Selective O-deallylation of o-allyloxyanisoles

Article abstract of DOI:10.1055/s-2008-1077962

o-Allyloxyanisoles are selectively and easily deallylated by treatment with sec- or tert-butyllithium at low temperature. The reaction is proposed to proceed through a tandem intermolecular carbolithiation-β;-elimination process, which can also be considered an S_N2′ attack of the organolithium on the allyl ether.

Full text of DOI:10.1055/s-2008-1077962

LETTER
1957
Selective O-Deallylation of o-Allyloxyanisoles
O
-Deallylation of
o
o
-Allyloxya
b
nisoles erto Sanz,*a Alberto Martínez,a César Marcos,a Francisco J. Fañanásb
a
Área de Química Orgánica, Departamento de Química, Facultad de Ciencias, Universidad de Burgos,
Pza. Misael Bañuelos s/n, 09001-Burgos, Spain
Fax +34(947)258831; E-mail: rsd@ubu.es
Instituto Universitario de Química Organometálica ‘Enrique Moles’, Universidad de Oviedo, C/Julián Clavería 8, 33006 Oviedo, Spain
b
Received 22 April 2008
cyclopropyl derivative 5a (42% isolated yield) and 4-
methyl-2-methoxyphenol (6a, 35% isolated yield,
Scheme 1). We thought that the presence of the methoxy
group at the ortho position with respect to the allyloxy
moiety could favor a competitive intermolecular carbo-
lithiation reaction of t-BuLi onto the double bond, afford-
ing a b-oxygen-substituted organolithium intermediate
such as 7a. Subsequent b-elimination, in an analogous
way as we have previously described for 2-arylallyl
ethers,3 would lead to 4-methylguaiacol (6a).
Abstract: o-Allyloxyanisoles are selectively and easily deallylated
by treatment with sec- or tert-butyllithium at low temperature. The
reaction is proposed to proceed through a tandem intermolecular
carbolithiation–b-elimination process, which can also be consid-
ered an SN2¢ attack of the organolithium on the allyl ether.
Key words: protecting groups, lithium, eliminations, phenols,
ethers
The selective introduction and removal of protecting
groups (PG) is of critical importance in many synthetic se-
quences.1 For this reason, there is a continuing demand for
more varied, robust, economical and/or chemically differ-
entiable protecting groups. Protection of the hydroxyl
functionality of phenols is required to prepare a number of
compounds. The use of allylic PG, which are stable under
both acidic and basic conditions, for the protection of al-
cohols will become more common provided that more ef-
fective procedures for the removal of the allyl groups
become available.2 In this context, we have described the
2-arylallyl group as a new PG for amines, amides, and al-
cohols.3 In 1965 Broaddus reported the cleavage of sever-
al alkyl allyl ethers upon treatment with n-BuLi in a
hydrocarbon solution at 70 °C leading to the lithium
alkoxide and 1-heptene.4 More recently, Bailey and co-
workers described that this O-deallylation of allyl ethers
could be carried out at room temperature by their treat-
ment with t-BuLi.5
E
R1 = H, Cl
or R2 = H
R2
O
Li
R1
X
1) TMEDA
–78 to 0 °C
2) E+ (H2O)
R2
4
R2
or
O
O
R1
R1
3
1: X = Br
2: X = Li
t-BuLi (2 equiv)
Et2O, –78 °C
R1 = H, Cl
and R2 = H
OH
R1
5
Br
O
1) t-BuLi (2 equiv)
Et2O, –78 °C
+
2) TMEDA,
–78 to 0 °C
3) H2O
OH
OH
OMe
6a (35%)
OMe
OMe
1a
5a (42%)
Li
O
During the last years, we have studied the intramolecular
carbolithiation of allyl o-lithioaryl ethers 2, generated by
bromine–lithium exchange from allyl o-bromophenyl
ethers 1, with different substituents at the allyl and the aryl
moieties (R1, R2 substituents).6 3-Functionalized 2,3-di-
hydrobenzofurans 4 or o-cyclopropyl phenols 5 could be
selectively obtained depending on the evolution of the 3-
t-Bu
OMe
Li
7a
Scheme 1 Competitive intramolecular carbolithiation reaction ver-
sus deallylation of allyl o-lithioaryl ether 2a
lithiomethyl-2,3-dihydrobenzofurans intermediates
3
(Scheme 1).6b,c In general, the presence of substituents at Due to the usefulness of o-methoxyphenols in organic
the R1 and/or R2 positions seems to inhibit the g-elimina- synthesis,7 and the current interest in the development of
tion process that gives rise to the cyclopropyl derivatives methods for their selective protection/deprotection,8 we
5. However, we have recently observed that the treatment decided to initiate a systematic study in order to check if
of allyl 2-bromo-6-methoxy-4-methylphenyl ether (1a) the allyl group removal was selective due to the ortho-di-
with t-BuLi in Et2O and TMEDA at low temperature, and recting effect of the methoxy group. Therefore, the reac-
further evolution to 0 °C, gives rise to a ca. 1:1 mixture of tivity of allyl phenyl ethers 8a and 8b,9 which differ on the
presence of a methoxy group, was studied with different
organolithium reagents. We found that reactions of 8a and
8b under several conditions afforded a variable mixture of
the corresponding deallylated products 6, the deuteriated
SYNLETT 2008, No. 13, pp 1957–1960
Advanced online publication: 15.07.2008
DOI: 10.1055/s-2008-1077962; Art ID: D12908ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8

1958
R. Sanz et al.
LETTER
derivatives 9 and 10, and, in some cases, starting materials Taking advantage of our finding with ether 1a, reactions
8 (Scheme 2 and Table 1). Formation of deallylated phe- were initially carried out with Et2O as solvent varying the
nols 6 could be explained, as described above, by intermo- nature of the organolithium reagent. As shown from
lecular carbolithiation reaction of the organolithium Table 1 (entries 1–3), allyl phenyl ether 8a was only par-
reagent and subsequent b-elimination, which could also tially deallylated with s-BuLi or t-BuLi at low tempera-
be formulated as a concerted process through 11 ture using 10 mL of solvent per mmol of ether.11 On the
(Scheme 2). Generation of deuteriated enol ether deriva- other hand, under the same reaction conditions, allyl o-
tives 9 and a-deuteriated ether derivatives 10 could be ex- methoxyphenyl ether 8b was almost completely deallylat-
plained through competitive deprotonation of the starting ed with these reagents (Table 1, entries 5–7). Not surpris-
ether 8 by the organolithium reagent that would lead to the ingly, worse results were obtained for both ethers 8a,b
allyllithium intermediate 12.10 Deuteration at both posi- when THF was used as solvent (Table 1, entries 4 and 8),
tions of the allyl moiety accounts for the formation of 9 being the deprotonation pathway favored over the carbo-
and 10 (Scheme 2).
lithiation one.12 From this study we can conclude that the
allyl removal from allyl phenyl ethers, by their reaction
with s-BuLi or t-BuLi, is easier when the starting material
contains a methoxy group in ortho position with respect to
the allyloxy moiety. The coordination of the methoxy
group with the organolithium reagent, which favors its ap-
proach to the double bond, probably facilitates the O-deal-
lylation reaction.
O
Li
G
R
11
D
OH
O
1) RLi, –78 °C
solvent
O
O
D
G
G
G
G
+
+
Thus, we decided to explore the generality of the reaction
by using different allyl o-methoxyphenyl ethers 8b–j un-
der the best reaction conditions previously established,
that is, treatment of the ether with a slight excess of s-
BuLi or t-BuLi in Et2O at –78 °C for 2 hours (Scheme 3
and Table 2).
2) MeOD
–78 to 20 °C
8a: G = H
8b: G = OMe
6a: G = H
9a: G = H
10a: G = H
6b: G = OMe 9b: G = OMe 10b: G = OMe
O
Li
G
R3
R3
12
R2
R1
O
R2
R1
OH
1) R4Li, Et2O, –78 °C
2) MeOH, –78 to 20 °C
R4Li = s-BuLi or t-BuLi
Scheme 2 Pathways for the reactions of ethers 8a,b with organoli-
thium reagents. Formation of phenols 6a,b and deuteriated ethers
9a,b and 10a,b
OMe
OMe
8b–j
6b–j
R3
Table 1 Reactivity of 8a,b with Organolithium Reagentsa
R2
R1
O
Entry Starting ether RLi
Solvent Ratio of 6/9 + 10b,c
Li
O
R4
d
1
2
3
4
5
6
7
8
8a
8a
8a
8a
8b
8b
8b
8b
n-BuLi
s-BuLi
t-BuLi
t-BuLi
n-BuLi
s-BuLi
t-BuLi
t-BuLi
Et2O
Et2O
Et2O
THF
Et2O
Et2O
Et2O
THF
–
Me
11
1:2
Scheme 3 Selective deallylation reactions of ethers 8b–j
1.5:1
0:1
Allyl ethers 8b,c derived from o-methoxyphenols or
naphthols are cleanly cleaved to give the corresponding
phenol derivatives in excellent yield (Table 2, entries 1
and 2). Interestingly, ethers 8d,e, bearing fluoro or chloro
substituents at the benzenoid moiety in a m-relationship
with the methoxy group were successfully deallylated as
shown in Table 2 (entries 3 and 4). However, bromo-sub-
stituted ether 8f mainly underwent bromine–lithium ex-
change (Table 2, entry 5). It is also significant that the
allyl group may be selectively cleaved in the presence of
other typical protecting groups for ethers like benzyloxy
or silyloxy groups (Table 2, entries 6 and 7). Also, an allyl
group on the aromatic ring, like those occurring in ethers
8i,j, were unaffected under the reaction conditions
(Table 2, entries 8 and 9).
1:2.5e
10:1
15:1
1:7
a All reactions were carried out by treatment of 8 (1 mmol) in the cor-
responding solvent (10 mL), with the organolithium reagent (1.1
mmol) for 2 h at –78 °C.
b Determined by 1H NMR analysis of the crude.
c In all the cases the isolated overall yield was higher than 85%.
d Starting ether 8a was recovered without deuterium incorporation.
e Starting ether 8b, without deuterium incorporation, was the major
product of the reaction mixture.
Considering the selectivity found for the allyl-group re-
moval from o-allyloxy anisole derivatives 8b–j, we decid-
Synlett 2008, No. 13, 1957–1960 © Thieme Stuttgart · New York

LETTER
O-Deallylation of o-Allyloxyanisoles
1959
Table 2 Selective Deallylation Reactions of Ethers 8b–ja
groups.14 Gratifyingly, treatment of 8m with s-BuLi or t-
BuLi selectively afforded 4-allyloxy-2-methoxyphenol
(6m) in high yield (Scheme 4), showing the high selectiv-
ity of this protecting-group removal and providing a use-
ful method for the easy preparation of 6m from 2-
methoxyhydroquinone. Remarkably, no partial O-deallyl-
ation of the other allyloxy group in none of these bisallyl-
oxy derivatives 8k–m was observed under these reaction
conditions.
Entry Ether R1
R2 R3
R4
Product Yield
(%)b
1
2
3
4
5
6
7
8
9
8b
8c
8d
8e
8f
Me
H
H
H
H
H
H
H
H
H
t-Bu 6b
s-Bu 6c
s-Bu 6d
88
95
86
90
–
-(CH)4-
F
H
H
H
H
H
H
H
Cl
t-Bu 6e
Having successfully developed an efficient selective O-
deallylation of o-allyloxyanisoles 8, we finally checked
the possibility of applying this methodology to the corre-
sponding o-thioanisole derivatives. However, reaction of
allyl o-methoxyphenyl thioether 1315 with t-BuLi (or s-
BuLi) in Et2O mainly afforded a mixture of deuteriated
thioethers 14 and 15, due to a predominant acid–base pro-
cess (Scheme 5).16 Furthermore, we were also interested
in studying the reactivity of a related substrate possessing
the methoxy group far away from the allyloxy moiety, as
it is the case of allyl o-methoxymethylphenyl ether 16. Its
reaction with t-BuLi led to the almost exclusive abstrac-
tion of the allylic proton a to the oxygen atom and, there-
fore, to the formation of a mixture of deuteriated ether 17
and enolether 18 after deuteriolysis (Scheme 5).17
c
Br
s-Bu
–
8g
8h
8i
CH2OBn
CH2OTBDMS
Allyl
s-Bu 6g
s-Bu 6h
t-Bu 6i
80
87
92
80
8j
H
Allyl s-Bu 6j
a All reactions were carried out by treatment of 8 (1 mmol, 10 mL of
Et2O) with s-BuLi or t-BuLi (1.1 mmol) for 2 h at –78 °C.
b Isolated yield.
c A bromine–lithium exchange occurred and o-methoxyphenol was
mainly obtained.
ed to test if this methodology could be applied to the
selective allyl-group removal from allyl o-methoxyphenyl
ethers bearing other allyloxy unit in their structure. In fact,
allyloxymethyl ether 8k could be selectively deprotected
as we only observed reaction at the allyloxy group in
ortho position with respect to the methoxy group
(Scheme 4). In the same way, ether 8l also underwent se-
lective O-deallylation reaction (Scheme 4). Finally, the 2-
methoxyhydroquinone derivative 8m that possesses the
two hydroxyl groups protected with allyl groups was test-
ed. To the best of our knowledge, direct selective
monoalkylation of methoxyhydroquinone is not possi-
ble,13 and O-monoalkylated methoxyhydroquinone deriv-
atives are usually prepared from Baeyer–Villiger
oxidation of vanillin, that precludes the use of allyl
D
S
1) t-BuLi, Et2O
–78 °C
S
S
OMe
OMe
+
+
D
OMe
2) MeOD
–78 to 20 °C
14
15
13
(5:1) (71%)
D
1) t-BuLi, Et2O
–78 °C
OMe
O
OMe
O
OMe
O
+
+
D
2) MeOD
–78 to 20 °C
17
18
16
(1:2) (75%)
Scheme 5 Attempts of allyl removal from related substrates 13 and
16
O
OH
1) t-BuLi, Et2O
–78 °C
O
O
OMe
OMe
2) MeOH
–78 to 20 °C
In summary, we have shown that the presence of an ortho-
methoxy group with respect to an allyloxy moiety allows
the selective removal of the allyl group affording the cor-
responding guaiacol derivatives in high yields. The effi-
cient two-step synthesis of unknown 4-allyloxyguaiacol
(6m) from 2-methoxyhydroquinone, shows the high se-
lectivity and potential applications of this methodology.
8k
6k (81%)
O
O
1) s-BuLi, Et2O
–78 °C
O
OH
2) MeOH
–78 to 20 °C
6l (65%)
OMe
OMe
8l
OH
OH
OH
O
O
OMe
General Procedure for the Selective Removal of the Allyl Group
from Allyl o-Methoxyphenyl Ethers 8 – Synthesis of 4-Allyloxy-
2-methoxyphenol (6m)
1) t-BuLi, Et2O
–78 °C
OMe
OMe
CH2=CHCH2Br
K2CO3, Me2CO
2) MeOH
–78 to 20 °C
To a solution of 1,4-bis-allyloxy-2-methoxy-benzene (8m, 0.220 g,
1 mmol) in dry Et2O (10 mL), t-BuLi (0.73 mL of a 1.5 M solution
in pentane, 1.1 mmol), or alternatively s-BuLi (0.77 mL of a 1.3 M
solution in cyclohexane–hexane, 1.1 mmol), was added under nitro-
gen at –78 °C. The reaction was stirred at this temperature for 2 h,
and then was quenched by the addition of MeOH (excess) at this
O
8m (92%)
6m (85%)
Scheme 4 Selective deallylation of bisallyloxy anisole derivatives
8k–m; preparation of 4-allyloxyguaiacol (6m)
Synlett 2008, No. 13, 1957–1960 © Thieme Stuttgart · New York

1960
R. Sanz et al.
LETTER
(6) (a) Barluenga, J.; Fañanás, F. J.; Sanz, R.; Marcos, C.;
temperature. The mixture was allowed to reach r.t., aq HCl (1 M, 10
mL) was added, and the mixture was extracted with Et2O (3 × 10
mL). The combined organic layers were dried with anhyd Na2SO4
and the solvent was removed under reduced pressure. The residue
was purified by silica gel column chromatography (hexane–EtOAc,
5:1) to afford 6m (0.153 g, 85%) as a pale brown oil. Rf = 0.17 (hex-
Trabada, M. Org. Lett. 2002, 4, 1587. (b) Barluenga, J.;
Fañanás, F. J.; Sanz, R.; Marcos, C. Org. Lett. 2002, 4,
2225. (c) Barluenga, J.; Fañanás, F. J.; Sanz, R.; Marcos, C.
Chem. Eur. J. 2005, 11, 5397.
(7) For a recent example, see: Hsu, D.-S.; Hsu, P.-Y.; Lee,
Y.-C.; Liao, C.-C. J. Org. Chem. 2008, 73, 2554.
(8) For the selective removal of the isopropyl group from aryl
isopropyl ethers bearing methoxy groups, see: (a) Banwell,
M. G.; Flynn, B. L.; Stewart, S. G. J. Org. Chem. 1998, 63,
9139. For the selective removal of the cyclopentyl group
from 4-(cyclopentyloxy)-3-methoxy benzaldehyde, see:
(b) Gajera, J. M.; Gharat, L. A.; Farande, A. V. Synth.
Commun. 2007, 37, 2877.
1
ane–EtOAc, 5:1). H NMR (400 MHz, CDCl3): d = 3.83 (s, 3 H),
4.46 (dt, J = 5.3, 1.4 Hz, 2 H), 5.26 (dq, J = 10.4, 1.4 Hz, 1 H), 5.42–
5.35 (m, 2 H, including OH), 6.09–5.98 (m, 1 H), 6.38 (dd, J = 8.7,
2.7 Hz, 1 H), 6.51 (d, J = 2.7 Hz, 1 H), 6.80 (d, J = 8.7 Hz, 1 H). 13
C
NMR (100.6 MHz, CDCl3): d = 55.7 (CH3), 69.4 (CH2), 100.1
(CH), 105.2 (CH), 113.9 (CH), 117.5 (CH2), 133.4 (CH), 139.7 (C),
146.9 (C), 152.3 (C). LRMS (EI): m/z (%) = 180 (44) [M+], 139
(100). HRMS: m/z calcd for C10H12O3: 180.0786; found: 180.0784.
(9) The synthesis of the starting allylated ethers 8 was carried
out under standard Williamson conditions (treatment of the
corresponding phenol with allyl bromide and K2CO3 as base
in refluxing acetone).
(10) [1,2] and [1,4] Wittig rearrangements of allyloxy
organometallics such as 12 are observed at higher
temperatures. See ref. 6a, and for a review dealing with
Wittig rearrangements: Schöllkopf, U. Angew. Chem., Int.
Ed. Engl. 1970, 9, 763.
Acknowledgment
We gratefully thank Junta de Castilla y León (BU012A06) and Mi-
nisterio de Educación y Ciencia (MEC) and FEDER (CTQ2007-
61436/BQU) for financial support. A.M. thanks MEC for a FPU
predoctoral fellowship. Many thanks are due to Dr. F. Rodríguez
(Universidad de Oviedo) for helpful comments.
(11) Ether 8a could be completely deallylated under the
conditions reported by Bailey (t-BuLi, pentane, –78 °C to
r.t., see ref. 5). We have also checked that 8a could also be
deallylated by treatment with t-BuLi in Et2O at –78 °C by
using 1 mL of solvent per mmol of 8a.
(12) This result could be due to the fact that t-BuLi is dimeric in
Et2O and monomeric in THF. See: (a) Bauer, W.;
Winchester, W. R.; Schleyer, P.v.R. Organometallics 1987,
6, 2371. (b) Bates, T. F.; Clarke, M. T.; Thomas, R. D.
J. Am. Chem. Soc. 1988, 110, 5109.
References and Notes
(1) Kocienski, P. J. Protective Groups, 3rd ed.; Thieme:
Stuttgart, 2003.
(2) For O-deallylation procedures, see: (a) Ito, H.; Taguchi, T.;
Hanzawa, Y. J. Org. Chem. 1993, 58, 774. (b) Guibe, F.
Tetrahedron 1997, 53, 13509. (c) Taniguchi, T.;
Ogasawara, K. Angew. Chem. Int. Ed. 1998, 37, 1136.
(d) Thomas, R. M.; Mohan, G. H.; Iyengar, D. S.
Tetrahedron Lett. 1997, 38, 4721. (e) Thomas, R. M.;
Reddy, G. S.; Iyengar, D. S. Tetrahedron Lett. 1999, 40,
7293. (f) Tsukamoto, H.; Kondo, Y. Synlett 2003, 1061.
(3) Barluenga, J.; Fañanás, F. J.; Sanz, R.; Marcos, C.; Ignacio,
J. M. Chem. Commun. 2005, 933.
(13) See, for instance: Wu, J.; Beal, J. L.; Doskotch, R. W. J. Org.
Chem. 1980, 45, 208.
(14) See, for instance: Rosa, C. P.; Kienzler, M. A.; Olson, B. S.;
Liang, G.; Trauner, D. Tetrahedron 2007, 63, 6529.
(15) Thioether 13 was prepared from 2-methoxythiophenol by its
treatment with NaOH and allyl bromide in water.
(16) A small amount of the expected 2-methoxythiophenol could
be detected in the crude product of the reaction.
(17) Although treatment of 16 with s-BuLi also afforded a
mixture of 17 and 18 as main products, in this case 2-
methoxymethyl phenol was also obtained as a minor
product.
(4) Broaddus, C. D. J. Org. Chem. 1965, 30, 4131.
(5) Bailey, W. F.; England, M. D.; Mealy, M. J.;
Thongsornkleeb, C.; Teng, L. Org. Lett. 2002, 4, 489.
Synlett 2008, No. 13, 1957–1960 © Thieme Stuttgart · New York