Controlled dealkylation by BBr3: Efficient synthesis of para-alkoxy-phenols

Article abstract of DOI:10.1016/j.tetlet.2012.08.132

Controlled dealkylation of dialkyl-aryl-ethers by substoichiometric BBr3 has been developed as a general tool for the differentiation of the oxygen functions in hydroquinone derivatives. The reaction proceeds smoothly at rt either on linear or branched al

Full text of DOI:10.1016/j.tetlet.2012.08.132

Tetrahedron Letters 53 (2012) 6191–6194
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Controlled dealkylation by BBr3: efficient synthesis of para-alkoxy-phenols
⇑
Chiara Pasquini , Alessandra Coniglio, Mauro Bassetti
Istituto CNR di Metodologie Chimiche, Sezione Meccanismi di Reazione, and Dipartimento di Chimica, Sapienza Università di Roma, P.le A. Moro 5, 00185 Rome, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 June 2012
Revised 5 August 2012
Accepted 29 August 2012
Available online 17 September 2012
Controlled dealkylation of dialkyl-aryl-ethers by substoichiometric BBr3 has been developed as a general
tool for the differentiation of the oxygen functions in hydroquinone derivatives. The reaction proceeds
smoothly at rt either on linear or branched alkyl-ethers and provides the corresponding p-alkoxy-phenols
RO-Ar-OH in high yields. With respect to the conventional alkylation path of Ar(OH)2, this process rep-
resents a tunable and convenient route to key intermediates for conjugated materials with differentiated
side chains.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Synthetic methods
Cleavage reactions
Phenols
Iodoarenes
Hydroquinone
A key aspect of synthetic chemistry is the need for proper
molecular design to be empowered by versatile synthetic routes.
These are precious tools in the pursuit of desired continuous
improvement in the properties of target compounds, whether
pharmaceuticals1 or organic functional materials.2 In particular,
the differentiation of the oxygen functions in hydroquinone
derivatives is a synthetic challenge which regards the synthesis
of aryl-ethers with antioxidant and antitumor activities,3 as well
functional diversity in polymers consists in the copolymerization
of two distinct monomers each endowed with one of the desired
side groups.8 Such an approach suffers from clear limitations, the
most evident being different solubilities and reactivities of the
two partners during the polymerization process.
In general, despite the recent advances in currently available
synthetic procedures,9 full control over the two oxygen positions
of hydroquinone remains an open task.
as the full exploitation of functional complexity in
p
-conjugated
Herein we propose the controlled dealkylation of 1,4-Ar(RO)2
with Ar = 2,5-diiodobenzene and R – Me (1) by boron tribromide
(BBr3) as a convenient and simple strategy to manipulate at plea-
sure the hydroquinone core and obtain p-alkoxy-phenols RO-Ar-
OH (2). The alkyl chains in 1 and 2, either linear or branched, are
polymers.4
In detail, bis-alkoxy compounds I, provided with iodine atoms,
are widely employed as precursors of -conjugated materials of
p
various types.5 Structures of type I bear R groups which are mostly
alkyl chains but can also be crown ethers, sugars, or peptides, infer-
ring solubility, processability, and functional properties. In per-
spective, the access to compounds of type II endowed with
differentiated oxygen substituents is highly desirable, according
to the most recent developments in the field (See Fig. 1). In fact,
such structures would ensure functional diversity and hence
molecular architectures suitable for tuning properties and complex
functions in the polymers. The straightforward route to such struc-
tures involves the p-alkoxy-phenol derivatives III whose hydroxyl
group can be subsequently transformed (Fig. 2). Efforts to prepare
intermediates III by controlled alkylation at one of the two hydro-
xyl groups of hydroquinone have been carried out to some extent,6
in most cases resulting in low yields, so that a few examples of
complex polymeric architectures have been obtained in this
way.7 As a consequence, nowadays an alternative strategy toward
those most commonly found in p
-conjugated polymers.10
Preliminary experiments were devoted to verify the effective
limits and potentials of the alkylation strategy and were performed
by treating 1,4-dihydroxy-2,5-diiodo-benzene (3) with octylbro-
mide as the alkylating reagent (Scheme 1). The corresponding
monoalkylated product, 2,5-diiodo-4-octyloxy-phenol (2a), was
isolated in poor yields (14–28%),11 in agreement with the synthesis
of this compound already reported in the literature.7c The product
distribution of a reactive process between a difunctional substrate
and a monofunctional reactant is predictable by means of statistics,
in the hypothesis that the transformation of one function does not
affect reactivity at the second site.12
By applying such a simple statistical treatment to the investi-
gated process, a first serious limitation to the usage of the con-
trolled alkylation strategy is the maximum yield of
monoalkylated product being fixed at 50% for alkylations per-
formed in a 1:1 molar ratio between the hydroquinone substrate
and the alkylbromide (see Fig. S1 in the Supplementary data).
⇑
Corresponding author. Tel.: +39 06 49913686; fax: +39 06 490421.
E-mail address: chiara.pasquini@uniroma1.it (C. Pasquini).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.132

6192
C. Pasquini et al. / Tetrahedron Letters 53 (2012) 6191–6194
Table 1
R
R'
O
O
O
OH
Controlled dealkylation for the synthesis of p-alkoxy-phenols 2a-d by BBr3
I
I
I
R
O
OH
I
I
I
I
BBr3
I
O
O
R
I
R
R
I
I
CH2Cl2
rt
II
III
O
O
R
R
Figure 1. Bis-alkoxy precursors of
p
-conjugated polymers.
1 a-d
2 a-d
a, OR =
b, OR =
O
O
c, OR =
d, OR =
O
O
HO
O
O
O
I
I
Ar
spacer
I
I
n
Entry
1:BBr3 (mol/mol)
Time (h)
Product
Yielda (%)
O
R
O
II
R
R
1
2
3
4
5
6
7
1a:1
24
24
4
4
4
2a
2a
2a
2b
2c
2d
2d
7
1a:0.5
1a:0.7
1b: 0.7
1c: 0.7
1d: 0.7
1d: 0.7
58
81
75
80
10
75
CONJUGATED MATERIALS
III
Figure 2. Route to complex
substituents.
p-conjugated polymers with differentiated oxygen
4
1.5
a
Moreover, comparing the isolated yields of our experiments with
the calculated values, we observed a negative deviation from the
statistical distribution, suggesting that the alkylation process is
not suitable for the efficient preparation of the monoalkylated
product, feasibly because this species can rapidly react a second
time evolving to the bisalkylated compound.13 Alternatively, the
low efficiency of the process could also be due to the increase, at
lower alkylating agent concentrations, of degradation, dispropor-
tion, or side reactions of the iodinated hydroquinone substrate in
the alkaline medium.14 These observations, along with the poor re-
sults reported in the literature for the process, confirm the need for
an efficient route to access p-alkoxy-phenols from hydroquinone
derivatives.
Isolated yields.
1.0
O
OH
OH
I
I
I
BBr3
0.8
I
I
I
O
O
OH
0.6
0.4
3
4
5
Inspired by the work of Bunz and co-workers who used boron
tribromide to remove only one of the ethereal bonds of 2,5-diio-
do-1,4-dimethoxy-benzene (4),10 we envisioned BBr3 as an eligible
candidate for convenient manipulation of the hydroquinone core.
Due to its well-known efficiency in ethereal bond removal, BBr3
is widely employed for methoxy- and ethoxy-arylethers exhaus-
tive cleavage, on either mono- or di-functional substrates.15,16 In
addition, with respect to other dealkylating reagents and condi-
tions (e.g. AlBr3 or HBr/AcOH), it is compatible with the presence
of iodine atoms in the substrates.17 No examples are available to
date of controlled cleavage reactions performed at only one ethe-
real function of dialkyl-aryl-ethers with R – Me, in spite of the po-
tential relevance in organic synthesis.
As a first experiment we performed the reaction of compound
1a (R = C8H17) with BBr3 at r.t. in dichloromethane, under the con-
ditions described for the controlled dealkylation of 410 (1a 0.4 M in
dry dichloromethane, 1a:BBr3 = 1:1 mol/mol, 24 h, Table 1, entry
1). Unfortunately, the isolated yield in the corresponding mono-
dealkylated species 2a was very low (7%),18 the main product of
0.2
0.0
0
1
2
3
4
5
6
7
24
time (h)
Figure 3. Controlled dealkylation of 4 with BBr3 (0.5 equiv).
this reaction being fully demethylated 1,4-dihydroxy-2,5-diiodo-
benzene (3). When compared to the isolated yield of 68% reported
for 2,5-diiodo-4-methoxy-phenol, this result points out to a higher
reactivity of the octyl substrate. The possibility of working in
substoichiometric ratios of BBr3 versus the dialkyl-aryl-ethers
was therefore investigated by carrying out a model reaction on 4
(4:BBr3 = 1:0.5 mol/mol). The reaction progress was followed by
GCMS analysis (Fig. 3). At 6 h reaction time, the amount of
H
(CH2)7CH3
OH
O
O
O
CH3(CH2)7Br
KOH
I
I
I
+
acetone/DMSO 9:1
I
I
I
reflux
O
O
H3C(H2C)7
H3C(H2C)7
H
3
2a
1a
Scheme 1. Alkylation of 1,4-dihydroxy-2,5-diiodo-benzene (3) with octylbromide.

C. Pasquini et al. / Tetrahedron Letters 53 (2012) 6191–6194
6193
Br
Br3B CH2R
Br2B CH2R
Br2B
I
CH2R
I
O
O
O
I
O
O
O
I
I
BBr3
- RCH2Br
I
I
I
O
O
RH2C
RH2C
RH2C
RH2C
Br2B
I
H
O
O
O
I
+
+ H3BO3
I
3 H2O
I
+ 2 HBr
O
RH2C
RH2C
Scheme 2. Accepted mechanism of dealkylation by BBr3 applied to substrates 1a–d.
monodemethylated product 5 is around 50%, already far beyond
the calculated value (38%). Moreover, the reaction did not evolve
further with time, as the mixture at 24 h did not show a higher
amount of product 3. This picture suggests a fortunate accumula-
tion of the desired p-methoxy-phenol. This is to be attributed to
the fact that the reactivity of the second site in the dealkylation
process is indeed lower than that of the first one.19 As a conse-
quence, the dealkylation process under substoichiometric amounts
of BBr3 seemed a viable synthetic tool for our purposes.
The reaction performed on compound 1a (1a:BBr3 = 1:0.5 mol/
mol, 24 h, Table 1, entry 2) allowed the isolation of product 2a in
58% yield, which represents a notable improvement with respect
to the 1:1 conditions and the previously discussed alkylation pro-
cedures. Encouraged by this result and taking into account that
17% of unreacted octyl-aryl-ether 1a was recovered from the reac-
tion mixture, we explored the use of a slightly higher [BBr3] while
carefully choosing the reaction time. The treatment of 1a with BBr3
for 4 h (1a:BBr3 = 1:0.7 mol/mol, Table 1, entry 3) gave an optimal
yield of 81% in 2a.
In order to evaluate the potential of the BBr3 controlled dealky-
lation as a general methodology, the study was extended to the
substrates 1b–d featuring different alkyl chains. Compound 1b, en-
dowed with a hexadecyl group, was chosen to test the effect of
chain length on the process.20 Substrates with branched alkyl
chains were also considered, as they might result critical due to in-
creased steric hindrance near the reaction center. Reactions were
performed on 1b–d (Table 1, entries 4–6) under the conditions
which were previously optimized for the octyl substrate
(1:BBr3 = 1:0.7 mol/mol, 4 h). Excellent yields were obtained for
2b and 2c, which show that the dealkylation process is not affected
by either chain length or substitution. By contrast, the isolated
yield for compound 2d (R = 2-ethylhexyl) was only 10%, the main
product for this reaction being fully dealkylated 3. This result sug-
gested that compound 1d is extremely reactive. Therefore, a more
detailed investigation was performed by using various substoichio-
metric 1d:BBr3 molar ratios and following the reaction over time
(see Table S2 in the Supplementary data). We found that simple
shortening of the reaction time from 4 to 1.5 h resulted in the iso-
lation of compound 2d in 75% yield (1d:BBr3 = 1:0.7 mol/mol, 1.5 h,
Table 1, entry 7).
A Lewis acid-base interaction leads to an ylide adduct, which
bears a negative charge on the boron atom and a positive charge
on the oxygen; this is followed by bromide transfer to the alkyl
chain, namely to the carbon (C ) next to the positively charged
a
oxygen atom.15 As a result, an alkyl-bromide and an aryloxy-boron
derivative are obtained. The hydrolysis of such aryloxy-boron spe-
cies in the workup yields the dealkylated product. Currently, there
is no information on the nature of the bromide transfer, whether it
proceeds according to SN2- or SN1-type mechanism. Reasonably,
branched substrates could be poorly reactive, if the bromide trans-
fer is SN2-like and hence impaired by steric hindrance, or highly
reactive, if the transfer is of SN1 type, favored by the formation of
a more stable carbocation. The observed reactivities of the two
branched substrates 1c and 1d, which differ in the position of
the substitution, on the C and Cb carbons respectively, shed light
c
on this aspect. In particular, the remarkable reaction rate of 1d
may be due to the possibility of the primary carbocation from
the ylide adduct to transpose to a tertiary one thanks to the stabi-
lizing effect of the ethyl group in the b position. The observation
that the reaction rate is dependent on the nature of the alkyl chain
suggests that the C–O bond breaking is in the rate determining step
of the BBr3-assisted ether cleavage and points out to its SN1
character.
In conclusion, we have reported on a novel protocol for the dif-
ferentiation of the hydroxyl groups of hydroquinone substrates
based on the controlled dealkylation of dialkyl-aryl-ethers by
BBr3. It represents a convenient alternative to the monoalkylation
path of bis-hydroxy substrates to the corresponding p-alkoxy-phe-
nols. The proposed synthetic procedure is efficient and versatile
under mild conditions (r.t.). It can be applied to iodoarene sub-
strates with different alkyl chains by tuning stoichiometric ratios
and reaction time parameters, with isolated yields above 75% in
each case. In all cases, no side products from transhalogenation
or dehalogenation reactions were observed. We believe that many
fields of application employing functionalized hydroquinone cores
will benefit the disclosure of sophisticated molecular architectures
from such a protocol, including pharmaceuticals, functional organ-
ic polymers or liquid crystals to name a few.
Acknowledgments
The whole of our experimental data highlights that various al-
kyl substituted substrates can be successfully reacted via con-
trolled cleavage with BBr3 by careful tuning of stoichiometric
ratios (>0.5 and <1 equiv) and reaction times. In particular, dealky-
lation of alkyl-ethers (1) with 0.7 equiv of BBr3 and reaction times
ranging from 1½ up to 4 h proved to give the corresponding p-alk-
oxy-phenols (2) in high yields.
We thank Mr. Augusto Latini and Mrs. Jessica C. Ekezie for assis-
tance in the synthesis.
Supplementary data
Our results can be explained by taking into account the ac-
cepted mechanism for the BBr3 cleavage of the ethereal bond,
which is depicted in Scheme 2.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
08.132.

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10. Previously reported strategies for functional polymers ( Kim, I.-B.; Erdogan, B.;
References and notes
Wilson, J. N.; Bunz, U. H. F. Chem. Eur. J. 2004, 10, 6247–6254. and ref. 6b)
employed p-methoxy phenols to differentiate hydroxyl groups of
hydroquinone, with the drawback that the corresponding polymers
1. (a) Lu, Y.-H.; Gao, X.-Q.; Wu, M.; Zhang-Negrerie, D.; Gao, Q. Mini-Rev. Med.
Chem. 2011, 11, 611–624; (b) Lemke, E. A.; Schultz, C. Nat. Chem. Biol. 2011, 7,
480–483.
2. (a) Hawker, C. J.; Wooley, K. L. Science 2005, 309, 1200–1205; (b) Li, Y.; Guo, Q.;
Li, Z.; Pei, J.; Tian, W. Energy Environ. Sci. 2010, 3, 1427–1436.
3. (a) Lerchova, J.; Obali, M.; Pospisil, J. J. Pol. Sci., Pol. Symposia 1973, 40, 297–306;
(b) Moridani, M. Y.; Moore, M.; Bartsch, R. A.; Yang, Y.; Heibati-Sadati, S. J.
Pharm. Pharmaceut. Sci. 2005, 8, 348–360.
4. (a)Functional Organic Materials Synthesis, Strategies and Applications; Mueller, T.
J. J., Bunz, U. H. F., Eds.; Wiley-VCH: Weinheim, Germany, 2007; (b) Grimsdale,
A. C.; Chan, K. L.; Martin, R. E.; Jokisz, P. G.; Holmes, A. B. Chem. Rev. 2009, 109,
897–1091.
5. These halogenated substrates are conveniently prepared by exhaustive
alkylation of hydroquinone followed by iodination (see Supporting
Information). They can be used directly as monomers in the polymerization
process (e.g.: PPs and PPVs), or they can be further functionalized with triple
bonds (e.g.: PPEs, and PPEVs).
6. Swager and coworkers in their pioneering work on functional polymers
explored several methods to introduce polyoxaethylene and/or polymethylene
chains on the hydroquinone core, which involved subsequent protection and
deprotection steps. (a) McQuade, D. T.; Kim, J.; Swager, T. M. J. Am. Chem. Soc.
2000, 122, 5885–5886; (b) Kim, J.; McHugh, S. K.; Swager, T. M. Macromolecules
1999, 32, 1500–1507; (c) Kim, J.; Swager, T. M. Nature 2001, 411, 1030–1034;
(d) Bailey, G. C.; Swager, T. M. Macromolecules 2006, 39, 2815–2818.
7. (a) Amara, J. P.; Swager, T. M. Macromolecules 2005, 38, 9091–9094; (b) Kim, J.;
McQuade, D. T.; McHugh, S. K.; Swager, T. M. Angew. Chem., Int. Ed. 2000, 39,
3868–3871; (c) Clark, A. P-Z.; Cadby, A. J.; Shen, C. K.-F.; Rubin, Y.; Tolbert, S. H.
J. Phys. Chem. B 2006, 110, 22088–22096.
presented
a methyl-protected oxygen function. Notably, the method we
propose allows a more versatile approach to complex architectures since the
presence of chains longer than methyl in 2 can be regarded as a functional
derivatization introduced at the intermediate building block level.
11. Yields are here percentages of conversion of 3.
12. If one mole of
a difunctional species (AA) reacts with n moles of a
monofunctional one (B), in the hypothesis of a fully statistic behavior, the
reaction mixture will be composed by (n/2)2% of bis-reacted product, [1À(n/
2)]2% of starting reagent (AA) and 2[n/2(1Àn/2)]% of mono-reacted product.
13. An easy rationale for this route can be given by the different extent of activation
offered to the phenoxide nucleophile by the –OH (lower effect) and the–OR
(higher effect) group, respectively, in the first and second nucleophilic event.
14. Yuan, Y.; Thomè, I.; Kim, S. H.; Chen, D.; Beyer, A.; Bonnamour, J.; Zuidema, E.;
Chang, S.; Bolm, C. Adv. Synth. Catal. 2010, 352, 2892–2894.
15. (a) McOmie, J. F. W.; Watts, M. L.; West, D. E. Tetrahedron 1968, 24, 2289–2292;
(b) Fraser, A. D.; Clark, S. J.; Wotiz, H. J. Org. Chem. 1976, 41, 170–171; (c) Press,
J. B. Synth. Commun. 1979, 9, 407–410.
16. The cleavage by BBr3 of alkoxy groups with carbon chains of length up to C10
was reported in 1972, with limited information on the experimental
procedure. Egly, J.-M.; Pousse, A.; Brini, M. Bull. Soc. Chim. Fr. 1972, 1357–1360.
17. Under electrophilic conditions the iodo moiety can be lost because of
protodeiodination
reactions,
resulting
in
transhalogenation
or
dehalogenation side processes Waldvogel, S. R. Sci. Syn., Knowledge Updates
2010, 1, 487–498. However, we did not observe the formation of products
other than the monodealkylated and the fully dealkylated hydroquinone.
18. Dealkylation yields are given as percentages of conversion of 1.
19. Higher stabilization offered to the ylide adduct (Scheme 2) by –OR (electron-
donor) in the first cleavage event, with respect to –OBBr2 (electron-
withdrawing), in the second cleavage event, might explain this evidence.
20. Conjugated polymers featuring hexadecyl side chains exhibit peculiar
surfactant properties ( Li, S.; Qin, Y.; Shi, J.; Guo, Z.-X.; Li, Y.; Zhu, D. Chem.
Mater. 2005, 17, 130–135. and behaviour in the solid state (Ref. 6a).
8. (a) Babudri, F.; Colangiuli, D.; Di Lorenzo, P. A.; Farinola, G. M.; Omar, O. H.;
Naso, F. Chem. Commun. 2003, 132, 130–134; (b) Bajaj, A.; Miranda, O. R.;
Phillips, R.; Kim, I.-B.; Jerry, D. J.; Bunz, U. H. F.; Rotello, V. M. J. Am. Chem. Soc.
2010, 132, 1018–1022.
9. Cazorla, C.; Pfordt, E.; Duclos, M.-C.; Métay, E.; Lemaire, M. Green Chem. 2011,
13, 2482–2488. and references cited therein.