 h 87

2 4.5 h 99
2b 10 99

3 10 99 3 6.5 h 93

4 14 97 4 10 h 97
Published on 31 July 2009. Downloaded by GlaxoSmithKline on 3/12/2025 10:46:02 PM.

5b 2 97
5 0.5 h 97

6 1 95
6 4h 99
7b 6 99

8 3 91
7 4h 99

9 1.5 98

8 10 min 94
10 2.5 97

11 3.5 94 9b 4h 77

12b 8 99
10 9h 76
a
All reactions were conducted with 1 mmol of substrate in 20 mL of water
at 100 1C. b The reaction was conducted under nitrogen atmosphere. a
All reactions were conducted with 1 mmol of substrate in 20 mL of
water at 100 1C. b The sticky substrate (1 mmol) was firstly dissolved
(Fig. 1). The reaction rate of the less soluble N-Boc-4-chloro- in 1 mL of 1,4-dioxane and then 19 mL of water was added.
aniline strongly depended on the amount of water. For the
more soluble N-Boc-3-hydroxymethylaniline, the amount of
of the N-Boc lactam is a desired method in organic synthesis.14
water was not important once the minimum volume of water
For a N-Boc lactam, removal of Boc group was effected
needed for efficient conversion was reached. We suppose that
without hydrolysis of the lactam ring (entry 5). However,
the electronic substitution effect was masked by the solubility
several acid-liable protecting groups such as THP, TMS and
effect of the substrate, the effect which we think to be
acetal cannot survive under the present conditions.
predominantly determining the rate of the deprotection.
Cleavage of N-Boc groups on amino acid and peptidic
N-Boc protected aliphatic amines with some solubility in
substrates was also tested. For N-Boc alanine methyl ester
water reacted smoothly (the deprotection of hydrophobic
(entry 6, Table 3), both the Boc group and methyl ester were
substrates is sluggish). The deprotection of relatively insoluble
unmasked within 4 h; this phenomenon was also observed in the
N-Boc-n-butylamine needed 13 h (entry 1, Table 3), but when
deprotection of N-Boc phenylalanine methyl ester in subcritical
a hydroxyl group is present in the substrate, such as in N-Boc-
water.13 For N-Boc serine cyclohexylamide (entry 7), only
5-amino-1-pentanol, N-Boc-trans-2-hydroxyl cyclohexylamine
the Boc group was removed after 4 h. No racemization of the
and N-Boc-4-hydroxypiperidine (entries 2–4), the reaction
a-carbon on the amino acid was found in the above two cases.
proceeded faster and high yields were obtained. Deprotection
The reactivities of different types of N-Boc are not the same in
boiling water. Strong acidic reagents cannot differentiate this and
remove all Boc groups at the same time. The current condition is
neutral and if the reaction is stopped at certain point, the more
liable Boc group can be removed (Boc group on aromatic
heterocycle or lactam) prior to the less reactive Boc group
(Boc group on aliphatic amine). For Na,Nim-diBoc-histamine
and Na,Nind-diBoc-tryptamine (entries 8 and 9, Table 3), the
heteroaromatic Boc group was selectively removed, while the
Fig. 1 Deprotection of 1 mmol of N-Boc-4-chloroaniline (&) and N-Boc on the aliphatic amine remained intact.15 Also, the Boc
N-Boc-3-hydroxymethylaniline (n) in different volumes of water at moiety on the amide nitrogen can be selectively removed from
100 1C (the conversion was measured separately at 6 h and 1 h). N,N0 -bis-Boc-proline-n-butylamide (entry 10).

This journal is 
c The Royal Society of Chemistry 2009 Chem. Commun., 2009, 5144–5146 | 5145
 View Article Online

The N-Boc group could be removed under thermal deprotection of one N-Boc group in molecules with two N-Boc
conditions (180 1C).16 We found the deprotection of N-Boc- protected sites. The investigation of the role of water suggested
3-hydroxymethylaniline did not occur in refluxing 1-propanol that it should act as a dual acid/base catalyst. Accordingly,
(b.p. = 97 1C), which indicates the deprotection does not this report demonstrates the potential of this most ancient dual
automatically initiate at 100 1C. Neither did the deprotection acid/base catalyst in catalyzing organic transformations,
occur in refluxing methanol, suggesting that the polar solvent which has not been essentially explored.
effect does not account for the reactivity observed in water. To This work was financially supported by The National
obtain further insight into the reaction mechanism, the N-Boc Natural Science Foundation of China (20402007, 20772065),
deprotection was performed in D2O and monitored by 1H the 111 Project (B06005) and the 863 Project of the Ministry of
NMR spectroscopy.w We found that with the decrease of the Science and Technology of China (2006AA020502). We thank
Boc group signal, the t-butanol signal increased, suggesting Prof. Chi Zhang for helpful discussions.
Published on 31 July 2009. Downloaded by GlaxoSmithKline on 3/12/2025 10:46:02 PM.

that the N-Boc group decomposed into tert-butanol rather

than iso-butene, the product of N-Boc deprotection in strong Notes and references
acidic conditions. It is possible that the t-BuOH was from the 1 For recent reviews on organic reactions in water, see: (a) Organic
water-trapped tert-butyl cation, but considering the reaction Reactions in Water, ed. U. M. Lindström, Blackwell, Oxford, UK,
conditions are neutral, it is quite unlikely that refluxing water 2007; (b) C.-J. Li, Chem. Rev., 2005, 105, 3095; (c) C.-J. Li and
plays the role of a strong acid (such as TFA). L. Chen, Chem. Soc. Rev., 2006, 35, 68; (d) U. M. Lindström,
Chem. Rev., 2002, 102, 2751.
We noticed a recent theory on water catalysis based on 2 D. C. Rideout and R. Breslow, J. Am. Chem. Soc., 1980, 102, 7816.
molecular dynamics studies from Prof. Houk’s research group. 3 N. Akiya and P. E. Savage, Chem. Rev., 2002, 102, 2725.
They predicted that ester hydrolysis in water is catalyzed by a 4 (a) N. Shapiro and A. Vigalok, Angew. Chem., Int. Ed., 2008, 47,
2849; (b) N. Azizi and M. R. Saidi, Org. Lett., 2005, 7, 3649;
water molecule acting as a dual acid/base catalyst.17 Judging by (c) S. V. Chankeshwara and A. K. Chakraborti, Org. Lett., 2006, 8,
the facts that methyl ester (entry 6, Table 3) is also hydrolyzed in 3259; (d) G. L. Khatik, R. Kumar and A. K. Chakraborti,
boiling water, it is likely that the N-Boc cleavage in water may Org. Lett., 2006, 8, 2433.
also undergo a similar pathway (Scheme 1).18 When the water 5 (a) I. Vilotijevic and T. F. Jamison, Science, 2007, 317, 1189;
(b) C. J. Morten and T. F. Jamison, J. Am. Chem. Soc., 2009, 131,
temperature rises, the self-ionization of water is enhanced 6678.
(the log Kw value of water at 100 1C is 12, while that of 6 Z. Wang, Y.-T. Cui, Z.-B. Xu and J. Qu, J. Org. Chem., 2008, 73,
ambient water is 14), and both H+ and OH are more abundant. 2270.
The carbamate is firstly activated by protonation of the carbonyl 7 T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, John Wiley & Sons, New York, 3rd edn, 1999 and
oxygen by a hydronium ion, and water (hydroxide ion serving as references cited therein.
a base) attacks the carboxyl, providing a tetrahedral inter- 8 For other recently reported N-Boc deprotection methods, see:
mediate, the geminal diol (attempts of monitoring the formation (a) A. Kuttan, S. Nowshudin and M. N. A. Rao, Tetrahedron
Lett., 2004, 45, 2663; (b) A. Thaqi, A. McCluskey and J. L. Scott,
of this intermediate by 1H NMR and MS did not succeed),w Tetrahedron Lett., 2008, 49, 6962; (c) U. Jacquemard, V. Bénéteau,
which then expels an amide ion (pathway A) or tert-butyloxide M. Lefoix, S. Routier, J.-Y. Mérour and G. Coudert, Tetrahedron,
(pathway B) depending on which one is the better leaving group. 2004, 60, 10039; (d) J. Choy, S. Jaime-Figueroa, L. Jiang and
The N-Boc on aromatic heterocycles should be deprotected P. Wagner, Synth. Commun., 2008, 38, 3840.
9 (a) R. A. Houghten, A. Beckman and J. M. Ostresh, Int. J. Peptide
through pathway A because aromatic heterocycle anions are Protein Res., 1986, 27, 653; (b) H. R. Brinkman, Jr., J. J. Landi, Jr.,
better leaving groups. This pathway can easily explain the finding J. B. Paterson, Jr. and P. J. Stone, Synth. Commun., 1991, 21, 459;
that boiling water may also remove methoxycarbonyl on (c) H. Miel and S. Rault, Tetrahedron Lett., 1997, 38, 7865.
10 P. Strazzolini, N. Misuri and P. Polese, Tetrahedron Lett., 2005, 46,
imidazole, while aniline methyl carbamate cannot be deprotected 2075.
in boiling water because neither the methoxide nor aniline 11 (a) G. Han, M. Tamaki and V. J. Hruby, J. Peptide Res., 2001, 58,
anion is good leaving group. So, the deprotection of tert- 338; (b) D. S. Coffey, M. K. N. Hawk, S. W. Pedersen, S. J. Ghera,
butoxycarbonyl on aromatic and aliphatic amines should go P. G. Marler, P. N. Dodson and M. L. Lytle, Org. Process Res.
Dev., 2004, 8, 945.
through pathway B, which was also proposed by Coudert’s 12 (a) B. Li, R. Bemish, R. A. Buzon, C. K.-F. Chiu, S. T. Colgan,
group when using Bu4NF as an N-Boc deprotection reagent.8c W. Kissel, T. Le, K. R. Leeman, L. Newell and J. Roth, Tetrahedron
Carrying out the organic reaction in water alone is the highest Lett., 2003, 44, 8113; (b) B. Li, M. Berliner, R. Buzon, C. K.-F. Chiu,
level of green chemical process. Our N-Boc deprotection also S. T. Colgan, T. Kaneko, N. Keene, W. Kissel, T. Le, K. R. Leeman,
B. Marquez, R. Morris, L. Newell, S. Wunderwald, M. Witt,
avoids the use of mineral acid and prevents the production of J. Weaver, Z.-J. Zhang and Z.-L. Zhang, J. Org. Chem., 2006, 71,
unwanted waste salt resulting from the subsequent neutralization. 9045.
Moreover, the neutral reaction conditions enable the selective 13 G. Wang, C.-J. Li, J. Li and X.-S. Jia, Tetrahedron Lett., 2009, 50,
1438.
14 S. Calimsiz and M. A. Lipton, J. Org. Chem., 2005, 70, 6218.
15 (a) K. Ravinder, A. V. Reddy, K. C. Mahesh, M. Narasimhulu and
Y. Venkateswarlu, Synth. Commun., 2007, 37, 281; (b) T. Apelqvist
and D. Wensbo, Tetrahedron Lett., 1996, 37, 1471.
16 V. H. Rawal and M. P. Cava, Tetrahedron Lett., 1985, 26, 6141.
17 (a) H. Gunaydin and K. N. Houk, J. Am. Chem. Soc., 2008, 130,
15232; (b) X.-Y. Zhang and K. N. Houk, J. Org. Chem., 2005, 70,
9712.
18 The possible effect of CO2 dissolved in water was evaluated by
conducting the reactions in double distilled water, Milli-Qs Water
and degassed water under a nitrogen atmosphere, but no difference
Scheme 1 Proposed mechanism of N-Boc deprotection. in reactivity was found.

5146 | Chem. Commun., 2009, 5144–5146 This journal is 

c The Royal Society of Chemistry 2009