Highly efficient chemoselective N-TBS protection of anilines under exceptional mild conditions in the eco-friendly solvent 2-methyltetrahydrofuran

Article abstract of DOI:10.1039/c1gc15574a

A straightforward chemoselective protection of anilines as N-TBS derivatives is described by using a suitable deprotonation of the amine with methyllithium in the environmentally friendly and safer substitute of THF, 2-methyltetrahydrofuran, under exceptional mild reaction conditions (0 °C, 30 min). Interestingly, the protecting group maybe cleaved efficiently by simple treatment of N-TBS-anilines with silica gel in ethanol-water.

Full text of DOI:10.1039/c1gc15574a

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COMMUNICATION
Highly efficient chemoselective N-TBS protection of anilines under
exceptional mild conditions in the eco-friendly solvent
2-methyltetrahydrofuran†
Vittorio Pace,*a,b Andre´s R. Alca´ntarab and Wolfgang Holzera
Received 18th May 2011, Accepted 6th June 2011
DOI: 10.1039/c1gc15574a
A straightforward chemoselective protection of anilines
as N-TBS derivatives is described by using a suitable
deprotonation of the amine with methyllithium in the
environmentally friendly and safer substitute of THF, 2-
methyltetrahydrofuran, under exceptional mild reaction
conditions (0 ◦C, 30 min). Interestingly, the protecting
group maybe cleaved efficiently by simple treatment of N-
TBS-anilines with silica gel in ethanol–water.
and hydrolytic conditions severely limits their employment
in synthesis:2 for example, N-TMS protected anilines (useful
7,8
materials for the Pd-catalyzed aryl amination in scCO2 or for
the synthesis of O-silylcarbamates and ureas in scCO2)9 must
be mandatorily stored under nitrogen at -20 ◦C to prevent
their degradation; in addition, solvents in which reactions are
performed should be removed via distillation under nitrogen.
Furthermore, their◦preparation both by amine deprotonation
with n-BuLi at -78 C7,8 or by an organic base (triethylamine,7–9
DBU10) requires long reaction times (17–48 h) to render only
moderate yields.
The use of protecting groups (PGs) in organic synthesis is a
widely known procedure that allows modulation of the chemical
reactivity of those functional groups which may react in an
undesired manner or lead to the destruction of the compound.1
It is evident that the use of PGs lengthens a synthesis by at
least two steps (protection/deprotection) with the inevitable
reduction in yield, in atom-economy and increase in cost;2 in
this sense, the 8th Principle of Green Chemistry3 clearly states
that these protective steps should be minimized or avoided, but
in those cases in which protection is mandatory, it is absolutely
necessary to develop highly efficient protocols.
In this context, the protection of amino groups is an
interesting research field, because of its well-established use
during the preparation of many different structures possessing
biological activity.4,5 In this regard, N-silylamines6 are widely-
used protecting groups because of the absolutely mild conditions
required for their removal2 (acidic treatment, TBAF), and thus
they may be viewed as ideal amine-protecting groups, when
increasing the nucleophilicity of the nitrogen is the desired
target. However, despite this advantage compared to N-alkyl
groups (demanding harsh conditions for their removal,1 such
as hydrogenolysis, photolysis, metal reduction or transition
metal isomerization), their high sensitivity towards moisture
In view of these well-documented difficulties involving the
use of TMS anilines, the use of tert-butyldimethylsilyl (TBS)
analogues has gained widespread attention, because these
compounds possess greater stability under different operational
conditions, including the presence of organometallics.2 Anyhow,
the synthesis of N-TBS structures, under analogous conditions
(silylation with TBDMSCl in benzene,11 or its activated form
TBDMS trichloroacetate in 18-crown-612), is not safe from
an environmental perspective, due to the high toxicity of the
solvents required for such functionalization, that without any
doubt constitutes a limitation for their application to the pro-
duction of fine chemicals (e.g. drugs).13 Similarly, the use of other
approaches, such as the transition-metal catalyzed reduction of
azo compounds (TBDMSCl-Li-FeCl3) is not always effective,
because of the possible concomitant ring silylation that may
take place.14 Alternatively, a Pd dehydrogenative silylation in
refluxing toluene has also been employed;15 however, such
technique involves the use of expensive and toxic Pd catalyst
and requires long reaction times to reach completion, which is
against the 3rd, 4th and 5th Principles of Green Chemistry.3 In
summary, these protocols are not suitable for green processes
because of the use of toxic solvents and expensive catalytic
systems, and even worse leading to only moderate yields of the
desired TBS-anilines.
aDepartment of Drug and Natural Products Synthesis, Faculty of Life
Sciences, University of Vienna, Althanstrasse, 14, 1090, Vienna, Austria.
E-mail: vpace@farm.ucm.es; Fax: +43-1-4277-55623;
Tel: +43-1-4277-9556
Due to our interest in developing sustainable methodologies
for the functionalization of carbon and heteroatoms,16–20 we
recently described a protocol for the regio- and chemoselective
alkylation of imidic-type nitrogen atoms21 in the eco-friendly
solvent 2-MeTHF.22 This solvent is being increasingly used for
replacing THF in different kind of reactions, ranging from
bOrganic and Pharmaceutical Chemistry Department, Faculty of
Pharmacy, Complutense University, Madrid, Spain
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1gc15574a
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Table 1 Optimization of the reaction under different conditions. Stoichiometric ratio: aniline (1.0 equiv.)/base (1.05 equiv.)/TBDMSCl (1.05 equiv.)
Entry
Base
Solvent
Temperaturea [◦C]
Reaction time [h]
Isolated yield [%]
1
2
3
4
5
6
7
8
MeLi
MeLi
MeLi
MeLi
MeLi
MeLi
MeLi
MeLi
MeLi
MeLi
MeLi
MeLi
MeLi
MeLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
s-BuLi
s-BuLi
s-BuLi
s-BuLi
s-BuLi
t-BuLi
t-BuLi
t-BuLi
MeMgBr
DBU
THF
THF
THF
THF
Et2O
Et2O
Et2O
Et2O
MeTHF
MeTHF
MeTHF
MeTHF
Toluene
Toluene
THF
THF
Et2O
Et2O
MeTHF
MeTHF
MeTHF
MeTHF
THF
THF
Et2O
THF
THF
MeTHF
MeTHF
MeTHF
MeTHF
-78 ◦C
-50 ◦C
-20 ◦C
3
2
2
1
4
3
2
2
3
2
1
0.5
6
4
2
1
2
1
1
0.5
1.5
2
3
2
3
5
3
2
3
3
81
86
83
75
78
82
76
66
85
89
94
100
63
69
80
75
71
62
86
91
80
83
72
66
61
65
61
68
72
65
56
0
◦C
-78 ◦C
-50 ◦C
-20 ◦C
0
◦C
9
-78 ◦C
-50 ◦C
-20 ◦C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
0
◦C
-20 ◦C
◦C
-20 ◦C
◦C
-20 ◦C
◦C
-20 ◦C
◦C
-20 ◦C
0
0
0
0
0
◦C
-50 ◦C
-20 ◦C
-20 ◦C
-50 ◦C
-20 ◦C
-20 ◦C
0
◦C
25 ◦C
25 ◦C
K2CO3
3
a Referred to the addition of the base to the amine then, after the trapping with TBDMSCl temperature was allowed to reach rt.
organometallics23–27 to organocatalysis28,29 or biocatalysis.30–32
Moreover, we have used it as a suitable solvent for the highly
1,2-regioselective addition of organolithiums to a,b-unsaturated
carbonyl-like compounds, thus evidencing a series of advantages
over usual ethereal solvents, especially the ability to carry out
such additions under mild conditions.33
(80.2 ◦C) decreases the amount of solvent released in the air;
and (c) as established very recently by scientists at Merck
in a toxicological study,36 the exposure to this solvent is not
associated with genotoxicity and mutagenicity, thus supporting
its employment in the preparation of fine chemicals. Unfortu-
nately, the well-known peroxide formation in the absence of
stabilizers inherent to the use of THF is also observed when using
2-MeTHF.22
In this work, we show a suitable protocol for the N-TBS
protection of aniline derivatives based on the deprotonation to
afford the corresponding lithium amide and subsequent trapping
with TBDMSCl. (Scheme 1)
This ethereal solvent possesses a series of chemical charac-
teristics that justify its employment as a good alternative of
THF:22 (a) its low solubility in water (14 g/100 g, at 20 ◦C)
does not require the addition of solvents (mainly diethyl ether
or aromatic hydrocarbons) during the reaction work-up, so that
extraction of reaction products is improved; (b) since it forms
an azeotrope with water, the drying procedure of this solvent is
effectively achieved by a simple distillation, avoiding the use of
the Na/benzophenone technique used for THF; (c) it presents
a constitutional higher stability34 compared to THF to undergo
degradation processes in the presence of organolithiums that by
abstracting a proton from THF may initiate fragmentations35
via reverse cycloaddition [3 + 2] (the so-called a-cleavage) with
obtainment of ethylene and the lithium enolate of acetaldehyde.
On the other hand, in the case of 2-MeTHF a significant
decrease of the a-cleavage was observed in the presence of
organolithiums (t1/2 = 130 min for 2-MeTHF vs. t1/2 = 10 min
for THF).34 In addition, its environmental and safety features
contribute to improve its profile compared to THF: (a) since
its precursor (furfural) proceeds from renewable sources (waste
biomass) CO2 emissions are eliminated and thus the 7th principle
of Green Chemistry is satisfied;3 (b) its high boiling point
Scheme 1 N-TBS protection of aniline.
The results of such a transformation under different con-
ditions are shown in Table 1: as can be seen, those reactions
performed with organolithium compounds (entries 1–28) give
the highest yields compared to organomagnesium (entry 29) or
no-organometallic conditions (entries 30–31). Among the series
of organolithium compounds, regardless the solvent employed,
methyllithium affords the best results (entries 1–14) compared to
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secondary (entries 21–25) or tertiary alkyl reagents (entries 26–
28), probably because its lower steric hindrance does not affect
the proton abstraction.
nucleophilic substitution on the Si atom of TBDMSCl occurs
so rapidly that the intrinsic different features relative to anilines
bearing substituents with opposite electronic effect may not be
invoked for such transformations. Similarly, steric hindrance
on the nitrogen atom did not affect its efficient protection, as
noted by the easy introduction of the TBS group in secondary
amines (both alkyl and alkylaryl, entries 13–15). In this context,
it should be emphasized that the superior performance of this
protection protocol compared to the previous one (involving the
reduction of not readily available azo compounds by Li metal),
which in the case of compound 4n afforded only a modest 72%
yield.14
The effect of the solvent is remarkable, and its correct choice
establishes the optimization of the reaction: thus, apolar aprotic
solvents afforded lower yields and contemporaneously increased
reaction times (entries 13–14). On the contrary, polar aprotic
ones led to higher yields in shorter reaction times, MeTHF
being the best solvent for such transformation (entries 9–12,
19–22, 28). The key role played by the solvent on the course
of the reaction is reaffirmed taking into account that the use
of both diethyl ether and THF allowed good yields (although
not comparable with those achieved with MeTHF), only when
temperature was kept below -50 ◦C during the addition of MeLi
(entries 1–2, 5–6, 23, 26). On the other hand, by increasing
temperature above -50 ◦C in diethyl ether and THF (entries 3–
4, 7–8, 15–18, 24–25, 27), the yields were significantly lower, and
some unidentified impurities in crude reaction were detected by
1H-NMR. Much to our surprise, the use of MeTHF allowed
a successful N-TBS protection to be performed under the
mildest reaction conditions (0 ◦C, 30 min), thus obtaining
the desired product 2 in quantitative yield (entry 12) without
needing further purification (only a filtration on a short pad of
Celite37 was effected to remove LiCl formed during the reaction).
This peculiarity of MeTHF can be explained on the basis
of its aforementioned higher stability in strongly basic media
compared to other ethers.
These impressive results prompted us to extend this effective
protocol to substituted anilines: in fact, as shown in Table 2,
those reactions performed under the optimized reaction con-
ditions afforded exclusively the N-TBS adducts in excellent
results, without the necessity of purification after the work-
up. As can be seen, no difference was observed switching
from electron-releasing substituted anilines (entries 1–3, 7) to
electron-withdrawing ones (entries 4–6, 8–12); presumably, as
a consequence of the rapid and complete deprotonation of
the amines to render the corresponding lithium amides, the
It is worth noting the effectiveness of the protocol in the
cases of anilines bearing a substituent that could per se react
with a powerful organolithium compound: thus, it should be
highlighted that no lithium/halogen exchange takes place at
0
◦C for sensitive iodo- and bromoanilines (entries 8–9) by
using MeTHF as the solvent: in contrast, this reaction was
reported for 4-bromoaniline at 0 ◦C with n-BuLi in diethyl
ether,38 as a consequence of the transmetallation. Analogously,
no traces of any ortho-lithiation were observed in the case
of fluoroanilines ◦(entries 4, 7) as observed by treating them
in THF at -78 C.39 These two examples clearly show the
importance of the choice of the solvent in order to achieve a
highly chemoselective procedure. Moreover, it was also possible
to protect anilines in which electrophilic moieties (nitrile, ester,
ketone) were constitutively present (entries 10–12), which could
suffer the attack of methyllithium: in no case this undesired
process was observed, so therefore we can conclude that N-TBS
aniline protection performed in 2-MeTHF is perfectly applicable
to a range of aromatic amines widely substituted, in much milder
reaction conditions (0 ◦C) than those previously described.
Finally, we were pleased to observe the fundamental role
played by the solvent system upon the regioselective control
in the presence of two different acidic amino groups (an
aromatic and an aryl one): as depicted in Scheme 2, the use
of 2-MeTHF dramatically improves the aromatic N-protection,
leaving unaltered the alkyl amino group. However, this last
example shows a remarkable effect of the temperature on the
regioselectivity of the process: working at -50 ◦C in 2-MeTHF
assures an excellent ratio between the monosilylated aniline 6
and the bis-silylated one 7 (90% vs. 4%), while it decreases at
Table 2 N-TBS protection of different substituted anilines
◦
(78% vs. 14%) at 0 C. On the other hand, the use of THF or
diethyl ether affords uniquely a 1 : 1 mixture of both protected
compounds, regardless the temperature (-78 ◦C, -50 ◦C). A
possible explanation of this solvent-dependant regioselectivity
is based on the different polarity of 2-MeTHF compared to
diethyl ether and THF: in these latter solvents, the concomitant
abstraction of the two different protons (the aryl-aminic one and
the alkyl-aminic one) would afford a highly polar dianion that
upon quenching with TBDMSCl would lead to the bis-silylated
product 7. On the other hand, in 2-MeTHF, the formation of this
Entry
R
R¢
Isolated yield [%]
1
2
3
4
5
6
7
8
2,3-dimethyl
3,5-dimethoxy
3-methoxy
3,4-difluoro
3-trifluoromethyl
4-nitro
3-fluoro-4-morpholino
2-iodo
4-bromo
4-acetyl
4-ethoxycarbonyl
4-cyano
H
H
H
H
H
H
H
H
H
H
H
H
H
H
methyl
benzyl
phenyl
4a (95)
4b (97)
4c (95)
4d (91)
4e (98)
4f (94)
4g (90)
4h (97)
4j (98)
4k (90)
4l (93)
4m (98)
4n (91)
4o (88)
4p (93)
9
10
11
12
13
14
15
Scheme 2 N-TBS protection of an aniline bearing two distinct amino
groups.
H
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highly polar dianion is dramatically reduced as a consequence
of the polarity of this solvent. It should be noted that in the
case of 2-MeTHF, the time to reach completion noticeably
increases from 0.5 to 3h, as a consequence of the low temperature
maintained during all the course of the reaction.
In order to explore the compatibility of this protecting group
with the 8th Principle of Green Chemistry, which states the
need for protection-group free syntheses,3 we developed a highly
efficient removal of this same TBS group under very mild
conditions: in fact, by simply stirring at room temperature
the corresponding N-TBS-protected anilines in a suspension
of silica gel in ethanol : water (1 : 5 v/v), starting anilines were
recovered within 2 h in almost quantitative yields, without any
need to purify them (Scheme 3). As can be seen, these deprotect-
ing conditions are extremely useful for sensitive functionalities
(ketones, esters, nitriles) that are not affected by this treatment,
thus representing also a chemoselective procedure.
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To conclude, we reported a highly efficient chemoselective
preparation of highly stable N-TBS-arylamines under excep-
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described (-78 ◦C) by performing reactions in 2-MetHF, an
eco-friendly and safer substitute of THF. This protocol presents
a series of advantages, including uniformly excellent isolated
yields in short reaction times and a remarkable effect of the
solvent on the chemoselectivity and regioselectivity and of the
process. The possibility to quantitatively remove the TBS group
under mild and environmentally friendly conditions improves
the usefulness of this protecting group in organic synthesis, thus
overcoming the well-known drawback associated to the use of
protecting-group, their low atom-economy. Thus, with this work
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its eco-friendly substitute MeTHF (which, as remarked in this
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allows to design a synthetic strategy in which the protection-
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Notes and references
1 T. W. Greene and P. G. M. Wuts, Greene’s Protective Groups in Organic
Synthesis, VCH, Weinheim, 2006.
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The Royal Society of Chemistry 2011
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