Simple Synthesis of Phytochemicals by Heterogeneous Pd- and Ir-Catalyzed Hydrogen-Borrowing C–C Bond Formation

Article abstract of DOI:10.1002/ejoc.201701489

Chitin-supported palladium and iridium catalysts (i.e., Pd/chitin, Ir/chitin) successfully promote the hydrogen borrowing C–C bond formation reaction to afford phytochemicals and aroma compounds in excellent yields.

Full text of DOI:10.1002/ejoc.201701489

DOI: 10.1002/ejoc.201701489
Communication
Phytochemicals
Simple Synthesis of Phytochemicals by Heterogeneous Pd- and
Ir-Catalyzed Hydrogen-Borrowing C–C Bond Formation
Yoji Hori,*[a] Chiharu Suruga,[a] Yuta Akabayashi,[a] Tomoka Ishikawa,[a] Marina Saito,[a]
Takao Myoda,[a] Kazuki Toeda,[a] Yuna Maeda,[b] and Yutaka Yoshida[c]
Abstract: Chitin-supported palladium and iridium catalysts rowing C–C bond formation reaction to afford phytochemicals
(i.e., Pd/chitin, Ir/chitin) successfully promote the hydrogen bor- and aroma compounds in excellent yields.
Introduction
biological activities. Although their syntheses have been re-
ported,[8,9] previous routes were typically long and low-yielding.
As such, the development of simple synthetic routes to these
compounds and their analogues, based on the use of easy-to-
handle solid catalysts, would allow the physiological activities
of such compounds to be studied in greater detail.
Heterogeneous catalysts, such as palladium on carbon (Pd/C),
are commonly employed in a number of oxidation and reduc-
tion reactions as they are readily recovered and recycled from
reaction mixtures compared to homogeneous catalysts. How-
ever, heterogeneous catalysts exhibit a range of issues related
to their chemoselectivities.
In this context, the hydrogen-borrowing C–C bond-formation
reaction is a powerful tool for the preparation of α-alkylated
ketones from ketones and alcohols without the formation of
waste.[10,11] For example, Ishii et al. reported that the homoge-
neous Ir(cod)Cl2/PPh3 catalyst was effective in the α-alkylation
of ketones with alcohols.[12] Recyclable palladium catalysts that
exhibit particularly high selectivities for this transformation
have been reported.[13] We therefore wanted to explore a facile
synthetic route to ketones from readily available starting mate-
rials; consequently we proposed that heterogeneous transition-
metal catalysts supported by waste chitin may exhibit high cat-
alytic activities in the hydrogen-borrowing C–C coupling reac-
tion to afford a range of phytochemicals. Considering the mech-
anism of the hydrogen-borrowing C–C coupling reaction shown
in Scheme 1, we proposed that raspberry ketone [4-(4-hydroxy-
phenyl)butan-2-one, 1] could easily be synthesized using this
reaction.
Recently, the use of novel supports has been reported to
address a number of issues that are commonly associated with
heterogeneous catalysts; examples include a fibroin-supported
Pd catalyst (Pd/Fib),[1,2] a DNA-supported Pd catalyst (Pd/
DNA),[3] and a chitin-supported Ru catalyst.[4] Pd/chitin was re-
ported to exhibit unique characteristics.[5] Interestingly, differ-
ent supports appeared to affect the catalytic properties of palla-
dium. As part of the ongoing search for inexpensive, highly
reactive, highly selective, and recyclable heterogeneous cata-
lysts, our research group has investigated ways of using the
waste chitin and chitosan from agricultural and fishery waste
(e.g., discarded crab shells). In this context, the preparation of
Pd/chitin, Ir/chitin, Pd/chitosan, Ir/chitosan, and Pd/cellulose
catalysts was achieved using methods similar to that reported
by Sajiki et al.[2] In addition, the preparation of the Pd/chitin
catalyst by an alternative method has also been reported.[5]
Raspberry ketone[6] and 6-paradol[7] are the main flavor in-
gredients of raspberries and guinea ginger (Aframomum mele-
gueta), respectively, and these compounds exhibit a range of
[a] Department of Food and Cosmetic Science, Tokyo University of Agriculture
196 Yasaka, Abashiri, Hokkaido 099-2493, Japan
E-mail: yh206286@bioindustry.nodai.ac.jp
www.nodai.ac.jp
[b] Department of Materials Science and Engineering,
Kitami Institute of Technology
Scheme 1. α-Alkylation of ketones with alcohols.
165 Koencho, Kitami, Hokkaido 090-8507, Japan
[c] School of Regional Innovation and Social Design Engineering,
Kitami Institute of Technology
Results and Discussion
165 Koencho, Kitami, Hokkaido 090-8507, Japan
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.201701489.
Herein we report the simple syntheses of phytochemicals based
on the hydrogen-borrowing C–C coupling reaction catalyzed
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by heterogeneous Pd and Ir catalysts. These compounds are give product 4b (Table 2) reveal that Pd/chitin is the most active
of particular interest due to the inhibitory effects exhibited by catalyst; consequently it was employed for all subsequent reac-
raspberry ketone, paradol, and their analogues, against the tions discussed herein.
tyrosinase enzyme.[14,15]
To compare the activities of the two chitin-supported cata-
lysts, we initially examined the reaction between benzyl alcohol
and acetophenone [Equation (1)]. From the results summarized
in Table 1, it is apparent that the Pd/chitin catalyst exhibits a
high catalytic activity compared to that of Pd/C. However, al-
though the Ir/chitin catalyst also exhibits a relatively high cata-
(2)
lytic activity, its selectivity towards ketone 2 over alcohol 3 was
considerably lower; results for other Pd catalysts are included
for comparison.
Based on the results presented in Tables 1 and 2, we turned
our attention to the facile synthesis of raspberry ketone (1) and
6-paradol (5) using the Pd/chitin catalyst. Hence, (4-methoxy-
phenyl)methanol, (2H-1,3-benzodioxol-5-yl)methanol, and (4-
methylphenyl)methanol were treated with acetone to give the
corresponding products 4a, 6, and 7 in excellent yields [Equa-
tion (3)].
(1)
Table 1. Reaction between benzyl alcohol and acetophenone.[a]
Entry
Catalyst (1 mol-%)
Yield [%] of 2[b]
Yield [%] of 3[b]
(3)
1
2
5 % Pd/chitin
5 % Ir/chitin
98
86
96
94
93
92
91
89
83
2
14
0
3
2
2
1
1
0
3[c]
4[c]
5[c]
6[c]
7[c]
8[c]
9[c]
5 % Pd/C AER type
5 % Pd/C K type
5 % Pd/C NX type
5 % Pd/C PE type
10 % Pd/C PE type
10 % Pd/C K type
5 % Pd/Al2O3
Likewise, methylparadols [i.e., 1-(3,4-dimethoxyphenyl)-3-alk-
anones, 8], which are similar in structure to paradol 5, were
easily obtained from veratryl alcohol [(3,4-dimethoxy-
phenyl)methanol, 9] and 2-alkanones in high yields [Equa-
tion (4)].
[a] The coupling reaction between benzyl alcohol (6.5 mmol) and aceto-
phenone (5.3 mmol) was performed in the presence of a catalyst (1 mol-% Pd
or Ir) and K3PO4 (1.5 mmol) in toluene (10 mL) under N2 at 110 °C for 15 h.
[b] Determined by GLC analysis based on benzyl alcohol. [c] Pd catalysts from
N.E. CHEMCAT Corp.
Similarly, examination of the results from reactions promoted
by various supported catalysts toward the α-alkylation of (4-
methoxyphenyl)methanol with 2-butanone [Equation (2)] to
(4)
Table 2. α-Alkylation of (4-methoxyphenyl)methanol with 2-butanone.[a]
Entry
Product
Catalyst (1 mol-%)
GC yield [%][b]
1
2
3
4
5
4b
4b
4b
4b
4b
5 % Pd/chitin
5 % Pd/chitin (recycled five times)
5 % Ir/chitin
>99 (85)
1st >99, 2nd >99, 3rd 76, 4th 78, 5th 80
31
86
25
5 % Pd/chitosan
5 % Pd/cellulose[d]
[a] The coupling reaction between (4-methoxyphenyl)methanol (5 mmol) and 2-butanone (20 mmol) was performed in the presence of a catalyst
(1 mol-% Pd or Ir) and K3PO4 (5 mmol) in toluene (10 mL) under N2 at 80 °C for 24 h. [b] Determined by GLC analysis based on (4-methoxyphenyl)methanol
[product/(alcohol + product) × 100]. Isolated yields are shown in parentheses. [c] 17 % of the over-reduced byproduct 1-(4-methoxyphenyl)pentan-3-ol was
also obtained. [d] Cellulose was obtained from beat waste.
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Scheme 2. Synthesis of 4-(4-hydroxyphenyl)butan-2-one (1).
Scheme 3. Synthesis of 6-paradol [1-(3-methoxy-4-hydroxyphenyl)decan-2-one, 5].
However, no reaction was observed between (4-hydroxy- copy (TEM). As shown in Figures 1 and 2, the particles approxi-
phenyl)methanol and acetone; consequently no corresponding mately 2–20 nm in size are visible in the chitin, indicating little
raspberry ketone was produced. Similarly, the reaction between change in morphology after five cycles.
(4-hydroxy-2-methoxyphenyl)methanol (10) and 2-nonanone
was also unsuccessful. We assumed that these reactions failed
due to the coordination of the phenoxide moiety to the Pd
surface, which blocks the active sites of the catalyst, thereby
deactivating it.
We therefore attempted the α-alkylation reaction using the
benzyl-protected substrates 11 and 12, and the corresponding
products 13 and 14 were obtained in high GC yields of 92 and
76 %,[16] respectively (Schemes 2 and 3). Subsequent deprotec-
tion of the benzyl group was achieved by catalytic hydrogen-
ation in the presence of a palladium catalyst to give the corre-
sponding raspberry ketone (1) and 6-paradol (5) in GC yields of
Figure 2. Size distribution of the 5 % Pd/chitin powder from Figure 1(A) and
(B). The particles with size of approximately 2–20 nm are visible in the chitin.
93 and 90 %, respectively. The reaction conditions and results
for these transformations are summarized in Table 3.
The average particle size changed from 8 to 3.7 nm.
Finally, we examined the structures of the 5 % Pd/chitin and
the five-times recycled catalyst by transmission electron micros-
Conclusions
We herein report that transition-metal (i.e., Pd and Ir) catalysts
supported on agricultural and fishery waste, such as chitin, chi-
tosan, and cellulose are effective in the hydrogen-borrowing C–
C bond-formation reaction. As such, we successfully synthesized
raspberry ketone and some analogues in addition to a range of
paradols in high yields by the reaction of 2-alkanones and
benzyl alcohols. Due to the ability to conveniently synthesize
various analogues of these compounds, we believe that these
catalysts will aid in the future search for novel bioactive com-
pounds.
Figure 1. TEM image of 5 % Pd/chitin powder. (A) Before reaction and (B) after
being recycled five times. Dispersed Pd particles are visible in the chitin.
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Table 3. α-Alkylation of ketones with benzyl alcohols.[a]
Although syntheses using homogeneous asymmetric cata-
lysts have become significant in industry, recyclable heteroge-
neous asymmetric catalysts have not yet been used. We believe
that any reaction involving a catalyst in which metallic nanopar-
ticles are loaded onto natural asymmetric ligands (e.g., chitin,
chitosan) is possible. Indeed, asymmetric reactions in the pres-
ence of homogeneous ruthenium–chitosan catalysts have been
reported.[17]
Experimental Section
Typical Procedure for the Preparation of the Palladium/Chitin
Catalyst: A suspension of Pd(OAc)2 (63.5 mg, 0.28 mmol) and chitin
powder (0.52 g) in methanol (25 mL) was stirred at room tempera-
ture under nitrogen for 3 d. The product was collected by filtration,
washed with methanol and ethyl acetate, and then dried to obtain
the 5 % Pd/chitin catalyst in quantitative yield.
Typical Procedure for the Palladium-Catalyzed α-Alkylation Re-
action of Ketones with Alcohols: 2-Pentanone (1.14 g, 10 mmol)
was added to a suspension of 5 % Pd/chitin (106 mg, 0.05 mmol),
(3,4-dimethoxyphenyl)methanol (0.42 g, 2.5 mmol), and K3PO4
(7.5 mmol) in toluene (5.0 mL) in a 50 mL reaction tube. The suspen-
sion was heated at 80 °C under nitrogen for 24 h. The reaction
mixture was cooled to room temperature, and the resulting mixture
was concentrated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate, 8:1) to afford 1-(3,4-di-
methoxyphenyl)octan-3-one (8d) in 90 % yield (0.59 g).
Acknowledgments
The authors are grateful to Mr. S. Tokuda for his help in install-
ing and operating the TEM system. We would like to thank Edit-
age (www.editage.jp) for English language editing.
Keywords: Chitin · Phytochemistry · Raspberry ketone ·
Paradol · Heterogeneous catalysis · Hydrogen borrowing ·
C–C coupling
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Received: October 25, 2017
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