Unexpected copper mediated benzyl O→O migration during an Ullmann ether coupling

Article abstract of DOI:10.1016/j.tetlet.2013.11.089

The synthesis of a highly functionalized phenolic diaryl ether 5,5′-oxybis(4-hydroxy-3-methoxybenzaldehyde) (1) potentially interesting as a new scaffold for drug design, has been carried out using Ullmann coupling conditions. An unusual benzyl migration in o-benzyloxyphenol moiety occurred during this reaction leading to an unexpected compound identified as 4-(benzyloxy)-3-(2-(benzyloxy)-4-formyl-6-methoxyphenoxy)-5-methoxy benzaldehyde (7). A rationale for this migration process is proposed.

Full text of DOI:10.1016/j.tetlet.2013.11.089

Tetrahedron Letters 55 (2014) 528–530
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unexpected copper mediated benzyl O?O migration during
an Ullmann ether coupling
⇑
⇑
Corinne Vanucci-Bacqué, Slim Chaabouni, Isabelle Fabing, Florence Bedos-Belval , Michel Baltas
Université Paul Sabatier, Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique, UMR-CNRS 5068, 118 route de Narbonne, 31062 Toulouse cedex 9, France
a r t i c l e i n f o
a b s t r a c t
The synthesis of a highly functionalized phenolic diaryl ether 5,50-oxybis(4-hydroxy-3-methoxybenzal-
dehyde) (1) potentially interesting as a new scaffold for drug design, has been carried out using Ullmann
coupling conditions. An unusual benzyl migration in o-benzyloxyphenol moiety occurred during this
reaction leading to an unexpected compound identified as 4-(benzyloxy)-3-(2-(benzyloxy)-4-formyl-6-
methoxyphenoxy)-5-methoxy benzaldehyde (7). A rationale for this migration process is proposed.
Ó 2013 Elsevier Ltd. All rights reserved.
Article history:
Received 28 July 2013
Revised 12 November 2013
Accepted 19 November 2013
Available online 28 November 2013
Keywords:
Diaryl ether
Ullmann condensation
Benzyl migration
Phenol dimers
The diaryl ether moiety is found in a number of natural or
synthetic products as well as in biologically important molecules
that exhibit pharmacologically outstanding activities, such as
anticancer, antifungal, antibiotic and antithrombotic.1 In a previ-
ous report concerning our search of new antiatherogenic molecules
originating from natural sources, we highlighted the antioxidant
and cytoprotective properties of functionalized diaryl phenols
derived from vanillin.2 In continuation of our work, we focused
on the preparation of diaryl ether scaffold 1 (Scheme 1). We report
herein our efforts to synthesize this target compound and an
unexpected benzylic migration observed during the key Ullmann
condensation step.
Various methods have been developed for the preparation of dia-
ryl ethers.3 The most popular ones are the palladium-catalyzed4 and
the copper-mediated5 coupling of a phenol and an aryl halide. How-
ever, synthetic access to highly functionalized symmetric diaryl
ether is rather scarce in the literature. The synthesis of symmetric
diaryl ether 1 was initially envisioned by starting from O-benzyl
3-hydroxyvanillin (2) and O-benzyl 3-bromovanillin (3) (Scheme 1).
Regioselective benzylation of commercial 3-hydroxyvanillin (4)
(BnCl, NaHCO3, NaI, DMF, 40 °C, 16 h)7 afforded 4-benzyloxy-
Scheme 1. Retrosynthesis of 5,50-oxybis(4-hydroxy-3-methoxybenzaldehyde) (1).
focusing on copper-mediated conditions. The first attempts were
carried out under the modified catalytic Ullmann conditions.
Unfortunately, screening of various reaction conditions (Cu(I) salt,
base, ligand, solvent, temperature, reaction time)8 did not afford
the targeted diaryl ether 6. Only starting materials were recovered
along with O-benzylvanillin resulting from the debromination of
compound 3. Noteworthy, no such copper-catalyzed coupling
reactions have ever been reported with such polysubstituted
partners. To investigate the behavior of the two reactants indepen-
dently, we first applied the usual Buchwald9 coupling conditions
(CuI (20 mol %), picolinic acid (40 mol %), K3PO4 (2 equiv), DMSO,
100 °C, 24 h) to phenol 2 with various poorly functionalized aryl
halides: iodobenzene, 4-bromobenzaldehyde and 4-iodo-1-trifluo-
romethylbenzene. The resulting diaryl ethers were obtained in
moderate to high yields (respectively, 30%, 50% and 99% yield).
On the other hand, coupling assay of the polyfunctionalized aryl
bromide 3 with the phenol (C6H5OH) under the same conditions
did not afford the expected diaryl ether. Starting materials were
3-hydroxy-5-methoxybenzaldehyde
2 in 86% yield. O-Benzyl-
3-bromovanillin 3 was readily prepared in 97% yield following a
reported protocol6 starting from commercially available
3-bromovanillin (5) (Scheme 2). With these starting materials in
hand, we next turned our attention to the coupling reaction
recovered in
a mixture with debrominated O-benzylvanillin,
⇑
Corresponding authors. Tel.: +33 (0)5 61 55 68 00.
E-mail addresses: bedos@chimie.ups-tlse.fr (F. Bedos-Belval), baltas@chimie.
suggesting that 3 is not reactive for coupling process under
copper-catalyzed conditions.
ups-tlse.fr (M. Baltas).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.089

C. Vanucci-Bacqué et al. / Tetrahedron Letters 55 (2014) 528–530
529
Scheme 2. Reagent conditions: (i) PhCH2Cl, NaHCO3, NaI, DMF, 40 °C, 16 h (86%); (ii) PhCH2Br, K2CO3, DMF, 80 °C, 4 h (97%); (iii) Cu(0), DMF, reflux, 2.5 h.
These unsuccessful results prompted us to examine the
Ullmann condensation using super-stoichiometric amount of
copper metal (5 equiv) as recently reported by Abe and
co-workers10 for polysubstituted phenols and aryl bromides. The
coupling reaction between compounds 2 and 3 was conducted in
the presence of 3 equiv of bromide derivative in refluxing DMF
for 2.5 h (Scheme 2). To our delight, careful HPLC separation
allowed us to obtain symmetric diaryl ether 6 for the first time
under these conditions albeit in poor yield (8%). Surprisingly, an
isomer of 6 was isolated as the major coupling product (15% yield).
The structure of this compound was assumed to be the
non-symmetric diaryl ether 7 based on spectroscopic analyses.
We reasoned that compound 7 was likely the result of the
coupling of phenol 8 with 3 (Scheme 3). To confirm this hypothesis,
we prepared 8 in three steps according to a reported procedure.11
As expected, reaction of 3 and 8 under Abe’s conditions (Cu(0),
DMF, reflux) afforded the non-symetric diaryl ether 7 in a 35%
modest yield, along with O-benzylvanillin. This result allowed us
to secure the structure of compound 7 obtained during the
coupling of phenol 2 with aryl bromide 3.
Noteworthy, all Ullmann condensations undertaken led to
O-benzylvanillin formation due to the efficient reductive dehalo-
genation side reaction12 of aryl bromide 3. This reaction rapidly
consumes this starting material, so that improved yields could
not be obtained by increasing the excess of 3 (4 equiv) nor the
reaction time.
This result also confirmed that phenol 8 was formed during the
Ullmann condensation step. This formation may stem from a 4,3
O?O migration of the benzyl group of phenol 2. To the best of
our knowledge, no such migration has ever been reported. Only
rearrangements of benzyl aryl ethers into diarylmethanes under
thermal or acidic conditions have been described.13
was first treated with CuBr2 (0.5 equiv) in refluxing DMF for
2.5 h, resulting in no transformation. Then, 2 was allowed to react
in the presence of CuBr under the same reaction conditions, lead-
ing to 25% conversion into 8, suggesting that Cu(I) rather than
Cu(II) plays a major role in this benzyl migration (Table 1, entry
1). Moreover, high temperature is required as no conversion was
observed in DMF at room temperature.
In additional experiments, the reaction conditions were
screened (Table 1). The same conversion rate (25%) was obtained
when using 0.5 or 0.1 equiv (Table 1, entries 1 and 2) of CuBr indi-
cating that a catalytic process is implicated. The conversion rate
grows up to 40% with increasing reaction time to 7.5 h (Table 1, en-
try 3). Noteworthy, longer reaction times (15 or 22 h) or switching
DMF to DMSO as the solvent led to major degradation by-product
formation. Other phenol derivatives were studied to ascertain the
influence of different substituents. To investigate the effect of the
5-OMe group, 4-benzyloxy-3-hydroxybenzaldehyde (9) was
prepared7 and reacted with CuBr (0.5 equiv) under the same exper-
imental conditions as above. Only 10% conversion of the starting
material into the expected migrated product was observed by 1H
NMR (Table 1, entry 4). Concerning the influence of the carbonyl
moiety, 2-benzyloxy-3-methoxyphenol15 (10) was initially
submitted to the same reaction conditions, and was recovered
unchanged (Table 1, entry 5). Moreover, when 4-benzyloxy-3-
hydroxy-5-methoxybenzonitrile (11), readily prepared16 in one
pot starting from aldehyde 2 was used, the corresponding migra-
tion product17 with 20% conversion rate (Table 1, entry 6) was
obtained. These results highlighted the key role of the carbonyl
or other electron-withdrawing groups on the benzyl migration
and the cooperative effect of the 5-OMe substituent. Furthermore,
the reaction was carried out on benzaldehyde derivative 12
obtained by regioselective benzylation of commercially available
2,5-dihydroxybenzaldehyde.18 No migration of the benzyl group
from the O-ortho to the O-meta position was detected indicating
that this process requires vicinal reacting centers (Table 1, entry
7). Finally, we checked that reverse benzyl migration reaction of
phenol 8 into 2 did not occur as anticipated according to the sole
coupling product 7 obtained when 8 was reacted with aryl
bromide 3 (Scheme 3).
To further understand this intriguing benzyl migration, we
undertook complementary experimental investigations. All the
following results rely on 1H NMR data.
Firstly, we pointed out the key role of the benzyl group in this
rearrangement process: when 3-hydroxy-4,5-dimethoxybenzalde-
hyde14 was used as the reactant, no methyl migration product was
observed.
When phenol 2 was heated in the presence of Cu(0) in DMF, the
rearrangement did not occur (2 was fully recovered) suggesting
that other copper intermediates (copper bromides) are formed
during the coupling reaction in the presence of aryl bromide 3a.
The current knowledge of the mechanism of the Ullmann conden-
sation that implicates Cu(I) or Cu(II) species5 led us to wonder
about the nature of the oxidative state of copper involved in this
rearrangement. To shed some light on this question, phenol 2
With these results in hand, there is no obvious mechanism that
would account for such reorganization. Nevertheless, we postulate
a plausible mechanism for this reaction. The absence of detection
of o-quinone or catechol products and the required vicinity of
the reaction centers suggest that an intramolecular process is
implicated. Indeed, as depicted in Scheme 4, copper bromide
would activate compound 2 to generate a copper(I) complex A.19
At this stage, the O-benzyl bond is weakened by the synergic effect
of the para electron-withdrawing substituent and the copper(I),
allowing the nucleophilic attack of the ortho hydroxy group leading
to intermediate B. Subsequent proton exchange would afford
product 8 and regenerate CuBr.
Finally, keeping in mind our initial aim to synthesize the pheno-
lic diaryl ether 1, debenzylation of protected derivative 6 was effi-
ciently carried out using BCl3 (6 equiv) in the presence of
20
pentamethylbenzene (6 equiv) in CH2Cl2 in 90% yield.
Scheme 3. Direct synthesis of non-symmetric diaryl ether 7.

530
C. Vanucci-Bacqué et al. / Tetrahedron Letters 55 (2014) 528–530
Table 1
Benzyl migration rate of O-benzyloxyphenol derivatives
R1
R1
CuBr, DMF
Reflux
R2
R3
R2
R3
OH
R4
R4
OH
Entry
Reactant
R1
R2
R3
R4
Equiv CuBr
Reaction time (h)
Conversion rate⁄ (%)
1
2
3
4
5
6
7
2
2
2
CHO
CHO
CHO
CHO
H
H
H
H
H
H
H
OBn
OMe
OBn
OBn
OBn
OBn
OBn
OBn
H
0.5
0.1
0.5
0.5
0.5
0.5
0.5
2.5
2.5
7.5
2.5
2.5
2.5
2.5
25
25
40
10
0
OMe
OMe
H
OMe
OMe
H
9
10
11
12
CN
CHO
20
0
*
As estimated by 1H NMR
Scheme 4. Proposed mechanism for the benzyl migration process.
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In summary, we have shown that reaction of 4-benzyloxy-3-hy-
droxy-5-methoxybenzaldehyde 2 with O-benzyl-bromovanilline 3
in the presence of Cu(0) in DMF furnishes the rearranged diaryle-
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activated intermediate as mentioned in the proposed mechanism.
The phenolic diaryl ether target 1 was obtained in global poor yield
pushing us to envision an alternative strategy under development
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2013.11.089.
8
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