Dimerization of ferulic acid and structure determination of phenylindane derivatives

Article abstract of DOI:10.1007/s11164-015-2232-x

Ferulic acid dimers with phenylindane skeletons were obtained from ferulic acid 1 in an acidic ethanol solution. The reaction conditions used to prepare the dimers or the ester were examined in detail, and the stereochemistries of the dimers were determined. The structural features of the dimers and the diastereoselective formation mechanisms involved in forming the two types of dimers (the racemic diastereomer 8α, which was a major product, and the racemic diastereomer 8γ, which was a minor product) were characterized.

Full text of DOI:10.1007/s11164-015-2232-x

Res Chem Intermed
DOI 10.1007/s11164-015-2232-x
Dimerization of ferulic acid and structure
determination of phenylindane derivatives
Eisaku Nomura1 Yasuhiro Kakimoto1
•
•
Tomoya Yamamoto1 Takumi Noda1
Yasuhito Miyake2 Hajime Mori2
•
•
•
Received: 29 April 2015 / Accepted: 13 August 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract Ferulic acid dimers with phenylindane skeletons were obtained from
ferulic acid 1 in an acidic ethanol solution. The reaction conditions used to prepare
the dimers or the ester were examined in detail, and the stereochemistries of the
dimers were determined. The structural features of the dimers and the diastereos-
elective formation mechanisms involved in forming the two types of dimers (the
racemic diastereomer 8a, which was a major product, and the racemic diastereomer
8c, which was a minor product) were characterized.
Keywords Ferulic acid Á Dimerization Á Cycloaddition Á Phenylindane
Introduction
Ferulic acid 1 is a propenylbenzene for which we have developed a mass production
method, starting from rice bran [1, 2], while 1 is commonly found in cereals,
grasses, vegetables, and so on [3]. Interest in the industrial use of 1 and its
derivatives has intensified in recent years, for example, it has been used in cancer
preventative agents [2–7], agents for controlling germination [8], UV absorbers [9],
and insulin secretagogues [10]. In a number of the related compounds of 1, various
types of dimerized products of 1 are known, for example, 5-5-, 8-5-, and 8-8-
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2232-x)
contains supplementary material, which is available to authorized users.
&
Eisaku Nomura
nomura@wakayama-nct.ac.jp
1
2
Department of Materials Science, National Institute of Technology, Wakayama College,
77 Noshima, Nada, Gobo, Wakayama 644-0023, Japan
Industrial Technology Center of Wakayama Prefecture, 60 Ogura, Wakayama 649-6261, Japan
123

E. Nomura et al.
coupled diferulates are important components in plant cell walls [11–15]. The
oxidative dimerization of feruloyl ester has been shown to afford dihydrobenzofuran
analogue 2, which is biologically active [16]. The photodimerization of
O-substituted ferulic acid in the crystal state was found to stereospecifically afford
its dimer 3 [17].
In our preliminary experiment, dimerized products were found to be produced, to
some extent, when 1 was esterified under acidic conditions, and the major product
was identified as being a phenylindane derivative. Various lignane-related dimers
have been found to be derived from propenylbenzene through biosyntheses or
organic syntheses. In particular, asarone dimer 5, which has a phenylindane
structure, has been found in the essential oil of Acorus calamus, and this oil is an
insect growth regulator [18]. Synthetic approaches to prepare the dimers from
asarone 4 or other starting materials have also been investigated under acidic
conditions [19–21]. Interest in the potential for the phenylindane skeleton to be a
valuable structure in pharmaceuticals has led to the stereoselective synthesis of
compounds containing an indane ring to be investigated using different types of
reactions and starting materials [22–28]. Phenylindanes dimerized from ferulic acid
have been obtained from the reaction of 1 in methanol in the presence of p-
toluenesulfonic acid [29], and various phenylindane derivatives 6a–d were iden-
tified from this reaction. Phenylindane 6a was the major product, and no other
diastereomers have been found from this reaction. However, the method used for
this reaction was poorly reproducible because the synthetic details were not
explored in any depth.
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Dimerization of ferulic acid and structure determination…
Here, we report the details of the synthesis and the stereochemistry of racemic
diastereomers with phenylindane structure that were prepared from ferulic acid.
Results and discussion
The ferulic acid reaction was performed in the presence of sulfuric acid and ethanol,
and the products were separated using a SiO2 column [eluted with a 1:1 mixture of
hexane and ethyl acetate (EtOAc)] to afford the ester 7 and a mixture of the
diastereomeric dimers 8, which each have a phenylindane structure (Scheme 1).
The indane 8 has three chiral carbons, so it has four different racemic
diastereomers (a, b, c, and d) [30], which are shown in Fig. 1. HPLC–MS (ESI-
TOFF) analysis showed four components indicating m/z of 443.1695, 443.1691,
443.1703, and 443.1689. These values agreed with the corresponding indane 8
(m/z 443.1706 [M–H?]-), suggesting four different enatiomeric racemates were
included (see Supplementary data). However, we could not isolate the diastereomers
using column chromatography because the two predominant dimers have almost the
same Rf values. Therefore, we recrystallized the major diastereomer again and again
from a mixture of hexane and EtOAc to give white crystals. The 1H NMR spectrum
of these crystals is shown in Fig. 2a. The crystals were identified as indane 8a from
1
1H and 13C NMR, COSY, NOESY, and ESI-TOFMS spectral data. The H NMR
signals for the protons, 1-H, 2-H, and 3-H bound to the three chiral carbons
appeared at d = 3.97, 3.41, and 4.62 ppm, respectively, and the inter-proton
coupling constants J1–2 and J2–3 for 8a were 8.2 and 10.3 Hz, respectively. The 3-H
is on the opposite side of the 8a to the 2-H, and the 1-H is on the same side as the
2-H. No cross peak was, therefore, observed between 1-H and 3-H in the NOESY
spectrum for 8a, but cross peaks between 1-H and 2-H and between 2-H and 3-H
were observed. The structure of the crystals was also determined by X-ray
diffraction, and the result of this analysis agreed with the molecular structure of 8a
(Fig. 3a). Two enantiomers were packed in the crystal lattice, as shown in Fig. 4a.
Therefore, indane 8a crystals were found to be racemates of 8a (cis–trans). Another
dimer 8c was isolated from the residual solid, which was obtained after
recrystallization of 8a, by preparative HPLC. The NMR and ESI-TOFMS spectra
of 8c were used to determine its molecular structure. The 1H NMR spectral data for
8c are shown in Fig. 2b. Proton signals for 1-H, 2-H, and 3-H appeared at d = 3.8
(overlapping the methoxy proton signal), 3.00, and 4.47 ppm, respectively, and the
Scheme 1 Synthesis of phenylindanes under the esterification conditions
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E. Nomura et al.
Fig. 1 Stereoisomers of ferulic acid dimer 8
coupling constants J1–2 and J2–3 were similar (J = 9.3 Hz). This indicates that, in
indane 8c, 1-H and 3-H are both either on the same side of the molecule as 2-H or
on the opposite side of the molecule to 2-H. Cross-peaks between 1-H, 2-H, and 3-H
were all observed in the NOESY spectrum of 8c. Fortunately, a crystal of indane 8c
was obtained, despite the small amount of the product that was isolated, and its
molecular structure, shown in Fig. 3b, was determined. The crystal contained two
enantiomers packed in the crystal lattice, as shown in Fig. 4b, therefore, the most
likely configuration is 8c because 1-H and 3-H are on the opposite side of this
molecule to 2-H allowing the bulky substituents to be arranged in a sterically
unhindered configuration.
The acid catalyzed [3 ? 2] cycloadditions of various propenylbenzenes such as
isosafrole 9, isohomogenol 10, and anethol 11 were investigated by Morris et al.
[31], and the configurations of the 1-H, 2-H, and 3-H in the a-, b-, and c-racemates
were established. The a-racemate is a major product of reactions of 9 and 10, and
the c-racemate is a major product of 11. The asarone dimer 5 also has a c-racemate
as a major product. Therefore, the configuration of the major dimer product seems to
depend on the substituent connected to the propenylbenzene aromatic ring.
The reaction conditions for the dimerization of ferulic acid were investigated in
detail. The effects of the sulfuric acid concentration on the yields of the ester 7 and
dimers 8a and 8c are shown in Table 1. At sulfuric acid to 1 molar ratios of below
ca. 5, the ester 7 was the main product (Table 1, Entry 1 and 2) and at molar ratios
of 10–30, dimers 8a and 8c were produced in 30–35 and 11–15 % yields,
respectively (Table 1, Entry 3–6). Next, the effects of the ethanol to 1 molar ratio on
the yields of 7, 8a, and 8c were determined, and these are also shown in Table 1.
The maximum yields of indane 8a were obtained at molar ratios of 50 and 60
(Table 1, Entry 12 and 13), and the yield decreased as the ratio was increased
further. Ester 7 was produced as a major product when the molar ratio was higher
than 70 (Table 1, Entry 14 and 15). Indane 8c was formed in approximately
14–16 % yield when the molar ratio was between 30 and 60 (Table 1, Entry 10–13).
Shorter reaction time gave better yields. The reaction profiles for products 7, 8a, and
123

Dimerization of ferulic acid and structure determination…
(a)
(b)
Fig. 2 1H NMR (400 MHz, CDCl3) spectra of a 8a and b 8c
8c over time were investigated, and the results are shown in Fig. 5. The
concentration of ester 7 increased in the initial stage of the reaction, and then it
decreased as the concentration of indanes 8a and 8c increased. The concentration of
each of the indanes stopped increasing after 30 min, despite the continuing
decreases in the concentration of ester 7. Other products of the transformation of the
123

E. Nomura et al.
Fig. 3 ORTEP drawing of indane a 8a and b 8c. The displacement ellipsoids are drawn at the 50 %
probability level, except for the H atoms
Fig. 4 Crystal structure of indane a 8a and b 8c. Hydrogen atoms 1-H, 2-H, and 3-H are shown in
yellow, and the other hydrogen atoms are omitted to improve the clarity of the diagrams. The projection is
along the b axis of the unit cell for 8a and along the a axis of the unit cell for 8c. (Colour figure online)
ester were not identified because only small amounts of these complex mixtures
were detected by TLC and only a trace of the mixtures were separated by column
chromatography.
This dimerization reaction is known to proceed by a formal [2 ? 3] cycload-
dition, and, assuming that the reaction follows a stepwise pathway, some points
related to the diastereoselectivity of the reaction were deduced, and these are shown
in Scheme 2. Ester 7 is first produced during the reaction, then the protonation of 7
affords benzylic cation 12. The methoxy group connected to the phenyl ring of 1
stabilizes the stacking configuration through CH–p interactions [32]. We assumed
123

Dimerization of ferulic acid and structure determination…
Table 1 Synthesis of ester and indanes in the different amounts of acid and ethanol
Entry
H2SO4/1 (mol/mol)
EtOH/1 (mol/mol)
Time (h)
Yield (%)
7
8a
0.0
8c
0.0
1
0.61
5.14
10.0
15.1
21.2
29.4
25
63.4
63.4
63.4
63.4
63.4
63.4
63.4
10
2
2
2
2
2
2
1
1
1
1
1
1
1
1
1
68.2
92.7
59.6
27.4
1.3
2
0.6
33.3
32.9
34.8
30.1
41.5
0.1
0.0
11.2
11.4
14.7
15.1
17.2
0.1
3
4
5
6
0.7
7
16.4
0.0
8
25
9
25
20
0.2
1.5
1.7
10
11
12
13
14
15
25
30
0.5
21.3
30.8
40.9
43.0
30.2
1.5
13.6
14.7
16.0
16.1
6.2
25
40
0.7
25
50
5.5
25
60
18.6
39.4
78.0
25
70
25
100
0.0
Reaction conditions: 1.35 mmol of 1, reflux temperature. The yields were estimated by HPLC
Fig. 5 Time courses of the concentrations of 7, 8a, and 8c during the reaction. Conditions: 2.70 mmol of
1, 10 mL of EtOH, 67.5 mmol of H2SO4, reflux
that cation 12 could react with an ester in two different ways (A) with strong
interactions between the phenyl rings of the esters or (B) with relatively weak
interactions between the phenyl rings of the esters. The A and B reaction modes of
cation 12 will afford benzylic cations 13A and 13B, respectively, retaining the trans
123

E. Nomura et al.
Scheme 2 Proposed reaction mechanism for the formation of the indanes
configuration of the ferulic acid moiety [28]. When the reaction occurs, 13A is the
major product, and it immediately cyclizes to afford 8a as the main product,
because it retains the former trans configuration of the cation (path a). The other
cation 13B, which can be produced, gives indane 8c as the main product (path b) for
the reason mentioned above. The 2-H and 3-H are most likely on opposite sides of
the indane 8a and 8c molecules, which indicate that the bulky phenyl ring will be
arranged in a sterically unhindered position. To support these results, experimental
work on the effect of the methoxy group connected to the phenyl ring of 1 to
produce phenylindanes enatioselectively are in progress.
Conclusion
Ferulic acid 1 is a renewable natural product that can be obtained from rice bran,
and now commercially available. It is important to develop a wide range of useful
derivatives of this molecule because of their potential uses. Here, we have presented
the synthesis of two types of dimers, having phenyl indane structure from 1, and we
have discussed the diastereoselectivity of the dimers. It was speculated that the
methoxy group at the meta position of the phenyl ring has an important role for
phenylindane derivative deastereoselectively. The optimum reaction conditions
(50–60 equiv ethanol, [10 equiv H2SO4, [0.5 h reaction time, reflux temperature)
gave dimers 8a and 8c in 30–43 % and ca. 15 % yields, respectively.
Experimental
All solvents and reagents were obtained commercially and used without further
purification. 1H NMR, 13C NMR, and two-dimensional NMR spectra were
recorded on a Bruker Avance-400 instrument using TMS as an internal standard.
123

Dimerization of ferulic acid and structure determination…
FT-IR spectra were recorded using a single reflection horizontal ATR. HRMS
(ESI-TOF) spectra and HPLC–MS (ESI-TOF) equipped with an octadecylsiliyl
column (150 mm long, 2 mm diameter) were measured in negative ionization
mode, and the data are reported in the form of m/z values. Melting points were
determined by using a differential scanning calorimeter and the peak top
temperatures are reported.
Preparation of indane 8a and 8c
To a solution of 900 mg of ferulic acid (4.64 mmol) in ethanol (15 mL), which
was cooled in an ice bath and kept under an Ar atmosphere, was added 5.4 mL
of sulfuric acid (101 mmol). The mixture was stirred for 1 h at reflux
temperature, then ice water was added to stop the reaction. The products were
extracted with dichloromethane, and the extract was washed with water, water
saturated with sodium bicarbonate, and water again. The organic portion was
dried over MgSO4. After evaporating the solvent, the product was dissolved and
purified through a SiO2 column (eluted with a 1:1 mixture, by volume, of hexane
and EtOAc), which afforded 86 mg of ester 7 and 500 mg of the indane mixture
(containing two diastereomers 8a and 8c). The mixture was recrystallized from a
mixture of hexane and EtOAc several times to give white crystals (indane 8a).
Indane 8c was isolated form the residual mixture by a preparative HPLC to give
9 mg of solid.
1
8a: 35 % yield (estimated from H NMR). mp 162 °C (from hexane/EtOAc).
(ATR) mmax (ATR) 3387 (OH), 1732 (CO). dH (400 MHz, CDCl3, Me4Si) 1.23 (3H,
t, J = 7.3 Hz, CH2CH3), 1.26 (3H, t, J = 7.3 Hz, CH2CH3,), 2.45 (1H, dd,
J = 15.9, 8.9 Hz, CH2), 2.62 (1H, dd, J = 16.1, 6.0 Hz, CH2), 3.41 (1H, dd,
J = 10.0, 8.3 Hz, CH), 3.82 (3H, s, OCH3), 3.86 (3H, s, OCH3), 3.97 (1H, td,
J = 8.5, 8.5, 6.1 Hz, CH), 4.07–4.17 (4H, m, CH2CH3), 4.62 (1H, d, J = 10.3 Hz,
CH), 5.54 (2H, s, OH), 6.47 (1H, d, J = 1.0 Hz, ArH), 6.69 (2H, d, J = 2.0 Hz,
ArH), 6.71 (2H, dd, J = 8.0, 2.0 Hz, ArH), 6.78 (1H, s, ArH), 6.84 (1H, d,
J = 8.0 Hz, ArH). dC (100 MHz, CDCl3, Me4Si) 14.2, 14.3, 36.9, 42.2, 51.3, 56.0,
56.1, 58.7, 60.5, 60.7, 106.6, 110.9, 111.0, 114.3, 121.4, 134.4, 135.1, 137.1, 144.5,
145.6, 146.1, 146.5, 172.3, 172.5. HRMS (ESI-TOFF) m/z found: 443.1682
[M–H?]- calcd. for [C24H27O8]-: 443.1706.
1
8c: 14 % yield (estimated from H NMR). mp 141 °C (from hexane/EtOAc).
mmax (ATR) 3390 and 3348 (OH), 1724 and 1709 (CO). dH (400 MHz, CDCl3,
Me4Si) 1.22 (3H, t, J = 7.2 Hz, CH2CH3), 1.27 (3H, t, J = 7.2 Hz, CH2CH3), 2.77
(1H, dd, J = 15.8, 6.8 Hz, CH2), 2.86 (1H, dd, J = 15.6, 6.3 Hz, CH2), 3.00 (1H, t,
J = 9.3 Hz, CH) 3.83 (3H, s, OCH3), 3.81–3.86 (1H, m, CH), 3.88 (3H, s, OCH3),
4.11–4.19 (4H, m, CH2CH3), 4.47 (1H, d, J = 9.3 Hz, CH), 5.53 (1H, s, OH), 5.54
(1H, s, OH), 6.46 (1H, d, J = 1.0 Hz, ArH), 6.69–7.71 (3H, m, ArH), 6.85 (1H, dd,
J = 7.5, 1.0 Hz, ArH). dC (100 MHz, CDCl3, Me4Si) 14.26, 14.28, 39.3, 43.8, 53.6,
56.0, 56.1, 60.6, 60.7, 61.2, 105.6, 110.75, 110.77, 114.3, 121.3, 134.5, 135.0,
137.1, 144.6, 145.5, 146.3, 146.6, 172.1, 173.9. HRMS (ESI-TOFF) m/z found:
443.1692 [M–H?]- calcd. for [C24H27O8]-: 443.1706.
123

E. Nomura et al.
Crystal structure analysis of 8a and 8c
Single crystals of 8a and 8c were recrystallized from hexane/EtOAc. X-ray
diffraction data were measured on a diffractometer (Rigaku R-AXIS RAPID II)
˚
using graphite-monochromated MoKa radiation (k = 0.71073 A) at 298 K for 8a
˚
and using CuKa radiation (k = 1.54187 A) at 123 K (cold gas stream) for 8c. The
crystal data have been deposited at the Cambridge Crystallographic Data Centre and
have deposition number CCDC 995488 for 8a and CCDC 995489 for 8c. Copies of
these data can be obtained free of change on application to CCDC, 12, Union Road,
Cambridge, CB2 1EZ, UK (fax: ?44-(0)1223-336033 or e-mail: deposit@ccdc.-
cam.ac.uk) or from http://www.ccdc.cam.ac.uk/data_request/cif.
Crystal data
˚
8a, M = 444.48, monoclinic, a = 18.879(6), b = 6.5980(16), c = 20.643(5) A,
3
U = 2376.4(11) A , T = 298 K, space group P2/c (no. 13), Z = 4, 22,244
˚
reflections measured, 5361 were unique (Rint = 0.054) and were used in all of the
calculations. The final wR(F2) was 0.2024 (all data). 8c, M = 444.48, monoclinic,
3
˚
˚
a = 10.6707(2), b = 16.1524(3), c = 12.7293(3) A, U = 2185.57(7) A ,
T = 123 K, space group P21/c (no. 14), Z = 4, 21,639 reflections measured,
3992 were unique (Rint = 0.0361) and were used in all calculations. The final
wR(F2) was 0.1166 (all data).
Determination of yields of the products at the various conditions
To a solution of 300 mg of ferulic acid (1.35 mmol) in ethanol (13.5–135 mmol),
which was cooled in an ice bath and kept under Ar atmosphere, was added sulfuric
acid (0.61–29.4 mmol). The mixture was stirred at reflux temperature for 1–2 h and
then ice water was added to stop the reaction. The products were extracted with
dichloromethane, and the extract was washed with water, water saturated with
sodium bicarbonate, and water again. The organic portion was dried over MgSO4.
After evaporating the solvent, the product was analyzed by HPLC, in which 7, 8a,
and 8c were separated using an octadecylsilyl column (75 mm long, 4 mm
diameter) at 30 °C and detected at a wavelength of 290 nm. The mobile phase was a
60:40 mixture of methanol and 0.2 % aq. formic acid, and it was used at a flow rate
of 1 mL/min.
Time-course measurement for the conversion of ferulic acid to ester
and indanes
To a solution of 600 mg of ferulic acid (2.70 mmol) in ethanol (10 mL), which was
cooled in an ice bath and kept under Ar atmosphere, was added 3.6 mL of sulfuric
acid (67.5 mmol). The mixture was stirred at reflux temperature. An aliquot was
withdrawn from the reaction mixture at each of the defined time points, and the
same volume of a 1:1 mixture, by volume, of methanol and water was then added to
123

Dimerization of ferulic acid and structure determination…
the original reaction mixture to keep its volume at 10 mL. The samples were
analyzed by HPLC.
Acknowledgments Ferulic acid was generously supplied by Tsuno Rice Fine Chemical Co. Ltd., for
which we are grateful.
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