The N-Boc group could be removed under thermal
conditions (180 1C).16 We found the deprotection of N-Boc-
3-hydroxymethylaniline did not occur in refluxing 1-propanol
(b.p. = 97 1C), which indicates the deprotection does not
automatically initiate at 100 1C. Neither did the deprotection
occur in refluxing methanol, suggesting that the polar solvent
effect does not account for the reactivity observed in water. To
obtain further insight into the reaction mechanism, the N-Boc
deprotection was performed in D2O and monitored by 1H
NMR spectroscopy.w We found that with the decrease of the
Boc group signal, the t-butanol signal increased, suggesting
that the N-Boc group decomposed into tert-butanol rather
than iso-butene, the product of N-Boc deprotection in strong
acidic conditions. It is possible that the t-BuOH was from the
water-trapped tert-butyl cation, but considering the reaction
conditions are neutral, it is quite unlikely that refluxing water
plays the role of a strong acid (such as TFA).
deprotection of one N-Boc group in molecules with two N-Boc
protected sites. The investigation of the role of water suggested
that it should act as a dual acid/base catalyst. Accordingly,
this report demonstrates the potential of this most ancient dual
acid/base catalyst in catalyzing organic transformations,
which has not been essentially explored.
This work was financially supported by The National
Natural Science Foundation of China (20402007, 20772065),
the 111 Project (B06005) and the 863 Project of the Ministry of
Science and Technology of China (2006AA020502). We thank
Prof. Chi Zhang for helpful discussions.
Notes and references
1 For recent reviews on organic reactions in water, see: (a) Organic
Reactions in Water, ed. U. M. Lindstrom, Blackwell, Oxford, UK,
¨
2007; (b) C.-J. Li, Chem. Rev., 2005, 105, 3095; (c) C.-J. Li and
L. Chen, Chem. Soc. Rev., 2006, 35, 68; (d) U. M. Lindstrom,
Chem. Rev., 2002, 102, 2751.
¨
We noticed a recent theory on water catalysis based on
molecular dynamics studies from Prof. Houk’s research group.
They predicted that ester hydrolysis in water is catalyzed by a
water molecule acting as a dual acid/base catalyst.17 Judging by
the facts that methyl ester (entry 6, Table 3) is also hydrolyzed in
boiling water, it is likely that the N-Boc cleavage in water may
also undergo a similar pathway (Scheme 1).18 When the water
temperature rises, the self-ionization of water is enhanced
(the ꢁlog Kw value of water at 100 1C is 12, while that of
ambient water is 14), and both H+ and OHꢁ are more abundant.
The carbamate is firstly activated by protonation of the carbonyl
oxygen by a hydronium ion, and water (hydroxide ion serving as
a base) attacks the carboxyl, providing a tetrahedral inter-
mediate, the geminal diol (attempts of monitoring the formation
2 D. C. Rideout and R. Breslow, J. Am. Chem. Soc., 1980, 102, 7816.
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8 For other recently reported N-Boc deprotection methods, see:
(a) A. Kuttan, S. Nowshudin and M. N. A. Rao, Tetrahedron
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1
of this intermediate by H NMR and MS did not succeed),w
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M. Lefoix, S. Routier, J.-Y. Merour and G. Coudert, Tetrahedron,
which then expels an amide ion (pathway A) or tert-butyloxide
(pathway B) depending on which one is the better leaving group.
The N-Boc on aromatic heterocycles should be deprotected
through pathway A because aromatic heterocycle anions are
better leaving groups. This pathway can easily explain the finding
that boiling water may also remove methoxycarbonyl on
imidazole, while aniline methyl carbamate cannot be deprotected
in boiling water because neither the methoxide nor aniline
anion is good leaving group. So, the deprotection of tert-
butoxycarbonyl on aromatic and aliphatic amines should go
through pathway B, which was also proposed by Coudert’s
group when using Bu4NF as an N-Boc deprotection reagent.8c
Carrying out the organic reaction in water alone is the highest
level of green chemical process. Our N-Boc deprotection also
avoids the use of mineral acid and prevents the production of
unwanted waste salt resulting from the subsequent neutralization.
Moreover, the neutral reaction conditions enable the selective
´
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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
in reactivity was found.
Scheme 1 Proposed mechanism of N-Boc deprotection.
5146 | Chem. Commun., 2009, 5144–5146
ꢀc
This journal is The Royal Society of Chemistry 2009