Ferric chloride-promoted efficient and facile BOC protection of amines

Article abstract of DOI:10.1080/00397911003642641

Amines are efficiently protected as their tertiary butyloxycarbonyl (BOC) derivatives under mild reaction condition when reacted with (BOC)₂O in the presence of FeCl₃. The present method is applicable to a variety of amines including aliphatic, aromatic, and hetero aromatic amines.

Full text of DOI:10.1080/00397911003642641

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Ferric Chloride–Promoted Efficient and
Facile BOC Protection of Amines
Tasneem a & K. C. Rajanna b
a Department of Chemistry, Nawab Shah Alam Khan Centre for P.G.
Studies and Research, Mallepally, Hyderabad, India
b Department of Chemistry, Osmania University, Hyderabad, India
Version of record first published: 31 Jan 2011.
To cite this article: Tasneem & K. C. Rajanna (2011): Ferric Chloride–Promoted Efficient and
Facile BOC Protection of Amines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 41:5, 715-719
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Synthetic Communications1, 41: 715–719, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003642641
FERRIC CHLORIDE–PROMOTED EFFICIENT AND FACILE
BOC PROTECTION OF AMINES
Tasneem1 and K. C. Rajanna2
1Department of Chemistry, Nawab Shah Alam Khan Centre for P.G. Studies
and Research, Mallepally, Hyderabad, India
2Department of Chemistry, Osmania University, Hyderabad, India
Abstract Amines are efficiently protected as their tertiary butyloxycarbonyl (BOC) deriva-
tives under mild reaction condition when reacted with (BOC)2O in the presence of FeCl3.
The present method is applicable to a variety of amines including aliphatic, aromatic, and
hetero aromatic amines.
Keywords Amine protection; FeCl3; Lewis acid; N-BOC
INTRODUCTION
The development of a mild and selective method for the protection and
deprotection of functional groups continues to be important in synthetic organic
chemistry.[1] The tertiary butyloxycarbonyl (BOC) group has been used extensively
for the protection of amines because of its ease of formation, stability under basic
conditions, and ease of removal.[2] BOC-protected aryl amines are important inter-
mediates in organic synthesis and have been used for the direct lithiation of aromatic
rings[3] and preparation of unsymmetrical urea.[4]
Aryl amines are particularly difficult to protect with the BOC group because of
the reduced nucleophillicity of the nitrogen atom when compared to primary or
secondary aliphatic amines. Thus, their synthesis often requires the Curtius
rearrangement of aryl azides followed by trapping with t-butyl alcohol.[5] However,
recent reports have demonstrated that the reaction of aryl amines with 1 equivalent
of di-tertiary butyldicarbonate (BOC)2O requires extended reaction times,[6] elevated
Received October 25, 2009.
Address correspondence to Tasneem, Department of Chemistry, Nawab Shah Alam Khan Centre
for P.G. Studies and Research, Mallepally, Hyderabad 500 0001, India. E-mail: tasneems_a@yahoo.co.in
715

716
TASNEEM AND K. C. RAJANNA
temperature,[7] or the addition of a base [i.e., dimethylaminopyridine (DMAP),[8]
aqueous NaOH,[9] pyridine,[10] and NaHMDS.[11] On the other hand, methods using
a Lewis acid catalyst to perform BOC protection are rare. Only a few studies on such
reaction have been reported (i.e., yttrium-zirconium-based strong Lewis acid used
for BOC protection). However, the preparation of this catalyst is quite elaborate.[12]
Recently, LiClO4,[13] Zn(ClO4)2,[14] ZrCl4,[15] sulfamic acids,[16] and indium(III)
halides[17] have been reported for BOC protection of amines.
In the past few years, ferric chloride has emerged as an oxidizing agent. It
oxidizes a wide array of functionalities, such as certain phenols to quinines, dithiols
to disulfides, and 2-hydroxycyclohexanone to 1,2-cyclohexanedione. Phenolic
ethylamines and N-acetyloxyamides can be cyclized to indoles[18] and oxindoles
respectively.[19] Dimerization of aryl lithium yields intermediates for cyclophane[20]
and perylenequinone[21] synthesis. Inter- and intramolecular[22] ketone enolates can
be converted to 1,4-diketones, and lithium salts of allylic sulfones afford 1,6-disulfones.
Although FeCl3 has been extensively used as a Lewis acid in various organic
transformations, it has not been used for the protection of amines as their BOC
derivatives. This prompted us to use FeCl3 for the BOC protection of amines.
Herewith, we report that FeCl3 promotes the selective BOC protection of amines
under mild conditions with excellent yield.
RESULTS AND DISCUSSION
When a variety of amines were treated with (BOC)2O in the presence of FeCl3,
the corresponding N-BOC-protected amines were obtained in excellent yields. The
substrates were examined in our studies, and the results obtained are summarized
in Table 1. Thus the present procedure to introduce the BOC protecting group is quite
general as a wide range of amines underwent reaction smoothly with (BOC)2O. In the
cases of 2-chloroaniline (entry h) and 3-nitroaniline (entry i), the yields are poor
(20%). It contributes to the low reactivity of these deactivated anilines. It is note-
worthy that the reaction is chemoselective in the case of 2-amino phenol (entry g)
as the amine; being more nucleophilic than alcohol, it underwent reaction faster, giv-
ing corresponding N-BOC-protected product in good yield. Moreover, it is important
to highlight that no side reaction, such as biscarbonylation or the formation of isocya-
nate or urea, was observed. Surprisingly, when this reaction condition was applied to
protect 6-aminoquinoline, 8-aminoquinoline, 2-ethyl aniline, and 4-isoproyl aniline,
product formation did not occur; only a white complex was obtained, which may
be due to complexation with FeCl3. The BOC protection of 2-aminophenol (entry
g) and b-alanine (entry j) was carried out in acetonitrile=water (1:1) as they are not
soluble in dichloromethane. The reaction with 0.25 equivalent or 0.5 equivalent of
FeCl3 was very slow. Therefore, the reaction was carried out using a 1:1:1 molar ratio.
The reaction was carried out easily at room temperature (rt) (Scheme 1).
To check the effect of other Lewis acids in the present reaction condition, the
BOC protection of aniline, 4-aminopyridine, and 3-nitroaniline was carried out using
AlCl3 (20% mol) as Lewis acid. Although AlCl3 promotes the BOC protection of
amines, comparatively it takes a longer reaction time to complete the reaction (i.e.,
aniline takes 3 h to afford the corresponding BOC-protected aniline, 4-aminopyridine
gave the required product in 5 h, and 3-nitroaniline gave only traces of BOC-protected

BOC PROTECTION OF AMINES
717
Table 1. FeCl3 promoted BOC protection of amines
Entry
a
Substrate
Producta
Reaction condition=Time
Yieldb (%)
94
CH2Cl2, 15 min, rt
CH2Cl2, 15 min, rt
b
c
92
92
94
CH2Cl2, 15 min, rt
CH2Cl2, 20 min, rt
d
e
f
CH2Cl2, 20 min, rt
CH2Cl2, 20 min, rt
94
94
g
ACN=H2O (1:1), 20 min, rt
92
20
h
CH2Cl2, 24 h, rt
i
j
CH2Cl2, 5 h, rt
20
90
ACN=H2O (1:1), 1 h, rt
aProducts were characterized by comparison with spectroscopic data.
bIsolated yields.
Scheme 1. R ¼ aliphatic and aromatic compounds.

718
TASNEEM AND K. C. RAJANNA
compound after 24 h). The plausible mechanism can be visualized as the activation of
carbonyl group of BOC anhydride by the attack of FeCl3 followed by nucleophillic
attack of amine to the BOC anhydride. This facilitates the extrusion of t-butanol
and carbon dioxide as leaving entities, eventually leading to the formation of
N-BOC-protected amines.
CONCLUSION
In summary, FeCl3 promotes the protection of amines as BOC derivatives. The
present method works with various aromatic and aliphatic amines under mild
conditions. Moreover, this protocol appears to be competitive and in some cases
superior to previously reported procedures that work under basic conditions. The
results show the completion of the reaction in 20–30 min with good to excellent yield
as compared to the various methods reported in literature. The present method also
offers advantages such as environmental safety, readily available, inexpensive
laboratory benchtop reagents, and mild reaction conditions with simple workup.
Thus, it is believed that the present method is a major step forward in the protection
of amines.
EXPERIMENTAL
General Procedure for BOC Protection of Amines
(BOC)2O (1 mmol) and FeCl3 (1 mmol) were added to a solution of amine
(1 mmol) in dichloromethane (10 ml), and the reaction mixture was stirred for the
time specified in Table 1. After completion of the reaction as indicated by thin-layer
chromatography (TLC), the solvent was removed under reduced pressure, and the
reaction mixture was diluted with water and extracted with ethyl acetate. The
organic layer was washed with water and brine. It was then separated, dried over
Na2SO4, and evaporated under reduced pressure. The residue obtained was purified
by column chromatography on silica gel by using 10% EtOAc–hexane as eluent to
give the pure product.
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