COMMUNICATION
2-Arylallyl as a new protecting group for amines, amides and alcohols{
Jose´ Barluenga,*a Francisco J. Fan˜ana´s,a Roberto Sanz,b Ce´sar Marcosb and Jose´ M. Ignaciob
Received (in Cambridge, UK) 27th September 2004, Accepted 12th November 2004
First published as an Advance Article on the web 20th December 2004
DOI: 10.1039/b414966a
The following conclusions can be inferred from Table 1.
Regardless of the electronic nature of the amines, the reactions
take place with specific removal of the 2-arylallyl group even in the
presence of allyl (Table 1, entries 2, 4, 6) or benzyl groups (Table 1,
entry 3). Also, a fluorine atom could be present in the amine
moiety (Table 1, entry 4). Interestingly, with secondary amines
such as 1e and 1g (Table 1, entries 5 and 7), the reactions
proceeded smoothly, provided that 2 equiv of t-BuLi were used in
order to first deprotonate the acidic N–H. A cyclic amine like
piperidine derivative 1h was also attempted and the reaction
proceeded without any problems (Table 1, entry 8). We next
examined the reaction of N-2-arylallyl five-membered nitrogen
hetero-aromatic compounds. As shown in entries 9–10 (Table 1),
the deprotection of N-2-phenylallylimidazole (1i) and N-2-
p-tolylallylindole (1j) occurred without difficulty to give the
corresponding N–H products in satisfactory yields.
Amines, amides and ethers containing 2-arylallyl groups are
selectively and easily deprotected with tert-butyllithium. This
transformation probably involves a carbolithiation reaction of
the styrenyl moiety followed by a b-elimination process.
Protecting groups (PGs) play an important role in multi-step
processes in synthetic organic chemistry.1 So, there is continuing
demand for more varied, robust, economical and/or chemically
differentiable PGs. Between the plethora of alternatives, the use of
allylic PGs, which are stable under both acidic and basic
conditions, for the protection of amines and alcohols will become
more common provided that more effective procedures for the
removal of the allyl-type groups become available.2,3 In general,
two strategies have been used for the removal of allylic PGs of
amines and ethers: a two-step process in which the double bond of
the allyl moiety is isomerised and single-step procedures employing
a variety of conditions.4 In this context, Bailey et al. have reported
the O-deallylation of allyl ethers by treatment of a hydrocarbon
solution of the ether with t-BuLi at 0 uC.5 However, this procedure
is not useful for the cleavage of allylamines6 and the relatively high
temperature needed prevents the use of this method with
functionalised substrates.
Due to the poor electrophilic nature of the amide group, we next
turned our attention to the possibility of using the 2-phenylallyl
group as a protecting group for amides. So, we prepared a series of
benzamides (1k–m), sulfonamides (1n–p) and pivalamides (1q–s)
from aniline, benzylamine and allylamine.
Similarly, as described for amines, amides undergo facile and
efficient removal of the 2-arylallyl group under treatment with
t-BuLi (1 equiv) in THF from 278 to 0 uC to give the corres-
ponding secondary amides (Scheme 1 and Table 1, entries 11–19).
Only in the case of amide 1k the deprotection was not essentially
quantitative, probably due to partial deprotonation of the phenyl
ring. However, addition of 2 equiv of t-BuLi solves the problem. In
all cases, the deprotection takes place selectively on the 2-arylallyl
group.
We have recently studied the reactivity of some allyl 2-lithioaryl
ethers and we have found different results depending on the allyl
moiety and the conditions of the reactions.7 Searching for new
carbolithiation processes, we found that 2-arylallyl 2-lithioaryl
ethers undergo intermolecular attack by t-BuLi instead of
intramolecular carbolithiation. This fact is supported by the
known intermolecular addition of t-BuLi to a-methylstyrenes that
takes place at 278 uC in hydrocarbon solvents in the presence of
ethers or tertiary amines as ligands affording a tertiary benzylic
carbanion.8 It is also known that styrene derivatives easily undergo
carbolithiation reactions due to the favoured formation of a
benzylic anion.9 We now report that 2-arylallyl groups are useful
PGs for amines, amides and alcohols due to their efficient single-
step removal with t-BuLi.
Moreover, we have also found that amines and amides
protected with two 2-arylallyl groups can be easily deprotected
to give the corresponding primary amines and amides. So, when
bis-(N-2-arylallyl)amines 1t, u or amides 1v, w were treated with
t-BuLi (2 equiv) under the same reaction conditions as described
above, the two 2-arylallyl groups were efficiently removed and the
Protected amines 1 were efficiently prepared by alkylation of the
corresponding primary or secondary amine or amide 3 with
a-bromomethylstyrene10 or with 2-p-tolylallyl mesylate.11 The
deprotection step was achieved by treatment of a solution of
different amines 1 in THF (ca. 1 mL per mmol of starting
substrate) with t-BuLi (1 equiv) at 278 uC and further evolution to
0 uC to afford, after hydrolysis and extractive workup, essentially
pure amines 3 along with a-neopentyl styrene derivative 5
(Scheme 1 and Table 1, entries 1–10).
{ Electronic supplementary information (ESI) available: experimental
procedures and characterization data for all compounds. See http://
Scheme 1 Deprotection of 2-arylallyl amines and amides 1 and ethers 2.
Reagents and conditions: (i) t-BuLi, THF, 278 to 0 uC for X 5 NR1 and
278 uC for X 5 O; (ii) H2O.
*barluenga@uniovi.es
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 933–935 | 933
Barluenga, Jose
