Valorisation of Cashew Nut Shell Liquid Phenolics in the Synthesis of UV Absorbers

Article abstract of DOI:10.1002/ejoc.201900743

With current concerns over the use of fossil resources for chemical synthesis of functional molecules and the effect of current UV absorbers in sunscreens have on the ecosystem, we describe a xylochemical synthesis of different classes of aromatic UV absorbers utilizing cashew nut shell liquid as a non-edible bio-renewable carbon source. Hydroxybenzophenones, xanthones, triazines, and flavones were synthesized starting from cardanol or anacardic acid. Several compounds exhibited favorable UVA and UVB absorption characteristics.

Full text of DOI:10.1002/ejoc.201900743

A Journal of
Accepted Article
Title: Valorisation of Cashew Nut Shell Liquid Phenolics in the
Synthesis of UV Absorbers
Authors: Kennedy Ngwira, Jonas Kühlborn, Quintino Mgani, Charles
de Koning, and Till Opatz
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900743
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900743
Supported by

10.1002/ejoc.201900743
European Journal of Organic Chemistry
Valorisation of Cashew Nut Shell Liquid Phenolics in the
Synthesis of UV Absorbers
Kennedy J. Ngwira, [a] Jonas Kühlborn, [b] Quintino A. Mgani, [c] Charles B. de Koning, [a]* and Till Opatz[b]*
Abstract: With current concerns over the use of fossil resources for
chemical synthesis of functional molecules and the effect of current
UV absorbers in sunscreens have on the ecosystem, we describe a
xylochemical synthesis of different classes of aromatic UV absorbers
utilising cashew nut shell liquid as a non-edible bio-renewable
carbon source. Hydroxybenzophenones, xanthones, triazines and
flavones were synthesized starting from cardanol or anacardic acid.
Several compounds exhibited favorable UVA and UVB absorption
characteristics.
approach for which the term “xylochemistry” was coined.6a
As a second example, a great deal of attention has been given
to Cashew Nut Shell Liquid (CNSL) as a non-edible biomass-
derived chemical feedstock. CNSL is
a product of little
commercial value but with high technological potential due to
abundant, readily extractable phenolic constituents as well as
biological activities of the constituents, including antimicrobial,
anti-inflammatory, antitumor, antioxidant and insecticidal
properties.6b However, the use of CNSL biomass for chemical
synthesis requires its valorisation for the production of novel
platform chemicals.2 CNSL through its main phenolic
constituents, namely anacardic acid, cardol and cardanol, fit this
profile. These phenolic platform compounds can readily be
isolated from CNSL through extraction. Their transformation into
useful functional molecules and materials is an active area of
research, including the use of a number recently developed
catalytic approaches.6c
Introduction
Biomass is defined as a renewable resource derived from the
agricultural or forestry sector. It has been estimated to provide
about 25% of global energy requirements.1 In recent times there
has been significant interest in developing strategies for the use
of non-edible biomass as a sustainable alternative to petroleum
and petroleum based products.2 This paradigm shift is
necessitated by diminishing petroleum reserves, the rise of oil
prices, the negative effects of petroleum on the environment and
the advantages of using fast-growing non-edible biomass as a
sustainable resource.3 The advantages of using biomass rather
than petroleum to manufacture chemicals include opportunities
for reducing the environmental burden, net CO2 neutral
production and possibly even economic benefits.4 While bio-
The protection of polymers, coatings, and even human skin
against solar UV radiation is an important task. The damaging
effects of UV rays are responsible for the discoloration of dyes
and pigments, weathering, yellowing of plastics, loss of gloss
and mechanical properties. Sunburnt skin, premature aging and
even the development of potentially lethal melanomas must be
prevented in livestock as well as in the human population.7 To
mitigate UV damage, both organic and inorganic compounds
have been used as UV filters. Ideal organic UV filters display a
high UV absorption in the region ranging from 315–400 nm
(UVA) and 280–315 nm (UVB).8 One important family of UV-
absorber molecules are derived from phenols of which whose
hydroxyl group plays an important role in the dissipation of the
absorbed energy. These UV absorbers feature intramolecular
O–H···O bridges. Prominent examples include salicylates, 2-
derived chemical products
a
priori have no better
biodegradability than their petrochemical antetypes, the redesign
of the chemical compounds and the way they are produced can
provide opportunities for a change to the better in this respect.
Although biomass and other renewable resources are primarily
utilized for energy production, their use as starting materials in
the pharmaceutical, chemical and cosmetic industries has been
demonstrated.5 This has led to a number of research activities
within the academic sector.6 For example, the groups of Opatz
and Arduengo have developed synthetic procedures in which all
carbon atoms are derived from wood-based chemicals, an
hydroxybenzophenones,
2,2ʹ-dihydroxybenzophenones,
3-
hydroxyflavones and xanthones. Also important are those that
form intramolecular O–H···N bridges, such as 2-(2-
hydroxyphenyl)benzotriazoles and 2-(2-hydroxyphenyl)-1,3,5-
triazines and 2-(5-aryl-1,3,4-oxadiazol-2-yl)- phenols.9 These
compounds also exhibit outstanding photo-stabilities and small
quantum yields of photo-decomposition in the range of 10-7 to
10-6.10 They dissipate UV radiation through an efficient
radiationless deactivation process by means of rapid
tautomerization via the excited-state intramolecular proton
transfer (ESIPT) mechanism.11 Some of the mentioned types of
absorbers have been used in human sunscreens. For example,
2-hydroxy-4-methoxybenzophenone, also known as oxobenzone
is a common ingredient that has also been added to plastics to
limit UV degradation.12 Apart from their petrochemical origin, a
major drawback of current UV protection agents is their negative
[a]
Dr K J Ngwira, Prof C B de Koning, Molecular Sciences Institute,
School of Chemistry, University of the Witwatersrand, P/Bag X3,
Wits 2050, Johannesburg, South Africa. E-mail:
Charles.deKoning@wits.ac.za
URL: https://www.wits.ac.za/science/schools/chemistry/staff/prof-
charles-de-koning/
[b]
[c]
Mr J Kühlborn, Prof Dr T Opatz, Institute of Organic Chemistry,
Johannes Gutenberg University, Duesbergweg 10–14, 55128
Mainz, Germany. E-mail: Opatz@uni-mainz.de
URL: https://ak-opatz.chemie.uni-mainz.de/prof-dr-till-opatz/
Dr Q A Mgani, Chemistry Department, University of Dar es Salaam,
P.O. Box 35061, Dar es Salaam, Tanzania.
effect on aquatic ecosystems13 associated with
a poor
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900743
European Journal of Organic Chemistry
biodegradability. As a result, there is growing attention from
regulatory bodies and hence stricter regulations are being
enforced.14 To this end, there is a need to develop new, efficient,
less toxic, and eco-friendly UV filters, ideally in a sustainable
fashion. More importantly, a broad spectrum of UV filters
capable of absorbing both UVA and UVB are required.
phenols. Exposure of 4a to AlCl3 afforded the second desired
compound 5, while the third hydrogen-bonded 2,2’-
dihydroxybenzophenones 6 was obtained by treatment of 4b
with BCl3.
One further benzophenone possessing two hydrogen bonded
phenols was synthesized utilising the CNSL derived cardanol 7
as a starting material. Esterification of 7 with benzoyl chloride in
the green solvent 2-Me-THF gave the ester 8 in excellent yields.
Here, we report the synthesis of a number of important classes
of organic UV filters using “xylochemical” strategies, and by
employing CNSL-derived phenolics as key starting materials.
Finally, the synthesized compounds were evaluated as potential
UV absorbers using UV spectroscopy.
This was followed by
a
microwave-promoted Fries
rearrangement of in the presence of AlCl3 to furnish
8
benzophenone 9. A ruthenium-mediated C‒H oxygenation of 9
gave 2,2ʹ-dihydroxybenzophenone 10 in 61% yield (Scheme
2).16
Results and Discussion
Scheme 2. Reagents and conditions: (a) PhCOCl, DMAP, Et3N, 2-Me-THF, 0°
C to rt, 2 h, 95%; (b) AlCl3, PhCl, Mw (160 °C, 150 W, 30 min), 78%; (c) [Ru(p-
cymene)Cl2]2 (2.5 mol %), K2S2O8, TFA/TFAA, 80 °C, 14 h, 72%.
Scheme 1. Reagents and conditions: (a) n-BuLi, THF, -78 °C to rt, 2-24 h, 3a-
c 10-47%; (b) Pd/C, H2, MeOH, EtOAc, rt, 24 h, 4a-c, 84-99%; (c) For 4a: AlCl3,
pyridine, PhMe, reflux, 4 d, 58%; For 4b: BCl3, CH2Cl2, -78 °C to rt, 4 d, 69%.
Initially, CNSL-derived cardanol and anacardic acid were used
as starting materials, and a range of classes of potential UV
absorbers were prepared in short synthetic sequences.
Hydrogen-bonding of the phenolic hydroxyl group to a C=X (X=
O or N)-moiety of the chromophore was a central design feature
to ensure an efficient ESIPT. As
a
starting point,
benzophenones and xanthones with neighbouring hydrogen-
bonded hydroxyl substituents were synthesized.
Scheme 3. Reagents and conditions: (a) CH3COCl, DMAP, Et3N, 2-Me-THF,
0 °C to rt, 2 h, 96%; (b) AlCl3, PhCl, Mw (160 °C, 150 W, 30 min), quant; (c) (i)
NaOH, PhCHO, MeOH, 3 h, 67% (ii) 0.5N aq. NaOH, H2O2, rt, 4 h, 88%.
Synthesis of hydroxybenzophenones 4c, 5 and 6
Synthesis of 3-hydroxyflavone 13b
Another class of potential UV absorbers possessing a hydroxyl
group hydrogen bonded to a carbonyl are the 3-hydroxyflavones.
Utilizing CNSL derived cardanol
accomplished in a similar manner to Scheme 2 by initial O-
acetylation of cardanol 7 to furnish 11. Again, a microwave
assisted Fries rearrangement of 11 under AlCl3 catalysis
afforded the 1-(2-hydroxyphenyl)ethanone 12 in an excellent
overall yield. Aldol condensation of 12 with benzaldehyde,
Starting from CNSL-derived anacardic acid, the benzyl protected
methyl ester 1 was prepared using known procedures (see
experimental). Halogen/lithium exchange on substituted
bromobenzenes 2a-c accessible from xylochemicals15a-c
followed by the addition of the ester 1 (as shown in Scheme 1)
led to the formation of protected benzophenones 3a-c in
moderate to poor yields. Hydrogenolytic O-debenzylation of 3a-c
7
the first step was
furnished
benzophenones
4a-c
in
excellent
yields.
Benzophenone 4c contained the desired two hydrogen-bonded
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10.1002/ejoc.201900743
European Journal of Organic Chemistry
afforded the chalcone intermediate 13a. In-situ oxidation of 13a
with hydrogen peroxide, the desired 3-hydroxyflavone 13b, was
obtained in a 67% yield over the two steps (Scheme 3). Since
acetic acid and benzaldehyde are xylochemicals, i. e. they can
be derived from wood and related types of biomass, the entire
molecular skeleton of 13a and 13b is derived from renewable
carbon.
to afford benzyl alcohol 19 (Scheme 5). Exposure of the alcohol
19 to benzamidine under Cu(OAc)2 catalysis afforded the 2-(4,6-
diphenyl-1,3,5-triazin-2-yl)phenol 20 in 62% yield.
Synthesis of 1, 8-dihydroxyxanthone 14
The next class of compounds investigated as potential UV-
absorbers were hydrogen-bonded xanthones. As an example,
the 1,8-dihydroxyxanthone 14 was synthesized from cardanol.
F
O
OH
F
O
OH
Scheme 5. Reagents and conditions: (a) SnCl4, Bu3N, (CH2O)n, PhMe, 100 °C,
O
(b)
(a)
18 h, 77%; (b) LiAlH4, THF, rt,
6 h, 81%; Benzamidine hydrochloride,
Cu(OAc)2, Na2CO3, PhMe, 110 °C, 12 h, 62%.
14
14
15
7
16
Since the second organic building block, benzamidine can be
prepared from benzoic acid or benzaldehyde this strategy is
compatible with xylochemical principles. In order to assess the
effect of increasing the number of intramolecular hydrogen
bonded N atoms on the UV absorbance, 2,2',2''-(1,3,5-triazine-
2,4,6-triyl)triphenol 21 was also prepared. It was envisioned that
this could be obtained from the formylated cardanol 18 (Scheme
6). Reacting aldehyde 18 with hydroxylamine hydrochloride and
FeCl3 in DMF under reflux conditions yielded nitrile 22 which
could be trimerized through microwave irradiation to furnish the
fully symmetrical s-triazine 21 in 73% yield.
14
O
O
OH
(c)
(d)
O
O
14
14
17
OH
O
OH
(e)
O
14
14
Scheme 4. Reagents and conditions: (a) 2-Flourobenzoyl chloride, DMAP,
Et3N, 2-Me-THF, 0 °C to rt, 2 h, quant.; (b) AlCl3, PhCl, Mw (160 °C, 150 W),
30 min, 84%; (c) K2CO3, Me2CO, reflux, 6 h, 86%; (d) [Ru(p-cymene)Cl2]2 (2.5
mol %), K2S2O8, TFA/TFAA, 80 °C, 12 h, 71%; (e) [Ru(p-cymene)Cl2]2 (2.5
mol %), K2S2O8, TFA/TFAA, 80 °C, 12 h, 64%.
Using the methodology previously described, the Fries
rearrangement of 15 provided benzophenone 16 (Scheme 4) in
84% over two steps. Refluxing of 16 with potassium carbonate in
acetone yielded the xanthone 17. A ruthenium catalysed C–H
oxygenation of 16 furnished the desired 1,8-dihydroxyxathone
14 over two steps in 54% yield.16 Since 2-fluorobenzoic acid can
be derived from the natural product anthranilic acid,15d the entire
molecular skeleton of 14 is formally derivable through
xylochemistry.
Scheme 6. Reagents and conditions: (a) NH2OH·HCl, FeCl3, DMF, reflux, 18
h, 80%; (b) Mw: 220 °C, 200 W, 1.5 h, neat, 73%.
Synthesis of oxadiazole 23
A final compound which should also display N···H hydrogen
bonding and hence be a possible UV filter was the oxadiazole
23. Exposure of the aldehyde 18 to the hydrazide of veratric acid
(24, synthesized from veratraldehyde by known methods17)
afforded 25. Oxidative oxadiazole ring formation yielded 23 in an
overall yield of 39% over two steps (Scheme 7). Since
veratraldehyde is derived from xylochemicals, the entire carbon
skeleton of 23 can be constructed from biomass without
petrochemical input.
Synthesis of triazines 20 and 21
Nitrogen containing compounds such as 2-hydroxytriazines have
also been reported to be suitable UV absorbers owing to
intramolecular O–H···N hydrogen bonding. For our purposes, 2-
(4,6-diphenyl-1,3,5-triazin-2-yl)phenol 20 was synthesized from
CNSL derived cardanol in three steps. The SnCl4-mediated
formylation of cardanol 7 gave benzaldehyde 18 in excellent
yield, which was followed by LiAlH4-reduction of the aldehyde 18
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10.1002/ejoc.201900743
European Journal of Organic Chemistry
31,659 L mol-1 cm-1 at 279 nm and 282 nm for mono- and
dihydroxy- benzophenones respectively as shown in Figure 2.
100000
10000
OH
O
OH
O
OH
R
R
10
Scheme 7. Reagents and conditions: ((a) Et2O, MeOH, rt, 18 h, 82%; (b)
PhI(OAc)2, Me2CO, rt, 5 h, 47%.
9
1000
100
ε = 47,909 (279 nm)
ε = 15,878 (340 nm)
ε = 31,659 (282 nm)
ε = 14,590 (355 nm)
Analysis of UV profiles of the synthesized compounds
The synthesized compounds 4c, 5, 6, 9, 10, 13a, 13b, 14, 20, 21,
and 23, were analysed for their UV absorbances and their molar
absorptivity coefficients (ε) were determined. Analysis of UV
absorbance was done in order to establish whether the
compounds exhibited ε values in the UV-B and UV-A regions of
the UV spectra commensurate with those for commercial UV
absorbers.
250
270
290
310
λ/nm
330
350
370
Figure 2: UV absorbance profiles of benzophenones 9 and 10 derived from
cardanol.
3-Hydroxyflavone 13b displayed an excellent absorption profile
in the UVA region with experimental ε values of 39,870 L mol-1
cm-1 at 314 nm and 44,979 L mol-1 cm-1 at 345 nm as shown in
Figure 3. The intermediate phenylpropenone 13a showed an
experimental ε value of 20,403 L mol-1 cm-1 at 314 nm and 10,
250 L mol-1 cm-1 at 347 nm. Dihydroxy xanthone 14 exhibited a
good UV absorption profile with ε value of 23,765 L mol-1 cm-1 at
254 nm (Figure 3). However, UVC is less relevant at sea level
due to the filtering function of the atmospheric ozone layer.
The 2,2ʹ-dihydroxybenzophenone 4c synthesized from anacardic
acid showed reasonable UV absorbance in the UVA region with
the experimental ε values of 10,538 L mol-1 cm-1 at 335 nm and
a high absorbance of 36,366 L mol-1 cm-1 at 261 nm albeit
outside both UVA and UVB region (Figure 1). The
benzophenone 5 exhibited ε values of 8,785 L mol-1 cm-1 at 374
nm and 18,439 L mol-1 cm-1 at 265 nm. Benzophenone 6
showed excellent UVA absorbance with ε values 25,014 L mol-1
cm-1 at 358 nm and 34,096 L mol-1 cm-1 at 287 nm.
OH
O
OH
OH
O
OH
OH
O
OH
100000
10000
1000
100000
10000
R
R
R
OMe
OMe
OMe
4c
5
6
OH
O
O
OH
O
OH
OH
1000
100
R
R
R
O
O
13a
14
13b
ε = 20,403 (314 nm)
ε = 10,250 (347 nm)
ε = 23,765 (278 nm)
ε = 6,469 (323 nm)
ε = 39,870 (314 nm)
ε = 44,979 (345 nm)
250
280
310
340
370
250
270
290
310
330
350
370
λ/nm
λ/nm
Figure 3: UV profiles of chalcone 13a, flavone 13b and xanthone 14.
Figure 1: UV absorbance profiles of benzophenones 4c, 5 and 6 derived from
anacardic acid.
The s-triazine 21 showed the best UV absorbance in both the
UVA and UVB region with experimental ε value of 21,452 L mol-1
cm-1 at 300 nm and 12,515 L mol-1 cm-1 at 364 nm. These
results suggest 21 to be classified as a broad spectrum UV
filtering agent as it showed excellent results in both relevant UV
regions. The 2-(4,6-diphenyl-1,3,5-triazin-2-yl)phenol 20 on the
In comparison, the benzophenones 918a and 10 derived from
cardanol showed excellent absorption at the edge of the UVB
region with experimental ε values of 47,909 L mol-1 cm-1 and
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10.1002/ejoc.201900743
European Journal of Organic Chemistry
other hand exhibited excellent UV absorbance at the beginning Conclusions
of the UVB region with an ε value of 29,252 L mol-1 cm-1 at 278
nm (Figure 4).
100000
Representatives of various classes of UV absorbers have been
synthesized using CNSL as
a non-edible, bio-renewable
chemical feedstock. In addition, wherever possible, the
principles of xylochemistry were utilized. As the properties of the
synthesized materials were to be investigated first, the employed
reaction conditions need further improvement so as to minimize
their environmental burden. For example, dichloromethane was
employed as an inert solvent for the bromination using NBS as
well as for the dealkylation reactions since a commercial solution
of BCl3 in CH2Cl2 was used in the latter. However, CH2Cl2 is
considered to be a less desirable solvent.20 Moreover, reactions
involving organolithium reagents should be replaced by Grignard
procedures when upscaling is to be considered. Another
attractive point for further investigations will be the role of
biocatalysis in facilitating several of the presented
transformations (e.g. the esterification reactions).21
10000
1000
ε = 21,452 (300 nm)
ε = 12,515 (364 nm)
ε = 29,252 (278 nm)
ε = 5,966 (354 nm)
100
250
270
290
310
λ /nm
330
350
370
Figure 4: UV profiles of triazines 20 and 21.
The oxadiazole 23 displayed moderate UV absorbance in the
UVA region with experimental ε values of 6,367 L mol-1 cm-1 at
326 nm and 3,373 L mol-1 cm-1at 293 nm as shown in Figure 5.
The UV profiles of the synthesized aromatic hydrogen-bonded
compounds (especially s-triazine 21) and their lipophilic or
amphiphilic character are promising for potential use as
sunscreens, in paints, coatings or polymers and other related
applications.22 However, in particular if these compounds are to
be used as sunscreen investigations into their toxicity to human
health still need to be conducted.
10000
1000
Experimental Section
For general experimental procedures please consult the supplementary
information.
ε = 6,367 (326 nm)
ε = 3,373 (293 nm)
100
250
270
290
310
330
350
370
Methyl 2-benzyloxy-6-pentadecylbenzoate 1
λ/nm
A suspension of calcium anacardate (20.0 g, ca. 52.3 mmol) in aqueous
HCl (10%, 100 mL) was stirred for 3 h at rt. Afterwards, EtOAc (100 mL)
was added and the mixture was stirred for 1 h and the layers were
separated. The aqueous layer was extracted with EtOAc (2 x 50 mL) and
the combined organic extracts were washed with brine (30 mL). After
Figure 5: UV profile of oxadiazole 23.
Commercially available sunscreen protectants oxybenzone (OB),
2-ethylhexyl 4-methoxycinnamate (OMC) and avobenzone) were
reported to show experimental molar absorption coefficients of
15,150 L mol-1 cm-1 at 287 nm, 39,470 L mol-1 cm-1 at 356 nm
and 31,670 L mol-1 cm-1 at 310 nm, respectively.19a Most of our
hydrogen-bonded aromatic compounds display similar UV
absorptions and the molecules may well possess emulsion-
stabilizing properties due to their amphiphilic nature. However,
newly proposed US-FDA legislation for sunscreens entails a
provision that would require broad-spectrum UVA and UVB
protection in sunscreens.19b Therefore, the results of this
research suggest that benzophenones 6, 9 and 10, as well as,
the s-triazine 21 might be suitable candidates for further
development.
drying over MgSO4 and evaporation of the solvent the anacardic acids
-1
ꢀ
were obtained as a brown oil (13.7 g, ca. 39.9 mmol, 76%). IR (ν/cm ):
2923, 2853, 1644, 1607, 1447, 1245, 1207, 1166, 910, 822, 783; 1H
NMR (300 MHz, Chloroform-d) δ 11.01 (s, 1H), 9.62 (s, 2H), 7.35 (dd, J =
8.3, 7.5 Hz, 1H), 6.86 (dd, J = 8.4, 1.2 Hz, 1H), 6.76 (dd, J = 7.5, 1.2 Hz,
1H), 5.81 (ddt, J = 17.3, 10.1, 6.2 Hz, 0.4H), 5.51–5.24 (m, 4H), 5.04 (dq,
J = 17.1, 1.8 Hz, 0.4H), 4.97 (dq, J = 10.1, 1.6 Hz, 0.4H), 3.05–2.94 (m,
2H), 2.87–2.68 (m, 2H), 2.04–1.94 (m, 3H), 1.69–1.53 (m, 2H), 1.44–1.19
(m, 21H), 0.99–0.83 (m, 3H); 13C NMR (76 MHz, Chloroform-d) δ 176.0,
163.5, 147.7, 136.8, 135.3, 130.4, 130.1, 129.9, 129.8, 129.3, 128.1,
128.0, 127.6, 126.8, 122.7, 115.8, 114.7, 110.5, 36.4, 32.0, 31.8, 31.5,
29.7, 29.4, 29.23, 29.0, 27.2, 25.6, 22.8, 22.6, 14.1; MS (ESI+): m/z (%)
= 343.5 (100) [M3DB+H]+, 345.5 (97) [M2DB+H]+, 347.4 (100) [M1DB+H]+,
365.5 (26) [M3DB+Na]+, 367.4 (35) [M2DB+Na]+, 369.4 (39) [M1DB+Na]+.
The index “DB” denotes the number of double bonds present. The
analytical data are in accordance with the literature.23
Palladium on activated charcoal (10 wt%, 600 mg, 0.56 mmol) was
added to a solution of anacardic acids (10.2 g, 29.6 mmol) in MeOH
(125 mL) under an atmosphere of nitrogen. The flask was purged with
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10.1002/ejoc.201900743
European Journal of Organic Chemistry
hydrogen and the suspension was stirred for 60 h at rt under an
atmosphere of hydrogen. Afterwards, the flask was purged with nitrogen
and the reaction mixture was filtered through Celite®. After rinsing with
MeOH (300 mL), the solvent was evaporated and 2-hydroxy-6-
The respective bromobenzene 2a-c (1.05 mmol) was added to a flame
dried 50 mL Schlenk flask and the flask was subsequently evacuated and
filled with nitrogen three times. Dry THF (5 mL) was added and the
solution was cooled to –83 °C while stirring. A solution of n-butyllithium in
hexane (1.39 m, 752 µL, 1.05 mmol) was added during 15 min. The
resulting mixture was left stirring at –83 °C for 1 h and a solution of
methyl 2-benzyloxy-6-pentadecylbenzoate 1 (430 mg, 0.95 mmol) in dry
THF (5 mL) was added during 15 min. After stirring for 1 h at –83°C the
solution was slowly brought to rt and stirred further. The mixture was
quenched with a saturated NH4Cl solution (10 mL) and extracted with
EtOAc (3 x 10 mL). The combined organic extracts were dried over
MgSO4 and evaporated. The crude product was purified by column
chromatography on silica gel (EtOAc/hexane).
pentadecylbenzoic acid was obtained as a brownish solid (10.0 g,
-1
ꢀ
28.8 mmol, 97%). Mp. 87–88 °C; IR (ν/cm ): 2916, 2850, 1651, 1604,
1445, 1248, 1218, 815, 724, 707; 1H NMR (300 MHz, Chloroform-d) δ
7.36 (t, J = 7.9 Hz, 1H, H4), 6.87 (d, J = 8.3 Hz, 1H, H3), 6.77 (dd, J = 7.5,
1.2 Hz, 1H, H5), 2.98 (dd, J =9.1, 6.4 Hz, 2H, H1‘), 1.65–1.55 (m, 2H,
H2‘), 1.39–1.25 (m, 24H, H3‘–H14‘), 0.88 (t, J = 6.3 Hz, 3H, H15‘); 13C
NMR (76 MHz, Chloroform-d) δ 176.0 (CO2H), 163.6 (C2), 147.8 (C6),
135.4 (C4), 122.7 (C5), 115.8 (C3), 110.4 (C1), 36.5 (C1’), 32.0 (C13’),
31.9 (C2’), 29.8, 29.7 (6C), 29.6, 29.5, 29.4, 22.7 (C14’), 14.1 (C15’); MS
(ESI–): m/z (%) = 347.3 (100) [M–H]–, 717.6 (12) [2M+Na–2H]–; HRMS
(ESI–): Found (M–H)– 347.2592, C22H35O3 (M–H)– requires 347.2592.
The analytical data are in accordance with the literature.24
[2-(Benzyloxy)-6-pentadecylphenyl](2,5-
dimethoxyphenyl)methanone 3a
Conc. sulfuric acid (2.50 mL, 139 µmol) was carefully added to a stirred
solution of 2-hydroxy-6-pentadecylbenzoic acid (2.00 g, 5.74 mmol) in
MeOH (50 mL). The resulting mixture was stirred at reflux overnight and
then cooled to rt. The solvent was evaporated and an aqueous saturated
NaHCO3 solution (30 mL) was added to the residue. After extraction with
EtOAc (3 x 25 mL), the combined organic extracts were subsequently
washed with water and brine (20 mL each) and dried over MgSO4. The
solvent was evaporated and the crude product was purified by column
chromatography on silica gel (20% EtOAc/hexane) affording methyl
The title compound was synthesized following the general procedure
from 2,5-dimethoxybromobenzene 2a (157 µL, 1.05 mmol) and methyl 2-
benzyloxy-6-pentadecylbenzoate 1 (430 mg, 0.95 mmol). The resulting
solution was stirred over night at rt and the crude product was purified by
column chromatography on silica gel (5–10% EtOAc/hexane) to yield [2-
(benzyloxy)-6-pentadecylphenyl](2,5-dimethoxyphenyl)methanone 3a as
-1
ꢀ
colourless solid (245 mg, 438 µmol, 46%). Mp. 53.5–54.5 °C; IR (ν/cm ):
2923, 2853, 1656, 1579, 1495, 1464, 1281, 1221, 1048, 745; 1H NMR
(300 MHz, Chloroform-d) δ 7.26–7.18 (m, 5H, H6, H4‘, Bn-H3, Bn-H4,
Bn-H5), 7.04–6.97 (m, 3H, H4, Bn-H2, Bn-H6), 6.86 (d, J = 7.9 Hz, 1H,
H5‘), 6.84 (d, J = 8.9 Hz, 1H, H3), 6.75 (dd, J = 8.3, 0.9 Hz, 1H, H3‘),
4.91 (s, 2H, Bn-CH2), 3.72 (s, 3H, C5-OCH3), 3.52 (s, 3H, C2-OCH3),
2.57–2.51 (m, 2H, H1‘‘), 1.57–1.50 (m, 2H, H2‘‘), 1.33–1.20 (m, 24H,
H3‘‘-H14‘‘), 0.88 (t, J = 7.0 Hz, 3H, H15‘‘); 13C NMR (76 MHz,
Chloroform-d) δ 196.5 (C=O), 155.6 (C2‘), 153.8 (C2), 153.3 (C5), 141.6
(C6‘), 136.8 (Bn-C1), 132.0 (C1‘), 129.6 (C1), 129.4 (C4‘), 128.1 (2C, Bn-
C3, Bn-C5), 127.4 (Bn-C4), 126.8 (2C, Bn-C2, Bn-C6), 122.1 (C5‘), 120.0
(C4), 115.2 (C6), 114.0 (C3), 109.3 (C3‘), 56.4 (C2-OCH3), 55.7 (C5-
OCH3), 33.1 (C1‘‘), 31.9 (C13‘‘), 31.2 (C2‘‘), 29.7 (6C), 29.6 (2C), 29.4
(2C), 22.7 (C14‘‘), 14.1 (C15‘‘); MS (ESI+): m/z (%) = 559.5 (100) [M+H]+,
581.5 (12) [M+Na]+; HRMS (ESI+): Found (M+H)+ 559.3776, C37H51O4
(M+H)+ requires 559.3782.
2-hydroxy-6-pentadecylbenzoate as
a
ꢀ
pale brown solid (1.67 g,
-1
4.71 mmol, 82%). Mp. 41.5–43 °C; IR (ν/cm ): 2914, 2850, 1662, 1578,
1441, 1315, 1201, 1120, 946, 817, 742; 1H NMR (300 MHz, Chloroform-
3
3
d) δ 11.10 (s, 1H, OH), 7.28 (dd, J4,3 = 8.4 Hz, J4,5 = 7.5 Hz, 1H, H4),
6.83 (dd, J = 7.5, 1.3 Hz, 1H, H3), 6.71 (dd, J = 7.5, 1.3 Hz, 1H, H5), 3.95
(s, 3H, CO2CH3), 2.88 (dd, J =8.8, 6.8 Hz, 2H, H1‘), 1.56–1.47 (m, 2H,
H2‘), 1.36–1.24 (m, 24H, H3‘–H14‘), 0.88 (t, J = 7.0 Hz, 3H, H15‘); 13C
NMR (76 MHz, Chloroform-d) δ 171.9 (CO2CH3), 162.6 (C2), 146.2 (C6),
134.1 (C4), 122.4 (C5), 115.6 (C3), 111.8 (C1), 52.0 (CO2CH3), 36.6
(C1’), 32.1 (C13’), 31.9 (C2’), 29.9, 29.7–29.6 (7C), 29.5, 29.3, 22.7
(C14’), 14.1 (C15’); MS (ESI–): m/z (%) = 361.4 (100) [M–H]–; HRMS
(ESI+): Found (M+H)+ 363.2889, C23H39O3 (M+H)+ requires 363.2894.
The analytical data are in accordance with the literature.24
A
suspension of methyl 2-hydroxy-6-pentadecylbenzoate (1.20 g,
[2-(Benzyloxy)-6-pentadecylphenyl](2,4,5-
trimethoxyphenyl)methanone 3b
3.31 mmol) and K2CO3 (915 mg, 6.62 mmol) in acetone (20 mL) was
stirred under reflux for 10 min. After cooling to rt, benzyl bromide (591 µL,
4.97 mmol) was carefully added and the mixture was stirred for 8 h under
reflux under an atmosphere of nitrogen. The mixture was cooled to rt,
filtered through Celite® and rinsed with acetone (100 mL). After
evaporating the solvent, the crude product was purified by column
chromatography on silica gel (5% EtOAc/hexane) to obtain methyl 2-
NBS (2.12 g, 11.9 mmol) was added to
a
solution of 1,2,4-
trimethoxybenzene (2.00 g, 11.9 mmol) in dry CH2Cl2 (20 mL) under an
atmosphere of nitrogen. The resulting solution was heated to reflux and
stirred overnight. After cooling to rt, the solution was washed with an
aqueous saturated Na2S2O3 solution (15 mL) before the aqueous layer
was extracted with CH2Cl2 (2 x 15 mL). The combined organic extracts
were dried over MgSO4 and evaporated. The crude product was purified
by column chromatography on silica gel (10% EtOAc/hexane) to obtain
benzyloxy-6-pentadecylbenzoate
1 as a colourless solid (1.25 g,
-1
ꢀ
2.76 mmol, 83%). Mp. 29–31 °C; IR (ν/cm ): 2922, 2852, 1732, 1583,
1453, 1264, 1109, 1066, 734; 1H NMR (300 MHz, Chloroform-d) δ 7.42–
7.29 (m, 5H, Bn-H2–Bn-H6), 7.23 (dd, J = 8.4, J7.7 Hz, 1H, H4), 6.83 (d,
J = 7.5 Hz, 1H, H5), 6.78 (dd, J = 7.7, 1.0 Hz, 1H, H3), 5.10 (s, 2H, Bn-
CH2), 3.89 (s, 3H, CO2CH3), 2.59–2.53 (m, 2H, H1‘), 1.63–1.54 (m, 2H,
H2‘), 1.33–1.23 (m, 24H, H3‘–H14‘), 0.88 (t, J = 6.5 Hz, 3H, H15‘); 13C
NMR (76 MHz, Chloroform-d) δ 168.8 (CO2CH3), 155.4 (C2), 141.5 (C6),
136.9 (Bn-C1), 130.1 (C4), 128.4 (2C, Bn-C3, Bn-C5), 127.7 (Bn-C4),
126.8 (2C, Bn-C2, Bn-C6), 124.1 (C1), 121.8 (C5), 110.0 (C3), 70.4 (Bn-
CH2), 52.0 (CO2CH3), 33.5 (C1’), 31.9 (C13’), 31.1 (C2’), 29.7 (6C), 29.5
(2C), 29.4, 29.3, 22.7 (C14’), 14.1 (C15’); MS (ESI+): m/z (%) = 21.5 (98)
[M–OMe+H]+, 453.5 (100) [M+H]+, 475.4 (54) [M+Na]+; HRMS (ESI+):
Found (M+H)+ 453.3358, C30H45O3 (M+H)+ requires 453.3363.
2,4,5-trimethoxybromobenzene 2b as
a colourless solid (2.61 g,
-1
ꢀ
10.6 mmol, 89%). Mp. 56–58 °C; IR (ν/cm ): = 2999, 2942, 2843, 1505,
1451, 1378, 1204, 1166, 1022, 838, 799; 1H NMR (300 MHz, Chloroform-
d) δ 7.02 (s, 1H, H6), 6.55 (s, 1H, H3), 3.87 (s, 3H, C4-OCH3), 3.85 (s,
3H, C2-OCH3), 3.82 (s, 3H, C5-OCH3); 13C NMR (76 MHz, Chloroform-d)
δ 150.3 (C2), 149.2 (C4), 143.8 (C5), 116.5 (C6), 101.1 (C1), 99.0 (C3),
57.2 (C2-OCH3), 56.7 (C5-OCH3), 56.3 (C4-OCH3); MS (ESI+): m/z (%) =
246.1 (100) [M(Br79)+H]+, 248.1 (98) [M(Br81)+H]+. The analytical data are
in accordance with the literature.25
The title compound was synthesized following the general procedure
from 2,4,5-trimethoxybromobenzene 2b (258 mg, 1.05 mmol) and methyl
2-benzyloxy-6-pentadecylbenzoate 1 (430 mg, 0.95 mmol). The resulting
General procedure for the synthesis of benzophenones 3a–c
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900743
European Journal of Organic Chemistry
solution was stirred for 1 h at rt and the crude product was purified by
column chromatography on silica gel (10–50% EtOAc/hexane) to yield [2-
(C4‘), 128.2 (2C, Bn-C3, Bn-C5), 128.1 (2C, Bn‘-C3, Bn‘-C5), 127.5 (Bn-
C4), 127.4 (Bn‘-C4), 127.1 (2C, Bn-C2, Bn-C6), 126.8 (2C, Bn‘-C2, Bn‘-
C6), 122.2 (C5‘), 120.6 (C5), 113.0 (C3), 109.4 (C3‘), 70.3 (Bn-CH2), 69.9
(Bn‘-CH2), 33.1 (C1‘‘), 31.9 (C13‘‘), 31.2 (C2‘‘), 29.7 (6C), 29.6, 29.5,
29.4, 29.3, 22.7 (C14‘‘), 14.1 (C15‘‘); MS (ESI+): m/z (%) = 605.5 (100)
[M+H]+, 627.5 (53) [M+Na]+; HRMS (ESI+): Found (M+H)+ 605.3976,
C42H53O3 (M+H)+ requires 605.3989.
(benzyloxy)-6-pentadecylphenyl](2,4,5-trimethoxyphenyl)methanone 3b
-1
ꢀ
as yellowish solid (264 mg, 448 µmol, 47%). Mp. 53.5–55 °C; IR (ν/cm ):
2923, 2852, 1599, 1579, 1511, 1464, 1272, 1213, 1029, 739; 1H NMR
(300 MHz, Chloroform-d) δ 7.38 (s, 1H, H6), 7.22–7.16 (m, 4H, H4‘, Bn-
H3, Bn-H4, Bn-H5), 7.07–7.02 (m, 2H, Bn-H2, Bn-H6), 6.86 (dd, J = 7.7,
0.9 Hz, 1H, H5‘), 6.75 (dd, J = 8.3, 0.9 Hz, 1H, H3‘), 6.41 (s, 1H, H3),
4.96 (s, 2H, Bn-CH2), 3.92 (s, 3H, C2-OCH3/C4-OCH3), 3.82 (s, 3H, C5-
OCH3), 3.49 (s, 3H, C2-OCH3/C4-OCH3), 2.55–2.48 (m, 2H, H1‘‘), 1.54–
1.48 (m, 2H, H2‘‘), 1.27–1.19 (m, 24H, H3‘‘–H14‘‘), 0.88 (t, J = 7.0 Hz, 3H,
H15‘‘); 13C NMR (76 MHz, Chloroform-d) δ 194.4 (C=O), 156.0 (C2/C4),
155.2 (C2‘), 154.1 (C2/C4), 143.1 (C5), 140.9 (C6‘), 137.1 (Bn-C1), 133.1
(C1‘), 128.8 (C4‘), 128.1 (2C, Bn-C3, Bn-C5), 127.4 (Bn-C4), 126.7 (2C,
Bn-C2, Bn-C6), 122.0 (C5‘), 120.7 (C1), 113.8 (C6), 109.3 (C3‘), 97.3
(C3), 70.0 (Bn-CH2), 56.5 (C2-OCH3/C4-OCH3), 56.3 (C5-OCH3), 56.0
(C2-OCH3/C4-OCH3), 33.0 (C1‘‘), 31.9 (C13‘‘), 31.0 (C2‘‘), 29.7 (6C),
29.6, 29.5, 29.4, 29.3, 22.7 (C14‘‘), 14.1 (C15‘‘); MS (ESI+): m/z (%) =
555.5 (100) [M–OMe+H]+, 587.7 (29) [M+H]+; HRMS (ESI+): Found
(M+H)+ 589.3882, C38H53O5 (M+H)+ requires 589.3888.
General procedure for the synthesis of Hydroxybenzophenones 4a–
c
Palladium on activated charcoal (10 wt%) was added to a solution of the
respective benzophenone 3a-c dissolved in a mixture of MeOH/EtOAc
(10/1) under an atmosphere of nitrogen. The flask was purged with
hydrogen and the suspension was stirred over night at rt. After filtration
through Celite® the residue was rinsed with MeOH and EtOAc (50 mL
each) and the solvents were evaporated to afford the desired products
4a-c.
(2-Pentadecyl-6-hydroxyphenyl)(2,5-dimethoxyphenyl)methanone
4a
[2-(Benzyloxy)-6-pentadecylphenyl](2-benzyloxyphenyl)methanone
3c
The title compound was synthesized following the general procedure
starting
from
[2-(benzyloxy)-6-pentadecylphenyl](2,5-
A suspension of 2-bromophenol (611 µL, 5.78 mmol) and K2CO3 (1.20 g,
8.70 mmol) in acetone (10 mL) was stirred at reflux under an atmosphere
of nitrogen for 10 min. Benzyl bromide (1.03 mL, 8.70 mmol) was then
added dropwise and the mixture was stirred for 17 h at reflux. After
cooling to rt, the solvent was evaporated and the residue was dissolved
in water and EtOAc (30 mL each). After separation of the layers, the
organic layer was washed with water and brine (15 mL each), dried over
Na2SO4 and evaporated. The crude product was purified by column
chromatography on silica gel (0–30% EtOAc/cyclohexane) to obtain 2-
dimethoxyphenyl)methanone 3a (217 mg, 384 µmol) using Pd/C (10 wt%,
22.0 mg, 20.1 µmol) and MeOH/EtOAc (10/1, 15 mL). The product 4a
was obtained as a brownish solid (181 mg, 380 µmol, 99%). Mp. 45–
47 °C; IR (ν/cm ): 3362, 2922, 2852, 1606, 1582, 1494, 1463, 1278,
1223, 1046, 813, 722; H NMR (300 MHz, Chloroform-d) δ 9.32 (s, 1H,
OH), 7.30 (dd, J = 7.5, 8.3 Hz, 1H, H4‘), 7.01 (dd, J = 9.0, 3.1 Hz, 1H,
H4), 6.91–6.85 (m, 3H, H3, H6, H5‘), 6.69 (dd, J = 7.5, 1.2 Hz, 1H, H3‘),
3.74 (s, 3H, C5-OCH3), 3.70 (s, 3H, C2-OCH3), 2.26 (dd, J = 9.8, 6.3 Hz,
2H, H1‘‘), 1.34–1.14 (m, 26H, H2‘‘–H14‘‘), 0.88 (t, J = 6.5 Hz, 3H, H15‘‘);
13C NMR (76 MHz, Chloroform-d) δ 200.9 (C=O), 160.3 (C6‘), 153.4 (C5),
151.5 (C2), 145.0 (C2‘), 134.0 (C4‘), 131.2 (C1), 122.6 (C1‘), 121.6 (C3‘),
118.2 (C4), 115.4 (C5‘), 114.4 (C6), 113.2 (C3), 56.4 (C2-OCH3), 55.8
(C5-OCH3), 34.7 (C1‘‘), 32.4 (C2‘‘), 31.9 (C13‘‘), 29.7 (6C), 29.6, 29.5,
29.4, 29.3, 22.7 (C14‘‘), 14.1 (C15‘‘); MS (ESI+): m/z (%) = 469.4 (100)
[M+H]+, 491.4 (16) [M+Na]+; HRMS (ESI+): Found (M+H)+ 469.3303,
C30H45O4 (M+H)+ requires 469.3312.
-1
ꢀ
1
benzyloxybromobenzene 2c as a colourless oil (1.38 g, 5.26 mmol, 91%).
-1
ꢀ
IR (ν/cm ): 3064, 2870, 1586, 1476, 1441, 1379, 1276, 1051, 1029, 742;
1H NMR (300 MHz, Chloroform-d) δ 7.55 (dd, J = 7.9, 1.6 Hz, 1H, H6),
7.49–7.46 (m, 2H, Bn-H2, Bn-H6), 7.41–7.35 (m, 2H, Bn-H3, Bn-H5),
7.34–7.31 (m, 1H, Bn-H4), 7.22 (ddd, J = 8.2, 7.4, 1.6 Hz, 1H, H4), 6.92
(dd, J = 8.3, 1.4 Hz, 1H, H3), 6.85 (td, J = 7.9, 1.4 Hz, 1H, H5), 5.15 (s,
2H, Bn-CH2); 13C NMR (76 MHz, Chloroform-d) δ 155.0 (C2), 136.5 (Bn-
C1), 133.4 (C6), 128.5 (2C, Bn-C3, Bn-C5), 128.4 (C4), 127.9 (Bn-C4),
127.0 (2C, Bn-C2, Bn-C6), 122.1 (C5), 113.9 (C3), 112.5 (C1), 70.8 (Bn-
CH2); MS (ESI+): m/z (%) = 277.0 (100) [M(Br79)+NH4]+, 279.0 (78)
[M(Br81)+NH4]+. The analytical data are in accordance with the
literature.26
(2-Pentadecyl-6-hydroxyphenyl)(2,4,5-trimethoxyphenyl)methanone
4b
The title compound was synthesized following the general procedure
starting
from
[2-(benzyloxy)-6-pentadecylphenyl](2,4,5-
Utilizing the synthesized 2-benzyloxybromobenzene 2c, the title
compound was synthesized following the general procedure from 2-
benzyloxybromobenzene 2c (275 mg, 1.05 mmol) and methyl 2-
benzyloxy-6-pentadecylbenzoate 1 (430 mg, 0.95 mmol). The resulting
solution was stirred for 48 h at rt and the crude product was purified by
column chromatography on silica gel (2.5–5% EtOAc/hexane) to yield [2-
(benzyloxy)-6-pentadecylphenyl](2-benzyloxyphenyl)methanone 3c as
colourless oil (57.5 mg, 94.5 µmol, 10%). IR (ν/cm-1): 2923, 2853, 1653,
1595, 1580, 1450, 1379, 1297, 1052, 925, 750; 1H NMR (500 MHz,
Chloroform-d) δ 7.74 (d, J = 7.7 Hz, 1H, H6), 7.42 (t, J = 7.9 Hz, 1H, H4),
7.25–7.21 (m, 3H, Bn-H3, Bn-H5, Bn‘-4), 7.17–7.13 (m, 4H, H4‘, Bn-4,
Bn‘-3, Bn‘-5), 7.03–7.01 (m, 3H, H5, Bn-H2, Bn-H6), 6.98–6.93 (m, 3H,
H3, Bn‘-H2, Bn‘-H6), 6.77 (d, J = 7.9 Hz, 1H, H5‘), 6.67 (d, J = 7.9 Hz, 1H,
H3‘), 4.86 (s, 2H, Bn-CH2), 4.84 (s, 2H, Bn‘-CH2), 2.49 (dd, J = 9.2,
7.3 Hz, 2H, H1‘‘), 1.46 (p, J = 7.3 Hz, 2H, H2‘‘), 1.28–1.16 (m, 24H, H3‘‘–
H14‘‘), 0.88 (t, J = 6.9 Hz, 3H, H15‘‘); 13C NMR (126 MHz, Chloroform-d)
δ 196.7 (C=O), 158.2 (C2), 155.6 (C2‘), 141.8 (C6), 136.9 (Bn‘-C1),
136.2 (Bn-C1), 133.5 (C4), 132.1 (C1‘), 131.6 (C6), 129.6 (C1), 129.4
trimethoxyphenyl)methanone 3b (243 mg, 413 µmol) using Pd/C (10 wt%,
25.0 mg, 23.5 µmol) and MeOH/EtOAc (10/1, 20 mL). The product 4b
was obtained as a brownish solid (190 mg, 381 µmol, 92%). Mp. 78–
-1
ꢀ
81 °C; IR (ν/cm ): 3314, 2922, 2852, 1581, 1513, 1462, 1354, 1270,
1212, 1025, 807; 1H NMR (300 MHz, Chloroform-d) δ 9.18 (s, 1H, OH),
7.25 (t, J = 7.9 Hz, 1H, H4‘), 7.02 (s, 1H, H6), 6.84 (dd, J = 8.2, 1.1 Hz,
1H, H5‘), 6.71 (dd, J = 7.6 1.1 Hz, 1H, H3‘), 6.49 (s, 1H, H3), 3.96 (s, 3H,
C2-OCH3/C4-OCH3), 3.82 (s, 3H, C5-OCH3), 3.68 (s, 3H, C2-OCH3/C4-
OCH3), 2.36–2.30 (m, 2H, H1‘‘), 1.36–1.12 (m, 26H, H2‘‘–H14‘‘), 0.88 (t,
J = 7.0 Hz, 3H, H15‘‘) ppm; 13C NMR (76 MHz, Chloroform-d) δ 198.7
(C=O), 158.1 (C6‘), 154.1 (C2/C4), 153.7 (C2/C4), 143.9 (C2‘), 143.2
(C5), 132.8 (C4‘), 124.6 (C1‘), 121.4 (C3‘), 121.4 (C1), 114.9 (C5‘), 113.1
(C6), 97.2 (C3), 56.6 (C2-OCH3/C4-OCH3), 56.5 (C5-OCH3), 56.1
(C2-OCH3/C4-OCH3), 34.4 (C1‘‘), 32.2 (C2‘‘), 31.9 (C13‘‘), 29.7 (6C),
29.5 (2C), 29.3 (2C), 22.7 (C14‘‘), 14.1 (C15‘‘); MS (ESI+): m/z (%) =
499.5 (100) [M+H]+, 521.4 (6) [M+Na]+; HRMS (ESI+): Found (M+H)+
499.3409, C31H47O5 (M+H)+ requires 499.3418.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900743
European Journal of Organic Chemistry
[2-(Hydroxy)-6-pentadecylphenyl](2-hydroxyphenyl)methanone 4c
hydroxy-4,5-dimethoxyphenyl)methanone as a yellow solid 6 (8.90 mg,
-1
ꢀ
18.3 µmol, 69%). Mp. 86.3–88 °C; IR (ν/cm ): 3439, 2922, 2852, 1626,
1441, 1238, 1204, 1164, 1126, 800; 1H NMR (300 MHz, Chloroform-d) δ
12.58 (s, 1H, C2-OH), 7.27 (tapp, Japp = 7.9 Hz, 1H, H4‘), 6.88 (dd, J = 7.7,
1.0 Hz, 1H, H3‘), 6.79 (dd, J = 8.1, 1.0 Hz, 1H, H5‘), 6.65 (s, 1H, H6),
6.52(s, 1H, H3), 5.78 (s, br, 1H, C6‘-OH), 3.94 (s, 3H, C4-OCH3), 3.62 (s,
3H, C5-OCH3), 2.47 (t, J = 7.8 Hz, 2H, H1‘‘), 1.50–1.42 (m, 2H, H2‘‘),
1.30–1.16 (m, 24H, H3‘‘–H14‘‘), 0.86 (t, J = 6.9 Hz, 3H, H15‘‘); 13C NMR
(76 MHz, Chloroform-d) δ 200.8 (C=O), 161.0 (C2), 157.6 (C4), 153.0
(C6‘), 142.2 (C5), 141.8 (C2‘), 131.1 (C4‘), 125.0 (C1‘), 121.8 (C3‘),
114.0 (C5‘), 113.4 (C6), 112.8 (C1), 100.5 (C3), 56.4 (C5-OCH3), 56.3
(C4-OCH3), 33.6 (C1‘‘), 31.9 (C13‘‘), 31.3 (C2‘‘), 29.7 (5C), 29.6 (2C),
29.5, 29.4, 29.3, 22.7 (C14‘‘), 14.1 (C15‘‘); MS (ESI+): m/z (%) = 485.4
(100) [M+H]+, 507.3 (22) [M+Na]+; HRMS (ESI+): Found (M+H)+
485.3258, C30H45O5 (M+H)+ requires 485.3262.
The title compound was synthesized following the general procedure
starting
from
[2-(benzyloxy)-6-pentadecylphenyl](2-
benzyloxyphenyl)methanone 3c (44.6 mg, 74.0 µmol) using Pd/C
(10 wt%, 5.00 mg, 4.70 µmol) and MeOH/EtOAc (10/1, 4 mL). The
product 4c was obtained as a yellowish oil (26.3 mg, 61.9 µmol, 84%). IR
-1
ꢀ
(ν/cm ): 3392, 2923, 2853, 1625, 1583, 1463, 1307, 1283, 1110, 939,
756; 1H NMR (300 MHz, Chloroform-d) δ 12.07 (s, 1H, C2-OH), 7.48
(ddd, J = 8.5, 7.2, 1.7 Hz, 1H, H4), 7.31 (dd, J = 8.0, 1.7 Hz, 1H, H6),
7.25 (t, J = 7.9 Hz, 1H, H4‘), 7.03 (dd, J = 8.5, 1.1 Hz, 1H, H3), 6.87 (d,
J = 7.7 Hz, 1H, H3), 6.83–6.79 (m, 1H, H5), 6.73 (dd, J = 8.2, 1.0 Hz, 1H,
H3’), 5.69 (s, 1H, C2’-OH), 2.42 (dd, J = 9.0, 6.7 Hz, 2H, H1‘‘), 1.45 (p,
J = 6.8 Hz, 2H, H2’’), 1.33–1.14 (m, 24H, H3‘‘–H14‘‘), 0.86 (t, J = 6.7 Hz,
3H, H15‘‘); 13C NMR (76 MHz, Chloroform-d) δ 203.8 (C=O), 162.7 (C2),
152.8 (C2’), 142.0 (C6’), 137.0 (C4), 133.2 (C6), 131.0 (C4‘), 125.1 (C1‘),
121.8 (C5‘), 120.7 (C1), 119.2 (C5), 118.2 (C3), 113.8 (C3’), 33.5 (C1‘‘),
31.9 (C13‘‘), 31.1 (C2‘‘), 29.7 (3C), 29.6 (3C), 29.4, 29.3, 29.2 (2C), 22.7
(C14‘‘), 14.1 (C15‘‘); MS (ESI–): m/z (%) = 423.4 (100) [M–H]–; HRMS
(ESI+): Found (M+H)+ 425.3047, C28H41O3 (M+H)+ requires 425.3050.
3-Pentadecylphenyl benzoate 8
To a stirred solution of 3-pentadecylphenol 7 (5.00 g, 16.42 mmol) in 2-
Methyl-THF (60 mL), triethylamine (4.58 mL, 32.84 mmol) and 4-
dimethylaminopyridine (0.200 g, 1.64 mmol) was added and the mixture
cooled to 0 °C. To this cooled mixture, benzoyl chloride (2.54 g, 2.10 mL,
18.06 mmol) dissolved in 2-Methyl-THF (20 mL) was slowly added and
the reaction mixture was warmed to rt and stirred for 2 h. Upon
completion, the reaction was quenched with water (50 mL) and the
mixture extracted with EtOAc (3 × 100 mL). The combined organic
extracts were washed with aq. NaHCO3 (100 mL) followed by brine (100
mL) and then dried over MgSO4 and the solvent removed under reduced
pressure. The crude product was purified by column chromatography on
silica gel (10 % EtOAc/cyclohexane) to afford the 3-pentadecylphenyl
(2-Hydroxy-5-methoxyphenyl)(2-hydroxy-6-
pentadecylphenyl)methanone 5
AlCl3 (9.05 mg, 67.9 µmol) and pyridine (16.4 µL, 203.6 µmol) were
added
to
a
solution
of
(2-pentadecyl-6-hydroxyphenyl)(2,5-
dimethoxyphenyl)methanone (15.9 mg, 33.9 µmol) in dry toluene (1 mL)
at room temperature under an atmosphere of nitrogen. The resulting
solution was stirred for 5 d under reflux and each day AlCl3 (9.05 mg,
67.9 µmol) and pyridine (16.4 µL, 203.6 µmol) were added. The mixture
was cooled to room temperature afterwards. Aqueous HCl (2 m, 5 mL)
was added and the mixture was extracted with diethyl ether (3 x 5 mL).
The combined organic extracts were dried over Na2SO4 and evaporated.
The crude product was purified by column chromatography on silica gel
benzoate 8 as a white crystalline solid (6.36 g, 95%). Mp. 52.1-53.9 °C;
-1
IR (ν/cm ): 2918, 2846, 1731, 1585, 1238, 1144, 1079, 710; 1H NMR
ꢀ
(400 MHz, Chloroform-d) δ 8.25 (dd, J = 8.3, 1.4 Hz, 2H, H2ʹ), 7.69–7.64
(m, 1H, H4ʹ), 7.55 (dd, J = 8.3, 7.0 Hz, 2H, H3ʹ), 7.36 (td, J = 7.6, 1.5 Hz,
1H, H5), 7.13 (dd, J = 7.7, 1.3 Hz, 1H, H4), 7.10–7.05 (m, 2H, H2, H6),
2.68 (t, J = 7.7 Hz, 2H, H1ʹʹ), 1.75–1.63 (m, 2H, H2ʹʹ), 1.30 (m, 24H, H3ʹʹ-
H14ʹʹ), 0.92 (t, J = 5.7 Hz, 3H, H15ʹʹ); 13C NMR (101 MHz, Chloroform-d)
δ 165.2 (C=O), 151.0 (C1), 144.8 (C3), 133.5 (C4ʹ), 130.2 (C2ʹ), 129.7
(C1ʹ), 129.2 (C5), 128.5 (C3ʹ), 126.0 (C4), 121.6 (C2), 118.8 (C5), 35.8
(C1ʹʹ), 32.0 (C13ʹʹ), 31.3 (C2ʹʹ), 29.7 (6C), 29.6 (1C), 29.5 (1C), 29.4 (1C),
29.3 (1C), 22.7 (C14ʹʹ), 14.2 (C15ʹʹ); HRMS (ESI+): Found (M+H)+
409.3107, C28H41O2 (M+H)+ requires 409.3101.
(17% EtOAc/cyclohexane) to obtain the product as a brown oil 5
-1
ꢀ
(8.60 mg, 18.9 µmol, 56%). IR (ν/cm ): 3377, 2922, 2853, 1612, 1484,
1463, 1284, 1040, 791; 1H NMR (300 MHz, Chloroform-d) δ 11.68 (s, 1H,
C2’-OH), 7.27 (tapp, Japp = 7.9 Hz, 1H, H4), 7.13 (dd, J = 9.1, 3.0 Hz, 1H,
H4‘), 7.00 (d, J = 9.1 Hz, 1H, H3‘), 6.88 (d, J = 7.5 Hz, 1H, H5), 6.76 (m,
2H, H3, H6’), 5.59 (s, br, 1H, C2-OH), 3.63 (s, 3H, C5’-OCH3), 2.46–2.43
(m, 2H, H1‘‘), 1.49–1.44 (m, 2H, H2‘‘), 1.25–1.15 (m, 24H, H3‘‘–H14‘‘),
0.88 (t, J = 6.7 Hz, 3H, H15‘‘); 13C NMR (76 MHz, Chloroform-d) δ 203.3
(C=O), 157.2 (C2’), 152.9 (C2), 151.9 (C5‘), 142.1 (C6), 131.2 (C4),
124.9 (2C, C1, C4’), 121.9 (C5), 120.3 (C1’), 119.2 (C3’), 115.4 (C6’),
113.9 (C3), 55.8 (C5’-OCH3), 33.6 (C1‘‘), 31.9 (C13‘‘), 31.2 (C2‘‘), 29.7
(4C), 29.6 (2C), 29.4 (2C), 29.2 (2C), 22.7 (C14‘‘), 14.1 (C15‘‘); MS
(ESI+): m/z (%) = 455.4 (100) [M+H]+, 477.3 (37) [M+Na]+; HRMS (ESI+):
Found (M+H)+ 455.3159, C29H43O4 (M+H)+ requires 455.3156.
(2-Hydroxy-4-pentadecylphenyl)(phenyl)methanone 9
3-Pentadecylphenyl benzoate 8 (0.20 g, 0.49 mmol) was dissolved in
chlorobenzene (3 mL) in a microwave reactor tube. To this solution, AlCl3,
(0.16 g, 1.23 mmol) was added. The tube was sealed and the reaction
mixture was subjected to microwave irradiation (150 W, 160 °C) for 30
min. After cooling to rt, the crude product was purified by column
chromatography (5% EtOAc/cyclohexane) to afford (2-hydroxy-4-
(2-Pentadecyl-6-hydroxyphenyl)(2-hydroxy-4,5-
dimethoxyphenyl)methanone 6
pentadecylphenyl)(phenyl)methanone 9 as an off-white solid (0.16 g,
-1
ꢀ
78%). Mp. 40.8-42.6 °C; IR (ν/cm ): 2912, 2848, 1626, 1600, 1470, 1334,
A solution of BCl3 in CH2Cl2 (1 m, 29.0 µL, 29.0 µmol) was added to a
1223, 915, 765, 700; 1H NMR (400 MHz, Chloroform-d) δ 12.19 (s, 1H,
C2-OH), 7.72–7.67 (m, 2H, H2ʹ), 7.62–7.56 (m, 1H, H4ʹ), 7.54–7.50 (m,
3H, H3ʹ and H6), 6.93 (d, J = 1.6 Hz, 1H, H3), 6.72 (dd, J = 8.2, 1.7 Hz,
1H, H5), 2.65 (t, 2H, H1ʹʹ), 1.73–1.60 (m, 2H, H2ʹʹ), 1.30 (m, 24H, H3ʹʹ-
H14ʹʹ ), 0.91 (t, J = 5.6 Hz, 3H, H15ʹʹ); 13C NMR (101 MHz, Chloroforn-d)
δ 201.1 (C=O), 163.5 (C2), 153.0 (C4), 138.2 (C1ʹ), 133.5 (C6), 131.7
(C4ʹ), 129.1 (C2ʹ), 128.3 (C3ʹ), 119.3 (C5), 117.8 (C3), 117.1 (C1), 36.3
(C1ʹʹ), 32.0 (C13ʹʹ), 30.7 (C2ʹʹ), 29.7 (6C), 29.6 (1C), 29.5 (1C), 29.4 (1C),
29.3 (1C), 22.7 (C14ʹʹ), 14.2 (C15ʹʹ); HRMS (ESI+): Found (M+H)+
409.3096, C28H41O2 (M+H)+ requires 409.3101. The analytical data are in
accordance with the literature.18
solution
of
(2-pentadecyl-6-hydroxyphenyl)(2,4,5-
trimethoxyphenyl)methanone 4b (13.3 mg, 26.7 µmol) in dry CH2Cl2 at –
78 °C under an atmosphere of nitrogen while stirring. The solution was
kept at this temperature for 8 h and then brought to rt overnight. Stirring
was continued for 4 d at rt and each day BCl3 in CH2Cl2 (1 M, 29.0 µL,
29.0 µmol) was added. Aqueous NaOH (1 m, 1 mL) was added and the
mixture was stirred for 1 h. Then aqueous HCl (2 m, 1 mL) was added
and the mixture was extracted with CH2Cl2 (2 x 3 mL). The combined
organic extracts were dried over Na2SO4 and evaporated. The crude
product was purified by column chromatography on silica gel (25%
EtOAc/cyclohexane)
to
obtain
(2-pentadecyl-6-hydroxyphenyl)(2-
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900743
European Journal of Organic Chemistry
(2-hydroxy-4-pentadecylphenyl)(2-hydroxyphenyl)methanone 10
1H, H5ʹ), 2.67 – 2.54 (m, 5H, H1 and H1ʹʹ), 1.70 – 1.57 (m, 2H, H2ʹʹ), 1.40
– 1.20 (m, 24H, H3ʹʹ-H14ʹʹ ), 0.89 (t, J = 5.5 Hz, 3H, H15ʹʹ); 13C NMR (101
MHz, Chloroform-d) δ 203.8 (C=O), 162.5 (C2ʹ), 153.0 (C4ʹ), 130.6 (C6ʹ),
119.6 (C5ʹ), 117.7 (C3ʹ), 36.2 (C1ʹʹ), 31.9 (C13ʹʹ), 30.7 (C2ʹʹ), 29.7(6C),
29.6 (1C), 29.5 (1C), 29.4 (1C), 29.3 (1C), 26.5 (C1), 22.7 (C14ʹʹ), 14.1
(C15ʹʹ); HRMS (ESI+): Found (M+H)+ 347.2942, C23H39O2 (M+H)+
requires 347.2945. The data is consistent with what has been reported in
literature.27
To
a
15 mL scintillation vial were added (2-hydroxy-4-
pentadecylphenyl)(phenyl)methanone 9 (0.30 g, 0.73 mmol), K2S2O8
(0.40 g, 1.47 mmol), [Ru(p-cymene)Cl2]2 (11 mg, 0.018 mmol), TFAA (5.0
mL) and TFA (2.0 mL). The vessel was sealed with a Teflon-lined cap
and the mixture was heated at 80 °C under TLC monitoring. After
completion, EtOAc was added to dilute the reaction mixture and
saturated aqueous NaHCO3 was added to neutralize TFA and TFAA.
Then the organic layer was dried over anhydrous Na2SO4 and
concentrated in vacuo. Finally, the residue was purified by silica gel
column chromatography (5% EtOAc/hexane) to give (2-hydroxy-4-
(E)-1-(2-hydroxy-4-pentadecylphenyl)-3-phenylprop-2-en-1-one 13a
To a round-bottom flask (10 mL), equipped with a magnetic stir bar were
added 1-(2-hydroxy-4-pentadecylphenyl)ethanone 12 (0.097 g, 0.28
mmol), benzaldehyde (28 µL, 30 mg, 0.28 mmol), sodium hydroxide (34
mg, 0.85 mmol) and methanol (2 mL). The pale yellow mixture was
refluxed until the colour was turned into orange (about 4 h). The mixture
was poured into ice-water and extracted with ethyl acetate (3 × 10 mL).
The organic layer was dried over Na2SO4, filtered and the solvent was
removed in vacuo. The crude product was subjected to column
chromatography (5% EtOAc/cyclohexane) to furnish ((E)-1-(2-hydroxy-4-
pentadecylphenyl)(2-hydroxyphenyl)methanone 10 as a white crystalline
-1
ꢀ
solid (220 mg, 72%). Mp. 31.4-32.6 °C; IR (ν/cm ): 3403, 2921, 2852,
1599, 1573, 1337, 1229, 755, 699; 1H NMR (300 MHz, Chloroform-d) δ
10.86 (s, 1H, C2-OH), 10.52 (s, 1H, C2ʹ-OH), 7.61 (dd, J = 8.0, 1.8 Hz,
1H, H6ʹ), 7.56–7.41 (m, 2H, H4ʹ and H6), 7.07 (d, J = 8.4 Hz, 1H, H3ʹ),
6.93 (d, J = 7.7 Hz, 1H, H5ʹ), 6.89 (s, 1H, H3), 6.74 (dd, J = 8.3, 1.8 Hz,
1H, H5), 2.62 (t, 2H, H1ʹʹ), 1.67-1.61 (m, 2H, H2ʹʹ), 1.26 (m, 24H, H3ʹʹ-
H14ʹʹ), 0.87 (t, J = 5.7 Hz, 3H, H15ʹʹ); 13C NMR (75 MHz, Chloroform-d) δ
201.8 (C=O), 162.3 (C2), 161.4 (C2ʹ), 152.8 (C4), 135.5 (C4ʹ), 133.1 (C6),
132.9 (C6ʹ), 120.1 (C1ʹ), 119.5 (C5), 118.7 (C5ʹ), 118.5 (C3ʹ), 118.0 (C3),
117.5 (C1), 36.2 (C1ʹʹ), 31.9 (C13ʹʹ), 30.6 (C2ʹʹ), 29.7 (6C), 29.6 (1C),
29.5 (1C), 29.4 (1C), 29.3 (1C), 22.7 (C14ʹʹ), 14.1 (C15ʹʹ); HRMS (ESI+):
Found (M+H)+ 425.3058, C28H41O3 (M+H)+ requires 425.3050.
pentadecylphenyl)-3-phenylprop-2-en-1-one 13a as a bright yellow solid
-1
ꢀ
(0.085 g, 67%). Mp. 54.7-56.4 °C; IR (ν/cm ): 2915, 2849, 1640, 1618,
1350, 1204, 1148, 788, 738; 1H NMR (400 MHz, Chloroform-d) δ 12.91 (s,
1H, C2ʹʹ-OH), 7.93 (d, J = 15.5 Hz, 1H, H3), 7.85 (d, J = 8.3 Hz, 1H, H6ʹʹ),
7.71 – 7.63 (m, 3H, H2 and H2ʹ), 7.50 – 7.43 (m, 3H, H3ʹ and H4ʹ), 6.87
(d, J = 1.5 Hz, 1H, H3ʹʹ), 6.79 (dd, J = 8.2, 1.7 Hz, 1H, H5ʹʹ), 2.64 (t, 2H,
H1ʹʹʹ), 1.90 – 1.47 (m, 2H, H2ʹʹʹ), 1.28 (m, 24H, H3ʹʹʹ-H14ʹʹʹ), 0.90 (t, J =
5.7, 3H, H15ʹʹʹ); 13C NMR (101 MHz, Chloroform-d) δ 193.1 (C=O), 163.8
(C2ʹʹ), 153.1 (C4ʹʹ), 144.9 (C3), 134.7 (C1ʹ), 130.8 (C4ʹ), 129.5 (C6ʹʹ),
129.0 (C3ʹ), 128.6 (C2ʹ), 120.3 (C2), 119.5 (C5ʹʹ), 118.0 (C3ʹʹ), 36.3 (C1ʹʹʹ),
31.9 (C13ʹʹʹ), 30.7(C2ʹʹʹ), 29.7 (6C), 29.6 (1C), 29.5 (1C), 29.4 (1C), 29.3
(1C), 22.7 (C14ʹʹʹ), 14.1 (C15ʹʹʹ); HRMS (ESI+): Found (M+H)+ 435.3259,
C30H43O2 (M+H)+ requires 435.3258.
3-Pentadecylphenyl acetate 11
To a stirred solution of 3-pentadecylphenol 7 (2.03g, 6.57 mmol) in 2-
Methyl-THF (20 mL), triethylamine (1.83 mL, 13.14 mmol) and 4-
dimethylaminopyridine (0.08g, 0.66 mmol) was added and the mixture
cooled to 0 °C. To this cooled mixture, acetyl chloride (0.62g, 0.56 mL,
7.88 mmol) dissolved in 2-methyl-THF (5 mL) was slowly added and the
reaction mixture was slowly warmed to rt and stirred at rt for 2 h. The
reaction was quenched with water (20 mL) and the mixture extracted with
EtOAc (3 × 50 mL). The combined organic extracts were washed with aq.
NaHCO3 (50 mL) followed by brine (50 mL) and then dried over MgSO4
and the solvent removed under reduced pressure. The crude product was
3-Hydroxy-7-pentadecyl-2-phenyl-4H-chromen-4-one 13b
((E)-1-(2-hydroxy-4-pentadecylphenyl)-3-phenylprop-2-en-1-one (0.156 g,
0.36 mmol) was dissolved in methanol (10 mL) in a 50 mL round-bottom
flask. To the stirred solution, sodium hydroxide (0.5 N, 2.7 mL) and
hydrogen peroxide (30%, 220 µL) were added and the mixture was
stirred at rt for 2 h upon which its colour changed to orange. The mixture
was acidified with aqueous HCl (15 mL) and extracted with ethyl acetate
(3 × 20 mL). The organic layer was dried over Na2SO4 and the solvent
was removed under reduced pressure. The crude product was subjected
to column chromatography (10% EtOAc/hexane) to give 3-hydroxy-7-
purified by column chromatography on silica gel (10
%
EtOAc/cyclohexane) to afford the 3-pentadecylphenyl acetate 11 as a
-1
ꢀ
low melting white solid (2.22 g, 96%). Mp. 36.9-37.5 °C; IR (ν/cm ): 2914,
2848, 1757, 1612, 1587, 1204, 1142, 1015, 952, 694; 1H NMR (400 MHz,
Chloroform-d) δ 7.34 – 7.27 (m, 1H, H5), 7.09 (d, J = 7.7 Hz, 1H, H4),
6.96 (d, J = 1.3 Hz, 1H, H2), 6.97–6.93 (m, 1H, H6), 2.66 (t, 2H, H1ʹʹ),
2.32 (s, 3H, H1ʹ), 1.73 – 1.60 (m, 2H, H2ʹʹ), 1.32 (m, 24H, H3ʹʹ-H14ʹʹ ),
0.94 (t, J = 5.7 Hz, 3H, H15ʹʹ); 13C NMR (101 MHz, Chloroform-d) δ 169.5
(C=O), 150.7 (C1), 144.7 (C3), 129.1 (C5), 125.9 (C4), 121.4 (C2), 118.7
(C6), 35.8 (C1ʹʹ), 32.0 (C13ʹʹ), 31.3 (C2ʹʹ), 29.8 (5C) 29.7 (1C), 29.6 (1C),
29.5 (1C), 29.4(1C), 29.3 (1C), 22.8 (C14ʹʹ), 21.1 (C1ʹ), 14.2 (C15ʹʹ);
HRMS (ESI+): Found (M+Na)+ 369.2761, C23H38O2Na (M+Na)+ requires
369.2764.
pentadecyl-2-phenyl-4H-chromen-4-one 13b as a yellow solid (0.141 g,
-1
ꢀ
88%). Mp. 81.2-83.7 °C; IR (ν/cm ): 3406, 2918, 2841, 1643, 1612, 1363,
1203, 1149, 747; 1H NMR (500 MHz, Chloroform-d) δ 8.26 (dd, J = 8.8,
1.5 Hz, 2H, H2ʹ), 8.15 (d, J = 8.1 Hz, 1H, H5), 7.54 (t, J = 7.6, Hz, 2H,
H3ʹ), 7.50–7.44 (m, 1H, H4ʹ), 7.40 (d, J = 1.4 Hz, 1H, H8), 7.28–7.22 (m,
2H, H6 and C3-OH), 2.76 (t, J = 7.7, Hz, 2H, H1ʹʹ), 1.75–1.65 (m, 2H,
H2ʹʹ), 1.41–1.20 (m, 24H, H3ʹʹ-H14ʹʹ), 0.88 (t, J = 6.9, Hz, 3H, H15ʹʹ); 13C
NMR (126 MHz, Chloroform-d) δ 173.4 (C=O), 155.7 (C8a), 150.1 (C7),
144.5 (C2), 138.3 (C3), 131.3 (C1ʹ), 130.0 (C4ʹ), 128.6 (C3ʹ), 127.7 (C2ʹ),
125.6 (C6), 125.2 (C5), 118.6 (C4a), 117.3 (C8), 36.2 (C1ʹʹ), 31.9 (C13ʹʹ),
30.9 (C2ʹʹ), 29.7 (5C), 29.6 (1C), 29.5 (2C), 29.4 (1C), 29.2 (1C), 22.7
(C14ʹʹ), 14.1 (C15ʹʹ); HRMS (ESI+): Found (M+H)+ 449.3054, C30H41O3
(M+H)+ requires 449.3050.
1-(2-Hydroxy-4-pentadecylphenyl)ethanone 12
3-Pentadecylphenyl acetate 11 (0.40 g, 1.16 mmol) was dissolved in
chlorobenzene (6 mL) in a microwave reaction vial. To this solution, AlCl3
(0.38 g, 2.88 mmol) was added. The vial was sealed and the reaction
mixture was subjected to microwave irradiation (150 W, 160 °C) for 30
min. After cooling, the crude product was purified by column
chromatography (10% EtOAc/cyclohexane) to afford 1-(2-hydroxy-4-
3-Pentadecylphenyl-2-fluorobenzoate 15
pentadecylphenyl)ethanone 12 as a light brown solid (0.39 g, 99%). Mp.
-1
ꢀ
49.1-50.5 °C; IR (ν/cm ):2915, 2848, 1636, 1573, 1471, 1365, 1249, 799,
To a stirred solution of 3-pentadecylphenol 7 (2.07g, 6.69 mmol) in 2-
methyl-THF (20 mL), triethylamine (1.37 g, 1.89 mL, 13.58 mmol) and 4-
717; 1H NMR (400 MHz, Chloroform-d) δ 12.31 (s, C2ʹ-OH), 7.65 (d, J =
8.2 Hz, 1H, H6ʹ), 6.81 (d, J = 1.6 Hz, 1H, H3ʹ), 6.74 (dd, J = 8.2, 1.7 Hz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900743
European Journal of Organic Chemistry
dimethylaminopyridine (0.083 g, 0.68 mmol) was added and the mixture
cooled to 0 °C. To this cooled mixture, 2-fluorobenzoyl chloride (1.19 g,
0.89 mL, 7.48 mmol) dissolved in 2-methyl-THF (5 mL) was slowly added
and the reaction mixture was slowly warmed to rt and stirred at rt for 2 h.
The reaction was quenched with water (20 mL) and the mixture extracted
with EtOAc (3 × 50 mL). The combined organic extracts were washed
with aq. NaHCO3 (50 mL) followed by brine (500 mL) and then dried over
MgSO4 and the solvent removed under reduced pressure. The crude
product was purified by column chromatography on silica gel (10%
= 5.8 Hz, 3H, H15ʹ) ppm; 13C NMR (101 MHz, Chloroform-d) δ 177.0
(C=O), 156.3 (C4a), 156.1 (C10a), 151.3 (C3), 134.5 (C6), 126.7 (C8),
126.5 (C1), 124.8 (C2), 123.7 (C7), 121.9 (C8a), 119.8 (C9a), 117.9 (C5),
117.0 (C4), 36.2 (C1ʹ), 31.9 (C13ʹ), 30.9 (C2ʹ), 29.7 (6C), 29.6 (1C), 29.5
(1C), 29.4 (1C), 29.3 (1C), 22.7 (C14ʹ), 14.1 (C15ʹ) ppm; HRMS (ESI+):
Found (M+H)+ 407.2940, C28H39O2 (M+H)+ requires 407.2945.
1,8-Dihydroxy-3-pentadecyl-9H-xanthen-9-one 14
EtOAc/cyclohexane) to afford the 3-pentadecylphenyl-2-flurobenzoate 15
To a 25 mL scintillation vial were added 3-pentadecyl-9H-xanthen-9-one
16 (0.54 g, 1.32 mmol), K2S2O8 (1.44 g, 5.31 mmol), [Ru(p-cymene)Cl2]2
(11 mg, 20.2 mmol), TFAA (10.5 mL) and TFA (4.5 mL). The reaction
vessel was sealed with a Teflon-lined cap and the mixture was heated to
80 °C under TLC-monitoring. After completion, EtOAc was added to
dilute the reaction mixture and saturated aqueous NaHCO3 was added to
neutralize TFA and TFAA. Then the organic layer was dried over
anhydrous Na2SO4 and concentrated in vacuo. Finally, the residue was
purified by silica gel column chromatography (5% EtOAc/hexane) to give
-1
ꢀ
as a white crystalline solid (2.78 g, 98%). Mp. 57.2-58.9 °C; IR (ν/cm ):
2932, 2813, 1702, 1596, 1214, 1130, 1081, 747, 712; 1H NMR (400 MHz,
Chloroform-d) δ 8.14 (td, J = 7.5, 7.5, 1.8 Hz, 1H, H6ʹ), 7.68–7.57 (m, 1H,
H4ʹ), 7.36 (td, J = 7.4, 7.4, 1.3 Hz, 1H, H5), 7.35–7.26 (m, 1H, H5ʹ ), 7.24
(ddd, J = 10.8, 8.3, 1.1 Hz, 1H, H3ʹ), 7.13 (dd, J = 7.7, 1.3 Hz, 1H, H4),
7.10 (d, J = 1.3 Hz, 1H, H2), 7.09–7.06 (m, 1H, H6), 2.68 (t, 2H, H1ʹʹ),
1.73–1.62 (m, 2H, H2ʹʹ), 1.31 (m, 24H, H3ʹʹ-H14ʹʹ), 0.92 (t, J = 5.7 Hz, 3H,
H15ʹʹ); 13C NMR (101 MHz, Chloroform-d) δ 163.6 (C=O), 162.9 (C2ʹ),
162.8 (C2ʹ), 161.0 (C2ʹ), 150.6 (C1), 144.8 (C3), 135.1 (C4ʹ), 132.5 (C6ʹ),
129.2 (C5), 126.1 (C4), 124.1 (C5ʹ), 124.1, 121.5 (C2), 118.8 (C6), 117.3
(C1ʹ), 117.1 (C3ʹ), 35.8 (C1ʹʹ), 32.0 (C13ʹʹ), 31.3 (C2ʹʹ), 29.7 (6C), 29.6
(1C), 29.5 (1C), 29.4 (1C), 29.3 (1C), 22.8 (C14ʹʹ), 14.2 (C15ʹʹ); HRMS
(ESI+): Found (M+Na)+ 449.2881, C28H39FNaO2 (M+Na)+ requires
449.2886.
1-hydroxy-3-pentadecyl-9H-xanthen-9-one as a white crystalline solid
-1
ꢀ
(395 mg, 71%). Mp. 93.7-95.9 °C; IR (ν/cm ): 3401, 2914, 2849, 1630
1
1597, 1498, 1319, 1239, 1077, 1057, 831, 749, 736; H NMR (300 MHz,
Chloroform-d) δ 12.56 (s, 1H, C1-OH), 8.27 (dd, J = 8.0, 1.7 Hz, 1H, H8),
7.73 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H, H6), 7.45 (dd, J = 7.5, 1.0 Hz, 1H, H5),
7.38 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H, H7), 6.77 (d, J = 1.4 Hz, 1H, H2), 6.65
(d, J = 1.4 Hz, 1H, H4), 2.67 (t, J = 7.7, Hz, 2H, H1ʹ), 1.77–1.56 (m, 2H,
H2ʹ), 1.31-1.19 (m, 24H, H3ʹ-H14ʹ), 0.88 (t, J = 6.3 Hz, 3H, H15ʹ) ppm;
13C NMR (76 MHz, Chloroform-d) δ 181.8 (C=O), 161.6 (C1), 156.2
(C4a), 156.2 (C10a), 154.0 (C3), 135.3 (C6), 126.0 (C8), 123.9 (C7),
120.7 (C8a), 117.8 (C5), 110.6 (C4), 107.2 (C9a), 106.8 (C2), 36.8 (C1ʹ),
31.9 (C13ʹ), 30.6 (C2ʹ), 29.7 (6C), 29.5 (1C), 29.5 (1C), 29.4 (1C), 29.2
(1C), 22.7 (C14ʹ), 14.1 (C15ʹ) ppm; HRMS (ESI+): Found (M+H)+
423.2894, C28H39O3 (M+H)+ requires 423.2894. To a 15 mL scintillation
vial was added a portion of the 1-hydroxy-3-pentadecyl-9H-xanthen-9-
one (0.18 g, 0.43 mmol), K2S2O8 (0.46 g, 1.70 mmol), [Ru(p-cymene)Cl2]2
(13.1 mg, 0.022 mmol), TFAA (5.0 mL) and TFA (2.0 mL). The reaction
vessel was sealed with a Teflon-lined cap the mixture was heated to
80 °C under TLC-monitoring. After completion, EtOAc was added to
dilute the reaction mixture and saturated aqueous NaHCO3 was added to
neutralize TFA and TFAA. Then the organic layer was dried over
anhydrous Na2SO4 and concentrated in vacuo. Finally, the residue was
purified by silica gel column chromatography (5% EtOAc/hexane) to
(2-Fluorophenyl)(2-hydroxy-4-pentadecylphenyl)methanone 16
3-Pentadecylphenyl-2-flurobenzoate 15 (0.101 g, 2.37 mmol) was
dissolved in chlorobenzene (12 mL) in a microwave reaction vial. To this
solution, AlCl3 (0.79 g, 5.92 mmol) was added. The vial was sealed and
the reaction mixture was subjected to microwave irradiation (150 W,
160 °C) for 30 min. After cooling, the crude product was purified by
column chromatography (5% EtOAc/cyclohexane) to afford (2-
fluorophenyl)(2-hydroxy-4-pentadecylphenyl)methanone 16 as an off-
-1
ꢀ
white solid (0.85 g, 84%). Mp. 41.4-43.2 °C; IR (ν/cm ): 2916, 2846,
1614, 1454, 1333, 1217, 1162, 914, 759; 1H NMR (400 MHz, Chloroform-
d) δ 12.09 (s, OH, C2-OH), 7.58–7.43 (m, 2H, H4ʹ and H6ʹ), 7.38–7.25 (m,
2H, H3ʹ and H6), 7.21 (ddd, J = 9.5, 8.3, 1.0 Hz, 1H, H5ʹ), 6.91 (d, J = 1.6
Hz, 1H, H3), 6.71 (dd, J = 8.3, 1.7 Hz, 1H, H5), 2.64 (t, 2H, H1ʹʹ), 1.74–
1.59 (m, 2H, H2ʹʹ), 1.30 (m, 24H, H3ʹʹ-H14ʹʹ), 0.91 (t, J = 5.8 Hz, 3H,
H15ʹʹ); 13C NMR (101 MHz, Chloroform-d) δ 197.8 (C=O), 163.3 (C2-OH),
160.3 (C2ʹ), 157.8 (C1ʹ), 153.8 (C4), 133.3 (C6), 132.7 (C6ʹ), 129.8 (C4ʹ),
128.6 (C1), 124.4 (C3ʹ), 119.7 (C4), 117.7 (C3), 116.1 (C5ʹ), 36.4 (C1ʹʹ),
32.0 (C13ʹʹ), 30.6 (C2ʹʹ), 29.8 (6C), 29.6 (1C), 29.5 (1C), 29.4 (1C), 29.3
(1C), 22.7 (C14ʹʹ), 14.2 (C15ʹʹ); HRMS (ESI+): Found (M+H)+ 427.3002,
C28H40FO2 (M+H)+ requires 427.3007.
furnish 1,8-dihydroxy-3-pentadecyl-9H-xanthen-9-one 14 as off-white
-1
ꢀ
solid (121 mg ,64%). Mp. 92.3-93.2 °C; IR (ν/cm ): 2915, 2849, 1633,
1595, 1490, 1471, 1316, 1233, 1079, 1055, 831, 747, 732; 1H NMR (600
MHz, Chloroform-d) δ 11.92 (s, 1H, C8-OH), 11.75 (s, 1H, C1-OH), δ
7.61 (t, J = 8.4, 8.4 Hz, 1H, H6), 6.91 (dd, J = 8.4, 0.9 Hz, 1H, H5), 6.80
(dd, J = 8.3, 0.9 Hz, 1H, H7), 6.77 (d, J = 1.4 Hz, 1H, H4), 6.66 (d, J = 1.4
Hz, 1H, H2), 2.69 (t, 2H, H1ʹ), 1.75–1.64 (m, 2H, H2ʹ), 1.39–1.24 (m, 24H,
H3ʹ-H14ʹ ), 0.89 (t, J = 5.9 Hz, 3H, H15ʹ); 13C NMR (151 MHz,
Chloroform-d) δ 185.7 (C=O), 161.3 (C8), 161.0 (C1), 156.3 (C10a),
156.2 (C4a), 154.9 (C3), 137.2 (C6), 111.0 (C2), 110.7 (C7), 107.8 (C8a),
107.1 (C4), 107.1 (C5), 106.0 (C9a), 36.8 (C1ʹ), 31.9 (C13ʹ), 30.6 (C2ʹ),
29.7 (5C), 29.6 (1C), 29.5 (1C), 29.4 (1C), 29.2 (1C), 26.9 (1C), 22.7
(C14ʹ), 14.2 (C15ʹ); HRMS (ESI+): Found (M+H)+ 439.2861, C28H39O4
(M+H)+ requires 439.2843.
3-Pentadecyl-9H-xanthen-9-one 17
To
a 25 mL round bottom flask were added (2-fluorophenyl)(2-
hydroxyphenyl)methanone 16 (0.225 g, 0.53 mmol), K2CO3 (0.146 g,
1.05 mmol) and 5 mL of acetone at rt. The reaction mixture was heated
to 50 °C for 4 h. The resulting mixture was allowed to cool to rt, the
filtered and then extracted with CH2Cl2. The organic layer was dried over
anhydrous Na2SO4 and the solvent was concentrated in vacuo. Finally,
the residue was purified by silica gel column chromatography (5%
2-Hydroxy-4-pentadecylbenzaldehyde 18
EtOAc/cyclohexane) to give the desired 3-pentadecyl-9H-xanthen-9-one
-1
ꢀ
17 as a white solid (0.183 g, 86%). Mp. 75.2-76.4 °C; IR (ν/cm ): 2915,
2848, 1663, 1606, 1463, 1431, 1344, 1179, 1149, 1109, 959, 758, 727;
1H NMR (400 MHz, Chloroform-d) δ 8.34 (dd, J = 7.9, 1.7 Hz, 1H, H8),
8.24 (d, J = 8.2 Hz, 1H, H1), 7.70 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H, H6), 7.47
(dd, J = 8.5, 1.0 Hz, 1H, H5), 7.36 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H, H7),
7.28 (d, J = 1.3 Hz, 1H, H4), 7.20 (dd, J = 8.2, 1.6 Hz, 1H, H2), 2.75 (t,
2H, H1ʹ), 1.76-1.64 (m, 2H, H2ʹ), 1.40–1.19 (m, 24H, H3ʹ-H14ʹ), 0.88 (t, J
To a stirred mixture of 3-pentadecylphenol 7 (3.04 9, 9.85 mmol), tri-n-
butylamine ((0.4 M), and tin tetrachloride (0.26 g, 0.115 mL, 0.96 mmol)
in toluene (50 mL), at ambient temperature, paraformaldehyde (0.65 g,
21.67 mmol) was added and after 30 min the yellow solution was heated
at 100 °C for 8 h. Then reaction mixture was then cooled and then
poured into water acidified with 2 m HCl and extracted with diethyl ether.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900743
European Journal of Organic Chemistry
The ether extract, was washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. The crude product was purified by
silica gel column chromatography (5 % EtOAc/cyclohexane) to furnish 2-
14.1 (C15ʹʹʹ); HRMS (ESI+): Found (M+H)+ 536.3643, C36H46N3O (M+H)+
requires 536.3636.
hydroxy-4-pentadecylbenzaldehyde 18 as a white solid (2.45 g, 77%).
2-Hydroxy-4-pentadecylbenzonitrile 22
-1
ꢀ
Mp. 50.6-51.8 °C; IR (ν/cm ): 2914, 2848, 1667, 1626, 1470, 1306, 1191,
1128, 797, 735; 1H NMR (400 MHz, Chloroform-d) δ 11.06 (s, 1H, C2-
OH), 9.85 (s, 1H, CHO), 7.46 (d, J = 7.8 Hz, 1H, H6), 6.85 (dd, J = 7.9,
1.5 Hz, 1H, H5), 6.82 (d, J = 1.4 Hz, 1H, H3), 2.63 (t, 2H, H1ʹ), 1.76–1.48
(m, 2H, H2ʹ), 1.40-1.18 (m, 24H, H3ʹ-H14ʹ), 0.89 (t, J = 5.7 Hz, 3H, H15ʹ );
13C NMR (101 MHz, Chloroform-d) δ 195.8 (CHO), 161.8 (C2-OH), 153.8
(C4), 133.6 (C6), 120.5 (C5), 118.8 (C1), 117.1 (C3), 36.4 (C1ʹ), 31.9
(C13ʹ), 30.7 (C2ʹ), 29.7 (6C), 29.6 (1C), 29.5 (1C), 29.4 (1C), 29.3 (1C),
22.7 (C14ʹ), 14.1 (C15ʹ); HRMS (ESI+): Found (M+H)+ 333.2786,
C22H37O2 (M+H)+ requires 333.2788. This data is consistent with that
reported in the literature.28
2-Hydroxy-4-pentadecylbenzaldehyde 18 (1.05 g, 3.15 mmol) and
hydroxylamine hydrochloride (0.29 g, 4.10 mmol) were added
successively to a solution of anhydrous ferric chloride (0.26 g, 1.58
mmol) in 20 mL dry DMF. The mixture was refluxed for 16 h. After
completion of the reaction, the solution was poured into 200 mL water
and extract with EtOAc (3 × 50 mL) and washed several times with water.
The combined organic mixture was dried over anhydrous Na2SO4,
concentrated under reduced pressure and the residue was purified by
column chromatography on silica gel (20% EtOAc/cyclohexane) to
furnish 2-hydroxy-4-pentadecylbenzonitrile 22 as a white solid (0.82 g,
-1
ꢀ
80%). Mp. 71.4-72.9 °C; IR (ν/cm ): 3273, 2957, 2915, 2851, 2229, 1615,
1585, 1470, 1439, 1310, 949, 874, 796; 1H NMR (400 MHz, Chloroform-
d) δ 7.42 (d, J = 7.9 Hz, 1H, H6), 6.85 (d, J = 1.4 Hz, 1H, H3), 6.82 (dd, J
= 7.9, 1.4 Hz, 1H, H5), 6.64 (s, 1H, C2-OH), 2.61 (t, 3H, H1ʹ), 1.67–1.56
(m, 2H, H2ʹ), 1.35–1.23 (m, 24H, H3ʹ-H14ʹ), 0.89 (t, J = 5.6 Hz, 3H, H15ʹ);
13C NMR (101 MHz, Chloroform-d) δ 158.7 (C2), 151.3 (C4), 132.6 (C6),
121.4 (C5), 116.8 (C1ʹ), 116.4 (C3), 96.5 (C1), 36.2 (C1ʹʹ), 31.9 (C13ʹʹ),
30.8 (C2ʹʹ), 29.7 (6C), 29.6 (1C), 29.4 (1C), 29.4 (1C), 29.2 (1C), 22.7
(C14ʹʹ), 14.1 (C15ʹʹ); HRMS: Found (M+Na)+ 352.2605, C22H35NNaO
(M+Na)+ requires 352.2611.
2-(Hydroxymethyl)-5-pentadecylphenol 19
2-Hydroxy-4-pentadecylbenzaldehyde 18 (0.48 g, 1.44 mmol) was
dissolved in 15 mL of freshly distilled dry THF under inert conditions in a
25 mL round bottom flask. The reaction was cooled 0 °C and LiAlH4 (0.22
g, 5.78 mmol) was carefully added. The reaction mixture was slowly
warmed to rt and was stirred for 2 h. Upon completion, the mixture was
cooled again to 0 °C and a 2% aq. NaOH (10 mL) was added dropwise to
quench the unreacted LiAlH4 followed by dilution with ice-cold water (25
mL). The organic material was the extracted with EtOAc (3 × 320 mL)
and combined organic phases were washed with brine (50 mL), dried
over anhydrous Na2SO4, filtered and the solvent was removed in vacuo
6,6',6''-(1,3,5-Triazine-2,4,6-triyl)tris(3-pentadecylphenol) 21
to obtain
a crude product which was then subjected to column
2-Hydroxy-4-pentadecylbenzonitrile 22 (0.37g, 1.12 mmol) was placed in
a microwave vial. The vial was sealed and then subjected to microwave
irradiation (200 W, 220 °C) for 3 h. After cooling, the crude product was
purified by column chromatography (5% EtOAc/cyclohexane) to afford
chromatography (20% EtOAc/cyclohexane) to obtain 2-(hydroxymethyl)-
5-pentadecylphenol 19 as a white crystalline solid (0.39 g, 81%). Mp.
94.6-95.9 °C; IR (ν/cm ): 3442, 3165, 2915, 2847, 1624, 1592, 1463,
-1
ꢀ
1440, 1284, 1125, 992, 826, 753; 1H NMR (400 MHz, Chloroform-d) δ
7.13 (s, 1H, C2-OH), 6.93 (d, J = 7.6 Hz, 1H, H6), 6.73 (d, J = 1.6 Hz, 1H,
H3), 6.67 (dd, J = 7.6, 1.6 Hz, 1H, H5), 4.83 (s, 2H, CH2OH), 2.54 (t, 2H,
H1ʹ), 2.13 (br, s, 1H, ), 1.68–1.49 (m, 2H, H2ʹ), 1.42-1.17 (m, 24H, H3ʹ-
H14ʹ), 0.87 (t, J = 5.6 Hz, 3H, H15ʹ ); 13C NMR (101 MHz, Chloroform-d)
δ 156.0 (C2), 145.0 (C4), 127.6 (C6), 121.9 (C1), 120.2 (C5), 116.5 (C3),
64.6 (-CH2OH), 35.7 (C1ʹ), 31.9 (C13ʹ), 31.3 (C2)ʹ, 29.7 (6C), 29.6 (1C),
29.5 (1C), 29.4 (1C), 29.3 (1C), 22.7 (C14ʹ), 14.1 (C15ʹ); HRMS (ESI+):
Found (M+Na)+ 357.2770, C22H38NaO2 (M+Na)+ requires 357.2764. This
data was consistent with that reported in the literature.29
6,6',6''-(1,3,5-triazine-2,4,6-triyl)tris(3-pentadecylphenol) 21 as
a light
ꢀ
-1
yellowish crystalline solid (0.133g, 73%). Mp. 75.8-77.7 °C; IR (ν/cm ):
2916, 2848, 1630, 1584, 1535, 1494, 1386, 1361, 1310, 1228, 1161,
799; 1H NMR (400 MHz, Chloroform-d) δ 12.98 (s, 1H, C1-OH), 8.04 (d, J
= 8.2 Hz, 1H, H5), 6.90 (s, 1H, H2), 6.85 (dd, J = 8.4, 1.5 Hz, 1H, H4),
2.64 (t, J = 7.7 Hz, 2H, H1ʹʹ), 1.73–1.61 (m, 2H, H2ʹʹ), 1.40–1.20 (m, 24H,
H3ʹʹ-H14ʹʹ), 0.89 (t, J = 5.6 Hz, 3H, H15ʹʹ); 13C NMR (101 MHz,
Chloroform-d) δ 169.2 (C2ʹ), 162.8 (C1), 152.9 (C3), 128.7 (C5), 120.7
(C4), 118.1 (C2), 113.4 (C6), 36.2 (C1ʹʹ), 31.9 (C13ʹʹ), 30.7 (C2ʹʹ), 29.7
(6C), 29.6 (1C), 29.5 (1C), 29.4 (1C), 29.4 (1C), 22.7 (C14ʹʹ), 14.1 (C15ʹʹ);
HRMS: Found (M+H)+ 988.8235, C66H106N3O3 (M+H)+ requires 988.8229.
2-(4,6-Diphenyl-1,3,5-triazin-2-yl)-5-pentadecylphenol 20
3,4-dimethoxybenzohydrazide 24
A mixture of 2-(hydroxymethyl)-5-pentadecylphenol 19 (0.19 g, 0.57
mmol), benzamidine hydrochloride (0.15 g, 0.97 mmol), Na2CO3 (0.10 g,
0.97 mmol) and Cu(OAc)2 (10 mol%) was stirred in toluene (3.5 mL) at
110 °C for 24 h. The resulting mixture was cooled to rt and then extracted
with EtOAc (3 × 10 mL) followed by a brine wash. The organic phases
were combined and dried over anhydrous Na2SO4 and evaporated under
reduced pressure. The crude product was purified by column
chromatography on silica gel (5% EtOAc/cyclohexane) to give 2-(4,6-
Palladium on activated charcoal (10 wt%, 645 mg, 0.61 mmol) was
added at rt to a stirred suspension of veratraldehyde (2.00 g, 12.0 mmol)
and NaOH (1.07 g, 26.4 mmol) in water (48 mL). The mixture was stirred
for 20 h at 80 °C and under a reduced pressure of 800 mbar. After
cooling to rt, the mixture was filtered through Celite® and poured onto 1 n
H2SO4 (60 mL). The resulting precipitate was collected by filtration and
washed with water (120 mL). The filtrate was extracted with EtOAc (3 x
20 mL) and the combined organic extracts were dried over Na2SO4. After
evaporation of the solvent, the resulting solid was combined with the
residue of filtration and dried under reduced pressure in order to obtain
diphenyl-1,3,5-triazin-2-yl)-5-pentadecylphenol 20 as a white crystalline
-1
ꢀ
solid (0.16 g, 62%). Mp. 117.6-119.4 °C; IR (ν/cm ): 2915, 2849, 1587,
1509, 1470, 1394, 1365, 1352, 1314, 1232, 753, 689; 1H NMR (400 MHz,
Chloroform-d) δ 13.27 (s, 1H, C1-OH), 8.66 (dd, J = 11.2, 7.8 Hz, 6H,
H2ʹʹ and H4ʹʹ), 7.77 – 7.49 (m, 5H, H3ʹʹ and H3), 6.93 (d, J = 1.6 Hz, 1H,
H6)), 6.89 (dd, J = 8.2, 1.7 Hz, 1H, H4), 2.68 (t, 2H, H1ʹʹʹ), 1.77–1.66 (m,
2H, H2ʹʹʹ), 1.41–1.22 (m, 24H, H3ʹʹʹ-H14ʹʹʹ) (0.90 (t, J = 5.8, 3H, H15ʹʹʹ);
13C NMR (101 MHz, Chloroform-d) δ 171.9 (C2ʹ and C6ʹ, 162.2 (C1),
151.5 (C5), 135.3 (C1ʹʹ), 133.0 (C2ʹʹ), 129.8 (C3), 129.0 (C3ʹʹ), 128.8
(C4ʹʹ), 120.1 (C4), 117.7 (C6), 115.2 (C2), 36.2 (C1ʹʹʹ), 31.9 (C13ʹʹʹ), 30.9
(C2ʹʹʹ), 29.7 (6C), 29.6 (1C), 29.5 (1C), 29.4 (1C), 29.3 (1C), 22.7 (C14ʹʹʹ),
3,4-dimethoxybenzoic acid as a colourless solid (1.92 g, 10.5 mmol,
-1
ꢀ
87%). Mp. 178.3–180.1 °C; IR (ν/cm ): 2964, 2836, 1671, 1516, 1298,
1266, 1232, 1023, 917, 758; 1H NMR (300 MHz, Chloroform-d) δ 11.39 (s,
1H, CO2H), 7.79 (dd, J = 8.4, 2.0 Hz, 1H, H6), 7.60 (d, J = 2.0 Hz, 1H,
H2), 6.92 (d, J = 8.5 Hz, 1H, H5), 3.96 (s, 3H, C4-OCH3), 3.95 (s, 3H,
C3-OCH3); 13C NMR (76 MHz, Chloroform-d) δ 172.0 (CO2H), 153.7 (C4)
148.7 (C3), 124.6 (C6), 121.7 (C1), 112.3 (C2), 110.3 (C5), 56.1 (C4-
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900743
European Journal of Organic Chemistry
OCH3), 56.0 (C3-OCH3); MS (ESI+): m/z (%) = 181.1 (100) [M–H]–. The
analytical data are in accordance with the literature.30 A solution of 3,4-
dimethoxybenzoic acid (800 mg, 4.39 mmol) and conc. H2SO4 (90.0 µL,
1.62 mmol) in EtOH (5 mL) was stirred for 18 h under reflux. After cooling
to rt the solvent was evaporated and the residue was dissolved in diethyl
ether (15 mL). After washing with saturated aq NaHCO3 (5 mL) and
drying over Na2SO4 the solvent was evaporated in order to obtain ethyl
3,4-dimethoxybenzoate as a colourless oil (868 mg, 4.13 mmol, 94%). IR
To a stirred solution of N'-[(2-hydroxy-4-pentadecylphenyl)methylidene]-
3,4-dimethoxybenzohydrazide 25 (100 mg, 196 µmol) in dry acetone
(4 mL) was added PIDA (126 mg, 392 µmol) under an atmosphere of
argon. The resulting mixture was stirred for 2.5 h at rt and another portion
of PIDA (63.1 mg, 196 µmol) was added. After stirring for a further 2.5 h,
the solvent was evaporated and the residue was purified by column
chromatography on silica gel (5–70% EtOAc/cyclohexane) in order to
obtain
2-[5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-5-
-1
1
ꢀ
(ν/cm ): 2979, 2839, 1708, 1514, 1345, 1290, 1269, 1177, 1025, 763; H
NMR (300 MHz, Chloroform-d) δ 7.68 (dd, J = 8.4, 2.0 Hz, 1H, H6), 7.55
(d, J = 2.0 Hz, 1H, H2), 6.88 (d, J = 8.4 Hz, 1H, H5), 4.36 (q, J = 7.1 Hz,
2H, CH2CH3), 3.93 (s, 6H, C3-OCH3 ,C4-OCH3), 1.39 (t, J = 7.1 Hz, 3H,
CH2CH3); 13C NMR (76 MHz, Chloroform-d) δ 166.4 (CO2Et), 152.8 (C4)
148.5 (C3), 123.4 (C6), 123.0 (C1), 111.9 (C2), 110.2 (C5), 60.8
(CH2CH3), 56.0 (2C, C3-OCH3, C4-OCH3), 14.4 (CH2CH3); MS (ESI+):
m/z (%) = 211.1 (100) [M+H]+, 233.1 (5) [M+Na]+. The analytical data are
pentadecylphenol 23 as a yellowish solid (46.3 mg, 91.0 µmol, 47%). Mp.
-1
ꢀ
106.5–107.9 °C; IR (ν/cm ): 2955, 2919, 2850, 1609, 1583, 1503, 1469,
1284, 1229, 1098, 721; 1H NMR (400 MHz, Chloroform-d) δ 10.12 (s, 1H,
OH), 7.75 (d, J = 8.0 Hz, 1H, H3), 7.71 (dd, J = 8.4, 2.0 Hz, 1H, H6‘),
7.64 (d, J = 2.0 Hz, 1H, H2‘), 7.00 (d, J = 8.4 Hz, 1H, H5‘), 6.97 (d, J =
1.4 Hz, 1H, H6), 6.86 (dd, J = 8.0, 1.6 Hz, 1H, H4), 4.01 (s, 3H, C3‘-
OCH3), 3.98 (s, 3H, C4‘-OCH3), 2.64 (t, J = 7.5 Hz, 2H, H1‘‘), 1.63 (q,
J = 7.3 Hz, 2H, H2‘‘), 1.33–1.23 (m, 24H, H3‘‘–H14‘’), 0.88 (t, J = 6.8 Hz,
3H, H15‘‘) ppm; 13C NMR (101 MHz, Chloroform-d) δ 164.0 (oxadiazole-
C2), 163.0 (oxadiazole-C5), 157.6 (C1), 152.3 (C4‘), 149.7 (C5), 149.4
(C3‘), 128.6 (C6‘), 126.2 (C3), 120.4 (C4), 117.2 (C6), 115.9 (C1‘), 111.1
(C5‘), 109.4 (C2‘), 105.8 (C2), 56.2 (C3‘-OCH3), 56.1 (C4‘-OCH3), 36.1
(C1‘‘), 31.9 (C13‘‘), 30.9 (C2‘‘), 29.7 (6C), 29.6, 29.5, 29.4, 29.2, 22.7
(C14‘‘), 14.1 (C15‘‘); MS (ESI+): m/z (%) = 509.6 (100) [M+H]+; HRMS
(ESI+): Found (M+H)+ 509.3372, C31H45N2O4 (M+H)+ requires 509.3379.
in accordance with the literature.31
A
solution of ethyl 3,4-
dimethoxybenzoate (868 mg, 4.13 mmol.) and hydrazine hydrate
(64 wt%, 600 µL, 12.4 mmol) in EtOH (0.3 mL) was refluxed for 18 h
while stirring. After cooling to rt, the solvent was evaporated and the
residue was dissolved in water (10 mL). The resulting solution was
extracted with EtOAc (10 x 10 mL) and the combined organic extracts
were dried over Na2SO4 and evaporated in order to obtain 3,4-
dimethoxybenzohydrazide 24 as a colourless solid (770 mg, 3.92 mmol,
-1
ꢀ
95%). Mp. 132.8–134.4 °C; IR (ν/cm ): 3307, 2939, 2845, 1626, 1500,
1275, 1148, 1073, 957, 635; 1H NMR (300 MHz, DMSO-d6) δ 9.62 (s, 1H,
NHNH2), 7.44 (dd, J = 8.2, 1.2 Hz, 1H, H6), 7.42 (d, J = 2.0 Hz, 1H, H2),
6.99 (d, J = 8.2 Hz, 1H, H5), 4.42 (s, 2H, NHNH2), 3.79 (s, 6H, C3-OCH3,
C4-OCH3); 13C NMR (76 MHz, DMSO-d6) δ 165.5 (CO2NHNH2), 151.0
(C4) 148.1 (C3), 125.4 (C1), 120.0 (C6), 110.8 (C5), 110.1 (C2), 55.5
(C3-OCH3/C4-OCH3), 55.4 (C3-OCH3/C4-OCH3); MS (ESI+): m/z (%) =
197.4 (100) [M+H]+, 219.3 (22) [M+Na]+. The analytical data are in
accordance with the literature.17
Acknowledgements
The authors would like thank the German Federal Ministry of
Education and Research (BMBF, grant no. 01DG17013) and the
South African National Research Foundation (NRF) for joint
funding of the project.
Keywords: keyword 1 anarcardic acid • keyword 2 cardanol•
keyword 3 UV spectra• keyword 4 aromatic compounds•
keyword 5 synthesis
2-[5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-5-pentadecylphenol
25
To a stirred solution of 2-hydroxy-4-pentadecylbenzaldehyde (500 mg,
1.51 mmol) in diethyl ether (3.5 mL) and MeOH (3.5 mL) was added 3,4-
dimethoxybenzohydrazide 24 (325 mg, 1.66 mmol). The resulting mixture
was stirred over night at rt. During that time a colorless solid precipitated
which was collected by filtration, washed with cyclohexane/EtOAc = 10/1
(30 mL) and dried under reduced pressure. Thus N'-[(2-hydroxy-4-
pentadecylphenyl)methylidene]-3,4-dimethoxybenzohydrazide 25 was
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H2’‘), 1.34–1.23 (m, 24H, H3‘‘–H14’‘), 0.87 (t, J = 6.9 Hz, 3H, H15‘‘) ppm;
13C NMR (151 MHz, acetone-d6) δ 162.2 (CONH), 158.6 (C2‘), 152.6
(C4), 149.2 (C3), 149.1 (CHN), 146.9 (C4‘), 130.7 (C6‘), 125.2 (C1),
120.7 (C6), 119.5 (C5‘), 116.5 (C3‘), 115.9 (C1‘), 110.9 (C5), 110.8 (C2),
55.2 (2C, C3-OCH3, C4-OCH3), 35.6 (C1‘‘), 31.8 (C13‘‘), 31.0 (C2‘‘), 29.5
(6C), 29.4, 29.3, 29.2 (2C), 22.5 (C14‘‘), 13.5 (C15‘‘) ppm; MS (ESI+):
m/z (%) 511.7 (100) [M+H]+; HRMS (ESI+): Found (M+H)+ 511.3514,
C31H47N2O4 (M+H)+ requires 511.3536.
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10.1002/ejoc.201900743
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10.1002/ejoc.201900743
European Journal of Organic Chemistry
FULL PAPER
The synthesis of aromatic UV
absorbers from the bio-renewables,
cardanol and anacardic acid is
described
Kennedy J. Ngwira, [a] Jonas Kühlborn, [b]
Quintino A. Mgani, [c] Charles B. de
Koning, [a]* and Till Opatz [b]
*
Key topic: Cashew Nut Shell Liquid, UV
absorbers
Page No. – Page No.
Title Valorisation of Cashew Nut Shell
Liquid Phenolics in the Synthesis of
UV Absorbers
This article is protected by copyright. All rights reserved.