Synthesis of unsymmetrical methylenebisphenol derivatives

Article abstract of DOI:10.1055/s-0032-1318394

A simple and efficient route towards unsymmetrical methylenebisphenol derivatives is reported. This straightforward strategy avoids the use of harmful or dangerous chemicals, allowing the synthesis of highly functionalized bisphenyls with no need of protecting groups. The alkylation of the phenyl ring is selective for the para position of the hydroxyl substituent. All methylenebisphenols were obtained in a completely regioselective manner and isolated in high yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318394

762▌
LETTER
lSetyternthesis of Unsymmetrical Methylenebisphenol Derivatives
Synthesis of Unsymmetrical Methylenebisphenol Derivatives
Samuel Guieu,*a,b João Rocha,a Artur M. S. Silva*b
a
CICECO, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
E-mail: rocha@ua.pt
b
QOPNA, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
Fax +351(234)370084; E-mail: sguieu@ua.pt; E-mail: artur.silva@ua.pt
Received: 05.02.2013; Accepted: 17.02.2013
atives. Nevertheless, a few syntheses of nonsymmetrical
derivatives have been published, with important draw-
backs. Bromomethylation of phenol derivatives followed
by reaction with a substituted phenol, generated methy-
Abstract: A simple and efficient route towards unsymmetrical
methylenebisphenol derivatives is reported. This straightforward
strategy avoids the use of harmful or dangerous chemicals, allowing
the synthesis of highly functionalized bisphenyls with no need of
protecting groups. The alkylation of the phenyl ring is selective for lenebisphenyls as precursors of calixarenes.10 This meth-
the para position of the hydroxyl substituent. All methylenebisphe-
nols were obtained in a completely regioselective manner and iso-
lated in high yields.
od involves the handling of gaseous hydrobromic acid,
and the use of a large excess of nucleophile to prevent
multiple substitution reactions. Another synthetic path-
way involves the synthesis of benzophenone derivatives,
Key words: benzylation, phenols, regioselectivity, methylene-
bisphenyls
which are subsequently reduced to the corresponding
methylenebisphenyls.11 This pathway has been success-
fully used for the multistep synthesis of forkienin (3), but
its scope is limited due to the use of benzoic acid deriva-
tives as starting materials.
Methylenebisphenyl derivatives are a class of versatile
compounds with potential applications in both medicinal
and material chemistry (Figure 1). Natural derivatives
have been extracted from algae and herbs, most of which
presenting nonsymmetrical cores, such as forkienin (3).1
Methylenebisphenol bearing diverse substituents and
methylenebisanthranilic acid and esters exhibit biological
properties, such as anti-obesity2 or antioxidant activities.3
Methylenebisphenyl is a good UV absorber and, thus, it
has been used in the protection of materials against UV
degradation. Some simple derivatives have already found
their way into industrial applications, as 2,2′- and 4,4′-
methylenebisphenols which are used as antioxidants3 and
stabilizers of polymeric materials.4
Developing new tools to synthesize the methylenebisphe-
nyl core with different substituents on each phenyl rings
is then highly desirable, as it would enlarge the scope of
potential applications by giving an easy access to a wider
range of compounds.
We first tested the simple benzyl chloride or bromide in
the Friedel–Craft alkylation of activated phenyl rings.
Thus, benzyl derivatives were treated with phenol or sali-
cylaldehyde in refluxing toluene (Scheme 1). Unfortu-
nately, only starting materials were recovered. Changing
to acidic conditions using glacial acetic acid as solvent,
even with catalytic quantities of concentrated sulfuric ac-
id, and raising the temperature to 90 ºC did not give better
results. All our attempts were unsuccessful, probably due
to the low reactivity of benzyl chloride and benzyl bro-
mide. The absence of O-benzylation can be explained by
the low reactivity of phenol in neutral or acidic conditions.
OH
OH
O
O
O
O
HO
OH
HO
OH
2
O
HO
OH
R
R
X
1
3
+
Figure 1 Compounds based on the methylenebisphenol core: 1. In-
hibitor of the phosphohydrolase activity of PTP1B5 that confers resis-
tance to diet-induced obesity; 2. Hemicarcerand6 precursor; 3.
OH
OH
X = Br or Cl
R = H or CHO
Forkienin,
a
natural diarylmethane derivative1 and polymer
Scheme 1 First attempts of direct benzylation of aromatic rings
precursor7
As our goal was to explore the synthesis of substituted
methylenebisphenyls, we decided to use a benzyl chloride
derivative already bearing the desired substituents. Chlo-
ride was preferred over bromide for practical reasons: its
synthesis involves hydrochloric acid, which is easier to
handle than gaseous hydrobromic acid, and chloromethyl
derivatives are relatively air and moisture stable. Thus,
chloromethylation of salicylaldehyde and 2′-hydroxyace-
Although methylenebisphenyl derivatives are usually
synthesized using mineral acids8 or bases9 and formalde-
hyde, this method only gives access to symmetrical deriv-
SYNLETT 2013, 24, 0762–0764
Advanced online publication: 06.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318394; Art ID: ST-2013-D0120-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Unsymmetrical Methylenebisphenol Derivatives
763
tophenone was performed following published proce- single crystal X-ray diffraction study of 6 (Figure 2).16 We
dures (Scheme 2).12,13 The reaction is selective for the tried to enlarge the scope of the reaction to aniline deriva-
para position of the hydroxyl group, and the products tives, but reactions with aniline, anthranilic acid or 2′-ami-
were obtained in reasonable yields (47–51%). Similar noacetophenone as nucleophiles did not give anything
conditions applied to salicylic acid, 2′-aminoacetophe- conclusive, only mixtures of non-identified compounds.
none and anthranilic acid only gave mixtures of starting
materials with unidentified compounds.
R
R
H2CO, concd HCl
Cl
O
O
OH
OH
4 R = H
5 R = Me
Scheme 2 Synthesis of the functionalized benzyl chlorides 4 and 5
In order to test the feasibility of the reaction, 5-(chloro-
methyl)-2-hydroxybenzaldehyde (4) was reacted with
phenol in refluxing toluene, without catalyst. These con-
ditions were used for the reaction using bromomethylphe-
nol derivatives,10 with the serious drawback that a large
excess of nucleophile must be used to avoid multiple al-
kylations. In our case, using one equivalent of each reac-
tant, a mixture of starting materials, methylenebisphenyl
3 and unidentified side products were obtained. The use of
basic conditions would lead to O-benzylation, so acidic
conditions were tested. Glacial acetic acid as solvent did
not prove to be successful, even on raising the temperature
to 90 °C. Addition of a catalytic amount of concentrated
sulfuric acid instantly changed the reaction mixture from
colorless to deep red. After two hours at 90 ºC, the product
was extracted with dichloromethane and filtrated over sil-
ica gel, yielding an off-white solid (Scheme 3). 1H and 13C
NMR analysis confirmed the formation of pure fokienin
3,1 demonstrating the para-position regioselectivity of the
reaction.
Figure 2 Molecular structure of compound 6. Thermal ellipsoids are
shown at the 50% probability level, hydrogen atoms are shown with
an arbitrary radius (0.30 Å), Intramolecular hydrogen bonds are
shown in dashed lines. C, grey; O, red; H, white.
In conclusion, we have developed a simple and efficient
access to methylenebisphenyl derivatives bearing differ-
ent functional groups on each phenyl rings. This approach
avoids the handling of gaseous hydrobromic acid and the
use of nucleophile in a large excess. The products were
obtained regioselectively in good yields. Application of
this methodology to the synthesis of biologically relevant
targets and hybrid materials is currently under investiga-
tion in our laboratory.
Acknowledgment
Thanks are due to the University of Aveiro and the Portuguese
Fundação para a Ciência e a Tecnologia (FCT) for funding the Or-
ganic
Chemistry
Research
Unit
(project
PEst-
R2
R1
C/QUI/UI0062/2011), the CICECO Associate Laboratory (PEst-
C/CTM/LA0011/2011) and the Portuguese National NMR Network
(RNRMN). S.G. also thanks the FCT for a postdoctoral grant
(SFRH/BPD/70702/2010).
R1
R2
O
Cl
O
HO
HO
OH
AcOH,
OH
concd H2SO4
90 °C
3
R1 = H, R2 = H
53%
4 R1 = H
5 R1 = Me
6
7
8
6
9
R1 = H, R2 = COMe 61%
R1 = H, R2 = COOH 92%
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
m
t
iornat
R1 = Me, R2 = H
71%
R1 = Me, R2 = CHO 66%
R1 = Me, R2 = COOH 66%
References and Notes
Scheme 3 Scope of the alkylation reaction: synthesis of methy-
lenebisphenols 3 and 6–9
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was enlarged using 4 or 5 as alkylating agents, and phenol,
salicylaldehyde, salicylic acid or 2′-hydroxyacetophenone
as nucleophiles.14,15 Products 3 and 6–9 were obtained in
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 762–764

764
S. Guieu et al.
LETTER
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NMR (300.13 MHz, CDCl3, 25 °C): δ = 12.18 (s, 1 H, OH),
10.92 (s, 1 H, OH), 9.84 (s, 1 H, CHO), 7.51 (d, 4JH–H = 2.1
Hz, 1 H, aromatic CH), 7.34 (dd, 4JH–H = 2.1 Hz, 3JH–H = 8.4
Hz, 1 H, aromatic CH), 7.31 (d, 4JH–H = 2.1 Hz, 1 H, aromatic
CH), 7.28 (dd, 4JH–H = 2.1 Hz, 3JH–H = 8.4 Hz, 1 H, aromatic
CH), 6.94 (d, 3JH–H = 8.4 Hz, 1 H, aromatic CH), 6.93 (d,
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(C=O), 196.4 (C=O), 161.0 (COH), 160.1 (COH), 137.5
(CH), 137.1 (CH), 133.1 (CH), 132.2 (Cq), 130.7 (Cq), 130.4
(CH), 120.4 (Cq), 119.5 (Cq), 118.7 (CH), 117.9 (CH), 39.6
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5.36.
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(14) Typical Experimental Procedure: A catalytic amount of
concd H2SO4 (0.1 mL) was slowly added to a solution of 4
or 5 (2.0 mmol) and the desired substituted phenol (2.0
mmol) in glacial AcOH (5 mL) at r.t., and the solution was
stirred at 90 °C during 2 h. The reaction mixture was then
poured on ice (5 mL) and extracted with CH2Cl2 (3 × 10
(16) Crystal data: C16H14O4, M = 270.27, triclinic, space group
P-1, Z = 2, a = 6.9901(6) Å, b = 8.2805(7) Å, c = 11.7324 (9)
Å, α = 93.845(4)°, β = 105.754(4)°, γ = 93.618 (4)°, V =
649.77(9) Å3, yellow block with crystal size of
0.40 × 0.20 × 0.06 mm3. Of a total of 3526 reflections
collected, 2959 were independent (Rint = 0.0540). Final R1 =
0.0627 [I >2σ(I)] and wR2 = 0.1607 (all data). CCDC
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Synlett 2013, 24, 762–764
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