Cathodic reductive coupling of methyl cinnamate on boron-doped diamond electrodes and synthesis of new neolignan-type products

Article abstract of DOI:10.3762/bjoc.11.21

The electroreduction reaction of methyl cinnamate on a boron-doped diamond (BDD) electrode was investigated. The hydrodimer, dimethyl 3,4-diphenylhexanedioate (racemate/meso = 74:26), was obtained in 85% yield as the major product, along with small amounts of cyclic methyl 5-oxo-2,3-diphenylcyclopentane-1-carboxylate. Two new neolignan-type products were synthesized from the hydrodimer.

Full text of DOI:10.3762/bjoc.11.21

Cathodic reductive coupling of methyl cinnamate on
boron-doped diamond electrodes and synthesis of
new neolignan-type products
Taiki Kojima1, Rika Obata2, Tsuyoshi Saito3,4, Yasuaki Einaga*1,4
and Shigeru Nishiyama*1,4
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 200–203.
1Department of Chemistry, Faculty of Science and Technology, Keio
University, Hiyoshi 3-14-1 Kohoku-ku, Yokohama 223-8522, Japan,
2Research and Education Center for Natural Sciences, Keio
University, Hiyoshi 4-1-1 Kohoku-ku, Yokohama 223-8521, Japan,
3International Institute for Integrative Sleep Medicine, University of
Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan and
4Japan Science and Technology Agency (JST), CREST, Hiyoshi
3-14-1, Yokohama 223-8522, Japan
doi:10.3762/bjoc.11.21
Received: 23 November 2014
Accepted: 16 January 2015
Published: 03 February 2015
This article is part of the Thematic Series "Electrosynthesis".
Guest Editor: S. R. Waldvogel
Email:
Yasuaki Einaga* - einaga@chem.keio.ac.jp; Shigeru Nishiyama* -
nisiyama@chem.keio.ac.jp
© 2015 Kojima et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
boron-doped diamond (BDD) electrode; cathodic reduction;
electrochemistry; electrosynthesis; neolignan
Abstract
The electroreduction reaction of methyl cinnamate on a boron-doped diamond (BDD) electrode was investigated. The hydrodimer,
dimethyl 3,4-diphenylhexanedioate (racemate/meso = 74:26), was obtained in 85% yield as the major product, along with small
amounts of cyclic methyl 5-oxo-2,3-diphenylcyclopentane-1-carboxylate. Two new neolignan-type products were synthesized from
the hydrodimer.
Introduction
Numerous lignans and neolignans were found as secondary erties may be utilized for biological research and as lead struc-
plant metabolites, and many of them are known to exhibit tures for chemotherapeutic agents. Despite consisting of two
interesting biological activities [1]. Due to their plausible roles phenylpropane (C6–C3) fragments, the variety of carbon frame-
as defense substances of plants, lignans, neolignans, and their works provides a huge library of lignans and neolignans [2-4].
congeners are promising candidates for agricultural chemicals, As a result of their structural diversity, they have been targets of
and some of their antioxidant and/or anti-inflammatory prop- synthetic and biological investigations. Several synthetic
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Beilstein J. Org. Chem. 2015, 11, 200–203.
approaches, including electrochemical oxidative coupling reac- depressed using a phosphate-buffered solution in the cathodic
tions mimicking biosynthetic pathways, were reported to cell (pH 7, Table 1, entries 7–11), and finally the optimized
construct the backbones of these molecules [5]. Recently, conditions for the synthesis of 2 (85% yield, racemate/meso =
boron-doped diamond (BDD) electrodes have attracted a great 74:26) were acquired in the case of 2.5 F/mol current (Table 1,
deal of attention for their wide potential window against evolu- entry 11).
tion of both hydrogen and oxygen and for their high stability
which is derived from their diamond carbon structure [6]. To check for a different behavior of the BDD electrode, several
Although anodic oxidation reactions mediated by BDD elec- electrode materials, including glassy carbon (GC), platinum
trodes have been exploited in organic synthesis, there have been (Pt), and magnesium (Mg), were examined as cathodes under
only few reports regarding their application in preparative-scale the optimized electrolytic conditions (Table 1, entry 11).
cathodic reduction of organic compounds [7].
Hydrogen evolution at the electrode was recognized when Pt
and Mg electrodes were used, and the educt 1a was recovered in
During our investigations of phenolic oxidation reactions using high yield. The GC electrode provided the coupling product 2
BDD electrodes, we observed the generation of solvent-derived (34%, racemate/meso = 74:26) and E-3 (25%), along with 41%
methoxy radicals that conducted an oxidation process of the of 1a. Similar cathodic reductions of cinnamate derivatives
phenol substrate to the corresponding coupling product [8]. In were carried out using Hg [10,11], Cu [12,13], Pb [13,14], Zn
our second investigation on the use of the BDD electrode in [13], Sn [13], and Ag [13], and the major products were the
organic synthesis, the electrochemical reduction of methyl cyclic products (type 3) through Diekmann-type cyclization,
cinnamate (1a) was investigated to assess the applicability of whereas the hydrodimer 2 was the predominantly produced
BDD electrodes under cathodic reduction conditions, and to product in the present BDD electrode mediated reduction.
obtain new neolignan-type bioactive substances. As shown in Despite a different product ratio, the GC electrode gave similar
Figure 1, the radical intermediate derived from phenylacrylate reaction products to that of the BDD electrode.
through a one-electron reduction (right) differs from that
obtained by anodic oxidation of 4-hydroxyphenyl-1-propene Synthesis of new neolignans
(left). Therefore, the reductive dimerization of cinnamic acid As shown in Scheme 1, after separation of the diastereomeric
derivatives was expected to provide access to unprecedented mixture, (±)-2 was submitted to the chemical conversion into
neolignan-type dimeric compounds.
the new neolignan-type derivatives E-5 and E-8. Thus, reduc-
tion of (±)-2 with LiAlH4 gave the alcohol (±)-4 [15] in quanti-
tative yield, which on oxidation with PCC [16] gave the lactone
E-5 in 32% yield. Selective DIBAL reduction of E-5 gave an
Results and Discussion
Cathodic reduction on BDD electrode
The ester methyl cinnamate (1a) was electrolyzed under inseparable mixture of 6 and 7, which were identified by
constant current electrolysis (CCE) conditions in a divided cell. 1H NMR spectroscopy. Subsequent treatment of the mixture
Solvents used for the reactions played a significant role in with Et3SiH in the presence of BF3·OEt2 finally gave E-8.
providing the desired coupling (Table 1, entries 1–5). Thus,
only acetonitrile (Table 1, entry 5) gave the desired coupling Conclusion
product (±)-2 [9] in 4% yield, recovered educt 1a and The cathodic reduction of 1a using BDD electrode pre-
hydrolyzed product 1b. The undesired hydrolysis could be dominantly gave the dimeric product 2 in 85% yield. A
Figure 1: Expected coupling products from one-electron oxidation (left) and one-electron reduction (right) of C6–C3 compounds.
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Beilstein J. Org. Chem. 2015, 11, 200–203.
Table 1: Cathodic reduction of 1a on a BDD electrode.
Entrya
Solvent
Current
Potential
F/mol
Yield (%)b
density (mA/cm2)
(V vs SCE)
1a
1b
2 [(±)/meso)]c
3d
1
2
DMSO
DMF
0.21
0.50
0.53
1.29
1.29
1.29
1.29
1.29
1.29
1.29
1.29
−2.08 to −1.93
−1.96 to −1.86
−2.00 to −1.85
−2.08 to −1.84
−2.00 to −1.88
−2.21 to −1.98
−2.07 to −1.89
−1.91 to −1.83
−2.02 to −1.84
−2.00 to −1.82
−2.12 to −1.93
1
1
32
43
100
74
42
10
23
45
26
15
1
51
43
0
0
0
0
0
0
0
3
5
3
5
5
4
0
3
TFEe
1
0
4
MeOH
MeCN
MeCNf
MeCNg
MeCNh
MeCNh
MeCNh
MeCNh
1
12
46
23
13
0
0
5
1
4 (100/0)
19 (79/21)
33 (85/15)
44 (73/27)
67 (73/27)
70 (73/27)
85 (74/26)
6
1
7
1
8
1
9
1.5
2.0
2.5
0
10
11
0
0
aUpon using undivided cell systems, the reaction proceeded slower than in the divided cell cases, and lower selectivity of 2 and 3 was observed.
bIsolated yields. cThe ratio of (±) and meso forms was determined by 1H NMR spectroscopy. dEnantiomeric mixture. e2,2,2-Trifluoroethanol.
fContaining 0.07 M pH 6.0 phosphate buffer. gContaining 0.07 M pH 7.0 phosphate buffer. hContaining 0.33 M pH 7.0 phosphate buffer.
Scheme 1: Chemical conversion of (±)-2 into E-5 and E-8.
remarkable solvent effect of MeCN was observed for
Supporting Information
this dimerization reaction, while stereoselectivity was
unaffected among the conditions tested and the racemic form
Supporting Information File 1
was predominant over the meso form in all cases. Electrochemi-
cally prepared (±)-2 was further converted into E-5 and E-8 as
novel unprecedented neolignan-type derivatives. These results
provide an example for an electroorganic synthesis using
cathodic reductive coupling on a boron-doped diamond elec-
trode.
Instrumental setup, general procedure for the
electrochemical reaction and physical and spectroscopic
data for (±)-2, meso-2, E-5, and E-8.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-21-S1.pdf]
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Beilstein J. Org. Chem. 2015, 11, 200–203.
Acknowledgements
License and Terms
This research was supported by grants from the Science
Research Promotion Fund from the Promotion and Mutual Aid
Corporation for Private Schools of Japan from MEXT, the
Research and Education Center for Natural Sciences Keio
University, and Keio Gijuku Academic Development Funds (to
RO).
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
References
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
1. Zhang, J.; Chen, J.; Liang, Z.; Zhao, C. Chem. Biodiversity 2014, 11,
1–54. doi:10.1002/cbdv.201100433
(http://www.beilstein-journals.org/bjoc)
2. Apers, S.; Vlietinck, A.; Pieters, L. Phytochem. Rev. 2003, 2, 201–207.
doi:10.1023/B:PHYT.0000045497.90158.d2
3. Ward, R. S. Nat. Prod. Rep. 1999, 16, 75–96. doi:10.1039/a705992b
4. Ward, R. S. Nat. Prod. Rep. 1997, 14, 43–74.
doi:10.1039/np9971400043
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.11.21
5. Quideau, S.; Pouységu, L.; Duffieux, D. Curr. Org. Chem. 2004, 8,
113–148. doi:10.2174/1385272043486016
And related references cited therein.
6. Fuchigami, T.; Atobe, M.; Inagi, S. New Methodology of Organic
Electrochemical Synthesis. In Fundamentals and Applications of
Organic Electrochemistry: Synthesis, Materials, Devices;
Fuchigami, T.; Atobe, M.; Inagi, S., Eds.; John Wiley & Sons:
Chichester, U.K., 2015; pp 129–186.
7. Waldvogel, S. R.; Mentizi, S.; Kirste, A. Top. Curr. Chem. 2012, 320,
1–31. doi:10.1007/128_2011_125
8. Sumi, T.; Saitoh, T.; Natsui, K.; Yamamoto, T.; Atobe, M.; Einaga, Y.;
Nishiyama, S. Angew. Chem., Int. Ed. 2012, 51, 5443–5446.
doi:10.1002/anie.201200878
9. Curtin, D. Y.; Dayagi, S. Can. J. Chem. 1964, 42, 867–877.
doi:10.1139/v64-129
See for a separation of the (±)-and meso-forms of 2.
10.Klemm, L. H.; Olson, D. R. J. Org. Chem. 1973, 38, 3390–3394.
doi:10.1021/jo00959a034
11.Fussing, I.; Güllü, M.; Hammerich, O.; Hussain, A.; Nielsen, M. F.;
Utley, J. H. P. J. Chem. Soc., Perkin Trans. 2 1996, 649–658.
doi:10.1039/P29960000649
12.Nishiguchi, I.; Hirashima, T. Angew. Chem., Int. Ed. Engl. 1983, 22,
52–53. doi:10.1002/anie.198300521
13.Kise, N.; Iitaka, S.; Iwasaki, K.; Ueda, N. J. Org. Chem. 2002, 67,
8305–8315. doi:10.1021/jo026183k
14.Kise, N.; Echigo, M.; Shono, T. Tetrahedron Lett. 1994, 35,
1897–1900. doi:10.1016/S0040-4039(00)73190-X
15.Brook, A. G.; Cohen, H. L.; Wright, G. F. J. Org. Chem. 1953, 18,
447–463. doi:10.1021/jo01132a012
16.Ohgiya, T.; Nakamura, K.; Nishiyama, S. Bull. Chem. Soc. Jpn. 2005,
78, 1549–1554. doi:10.1246/bcsj.78.1549
203