Transfer Hydrogenation of Flavanones and ortho-Hydroxychalcones to 1,3-Diarylpropanols Catalyzed by CNN Pincer Ruthenium Complexes

Article abstract of DOI:10.1002/cctc.202002025

The transfer hydrogenation of flavanones and ortho-hydroxychalcones catalyzed by ruthenium pincer complexes RuCl(CNNPh)(disphosphine) has allowed the synthesis of ortho-hydroxy 1,3-diarypropanols in 80–88 % yield, under mild reaction conditions and short reaction times (1 h) in 2-propanol. The amount of the co-catalyst NaOiPr has been found crucial for the selective reduction of flavanones to ortho-hydroxy 1,3-diarypropanols vs. flavan-4-ols. Preliminary results show that with pincer catalysts bearing (S,R)-Josiphos, flavanone is reduced to the corresponding (S)-alcohol in moderate conversion (36 %) and up to 92 % ee.

Full text of DOI:10.1002/cctc.202002025

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Transfer Hydrogenation of Flavanones and ortho-
Hydroxychalcones to 1,3-Diarylpropanols Catalyzed by CNN
Pincer Ruthenium Complexes
Martín Soto,[a] Vicente Gotor-Fernández,[a] Humberto Rodríguez-Solla,*[a] and
Walter Baratta*[b]
The transfer hydrogenation of flavanones and ortho-hydrox-
ychalcones catalyzed by ruthenium pincer complexes RuCl
(CNNPh)(disphosphine) has allowed the synthesis of ortho-
hydroxy 1,3-diarypropanols in 80–88% yield, under mild
reaction conditions and short reaction times (1 h) in 2-propanol.
The amount of the co-catalyst NaOiPr has been found crucial
for the selective reduction of flavanones to ortho-hydroxy 1,3-
diarypropanols vs. flavan-4-ols. Preliminary results show that
with pincer catalysts bearing (S,R)-Josiphos, flavanone is
reduced to the corresponding (S)-alcohol in moderate con-
version (36%) and up to 92% ee.
Introduction
Among the reported methods for the synthesis of ortho-
hydroxy 1,3-diarylpropanols, the model compound 2-(1-
hydroxy-3-arylpropyl)phenol entails the C=C reduction of
chalcones via hydrogenation under pressure using Pd/C
followed by C=O reduction with NaBH4, affording the product
in low yield.[10] Katagi and co-workers described the reduction
of flavone using NaAlH2(OCH2CH2OCH3)2 to afford the desired
product in 33% yield,[14] with concomitant formation of a
functionalized indane from a rearrangement-side reaction.
More recently, Zheng and Hall reported the synthesis of 2-(1-
hydroxy-3-phenypropyl)phenol in moderate yield via zirco-
Flavonoids are polyphenolic compounds displaying broad bio-
logical activities in plants and animals and have been inves-
tigated as drugs in the treatment of several disorders, such as
diabetes, inflammatory processes, malaria and cancer.[1] Among
the flavonoid derivatives, flavanones and ortho-hydroxychal-
cones, which are in a pH dependent equilibrium (oxa-Michael
reaction),[2] are relevant precursors in the biosynthesis of a large
number of biologically active products. For this reason, the
chalcone scaffold is considered
a privileged structure in
medicinal chemistry.[3]
nium-catalyzed
condensation
between
3,5-bis
Flavanones can be reduced at the C=O group affording
flavan-4-ols (Scheme 1, left), whereas ortho-hydroxychalcones
are hydrogenated to dihydrochalcones, 1,3-diarylpropanols and
1,3-diarylpropanes (Scheme 1, right), which are compounds of
high biological relevance.[4] While the syntheses of flavan-4-
ols,[5] dihydrochalcones[6] and 1,3-diarylpropanes[7–9] have been
widely described in the literature, the preparation of ortho-
hydroxy 1,3-diarylpropanols has not been properly covered yet.
Interestingly, compounds containing this motif have shown to
display inhibitory properties in the transcription factor NF-kB,[10]
anti-cholinesterase,[11] anti-inflammatory activity[12] and P-glyco-
protein-inhibitory effects (GP-88)[13](Figure 1).
(trifluoromethyl)phenylboronic acid, phenol and 2-phenyl-
propanal followed by hydrolytic oxidation of the correspond-
ing dioxaborin intermediate with H2O2.[15] Recently, our
research group published a stereodivergent methodology for
the hydrogenation of 2’-hydroxychalcones to generate their
reduction products, but the preparation to 1,3-diarylpropa-
nols was no general and difficult to achieve due to over-
reduction problems.[7]
The lack of general and efficient methods for the
preparation of ortho-hydroxy 1,3-diarylpropanols, prompted
us to develop an alternative procedure via catalytic reduction
[a] Dr. M. Soto, Prof. V. Gotor-Fernández, Prof. H. Rodríguez-Solla
Departamento de Química Orgánica e Inorgánica
University of Oviedo
Avenida Julián Clavería 8
33006, Oviedo (Spain)
E-mail: hrsolla@uniovi.es
[b] Prof. W. Baratta
Dipartimento di Scienze Agroalimentari, Ambientali e Animali
Università di Udine
Via Cotonoficio 108
33100, Udine (Italy)
E-mail: walter.baratta@uniud.it
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cctc.202002025
Scheme 1. Reduction of flavanones and ortho-hydroxychalcones
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Figure 1. Structure of biologically relevant compounds containing the 1,3-diarylpropanol motif.
of flavanones and ortho-hydroxychalcones, which are acces-
sible from natural sources or can be easily synthesized
following diverse approaches, including aldol condensation
between ortho-hydroxyacetophenones and benzaldehydes in
basic media and further cyclation[16,17] and arylation of
chromanones with arylboronic acids in the presence of a
palladium catalyst.[18]
Employment of well-defined homogeneous catalysts has
been demonstrated crucial for achieving high selectivity in
several organic transformations,[19] reducing the formation of
by-products and waste.[20] The transfer hydrogenation
Figure 2. Ampy and benzo-[h]quinoline pincer ruthenium catalysts A-D.
(TH)[21–25] of carbonyl compounds catalyzed by ruthenium(II)
complexes[26] is a well-established way for the preparations of
(chiral) alcohols by using 2-propanol as hydrogen donor. This
protocol avoids the employment of reducing agents such as
NaBH4 or LiAlH4, facilitating the work-up and decreasing the
amount of side-reaction products.[27] It is worth pointing out
that the derivatives cis-RuCl2(ampy)(PP)[28–30] and the related
pincer complexes RuCl(CNN)(PP)[31–33] (PP=diphosphine) con-
taining the 2-(aminomethyl)pyridine (ampy) motif[34] are
among the most active catalysts for the TH of carbonyl
compounds with 2-propanol. Particularly challenging is the
TH of substrates containing additional functional groups (i. e.
phenols) which can coordinate to the metal center resulting
in catalyst deactivation.
Table 1. TH of flavanone 1a (0.1 M) with the ruthenium catalysts A-D
(0.5 mol%) in 2-propanol at reflux after 6 h.
Entry Catalyst Conv. [%][a] 2a [%][b] 3a [%][b] 4a [%][b] 5a [%][b]
1
2
3
4
5
A
B
C
D
–
49
99
93
98
13
19
59
47
46
0
8
0
0
3
3
7
8
8
0
19
33
38
41
0
13
[a] The conversion was determined by 1H-NMR measurements. [b] The
percentages of 2a, 3a, 4a and 5a were determined by 1H-NMR analysis on
the crude reaction products.
Herein, we describe a straightforward synthesis of ortho-
hydroxy 1,3-diarylpropanols from flavanones and ortho-hydrox-
ychalcones via TH in 2-propanol, employing the pincer
ruthenium catalyst RuCl(CNN)(PP) in basic media, including
preliminary results on the asymmetric TH version.
RuCl(CNNPh)(PP)[32] (PP=dppf B, dppp C and dppb D)[37]
resulted in a higher conversion (93-99%, entries 2–4, Table 1).
The type of diphosphine slightly affects the selectivity, the
cyclic alcohol 2a and 1,3-diarylpropanol 5a being the main
products. With catalyst B containing the dppf diphosphine,
2a (cis:trans=9:1 relative ratio) is formed in 59%, whereas
with D, bearing dppb, 2a is obtained in 46% (entries 2 and
4). Conversely, the use of D resulted in a higher yield for 5a
(41%, entry 4), compared to C and B (38 and 33%, entries 2
and 3). In all these cases the formation of compounds 3a and
4a was lower than 8% (entries 2–4), while no TH occurred
without ruthenium catalyst and in the presence of NaOiPr,
affording only 3a (13%) via the flavanone ring opening
(entry 5). In addition, a very small amount of the allyl alcohol
(E)-2-(1-hydroxy-3-phenylallyl)phenol (<2%) was also de-
tected during the TH of 1a (see ESI). The use of RuCl3 hydrate
Results and Discussion
The reduction of the commercially available flavanone 1a has
been performed via TH using the ampy[34] and benzo-[h]
quinoline[32] pincer ruthenium complexes A-D in 2-propanol and
in the presence of an alkaline base (Figure 2).[28,29,35,36]
Compound 1a (0.1 M) with 0.5 mol% RuCl2(ampy)(dppf) A
°
and NaOiPr (2 mol%) in 2-propanol at 82 C was poorly
converted (49%), after 6 h, affording a mixture of the cyclic
alcohol flavan-4-ol 2a (19%), ortho-hydroxychalcone 3a (8%)
and the hydrogenated products dihydrochalcone 4a (3%)
and 2-(1-hydroxy-3-phenyl)phenol 5a (19%) (entry 1, Ta-
ble 1). Employment of the more robust pincer complexes
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and [Ru(p-cymene)Cl2]2 (0.5 mol%) 1a under these catalytic
conditions affords a mixture of 1a and 3a in about 7:1 molar
ratio, according to the Michael reaction, without formation of
reduction products.
These results show that with catalysts A-D, flavan-4-ol 2a is
formed from 1a by reduction at the C=O bond, while the other
derivatives entail a retro oxa-Michael reaction. Although the
reduction of flavanones towards flavan-4-ols has been
described,[5,38] no reports on the synthesis of 1,3-diarylpropanols
via TH from flavanones or ortho-hydroxychalcones has been
reported.
observed, indicating that the substrate concentration has a
slight effect on the selectivity (entries 5 and 6). At 150 mol %
of base, the TH was performed at 0.05 M concentration of
substrate 1a due to the poor solubility of the chalcone
phenoxide in 2-propanol. Control experiments show that
ortho-hydroxychalcone 3 a with D (0.5 mol%) and NaOiPr
(2 mol%) is easily converted into a mixture of 2a, 4 a, and 5a
in 47, 9, 42%, respectively, whereas with 150 mol% of NaOiPr
5a is formed in 85% yield indicating that the base has strong
influence on the selectivity for 5a. The similar results
obtained for 1a and 3a are in agreement with a fast pre-
equilibrium between 1a and 3a, shifted to the phenoxide of
3a in the strong basic media, followed by C=O reduction.
The influence of the temperature and the amount of
catalyst on the selectivity of the TH of 1a was also
Since the Michael reaction is base dependant,[2] the role
of NaOiPr was explored to improve the selectivity of the
flavanone TH (Table 2). Reaction of 1a with catalyst D
(0.5 mol%), in absence of NaOiPr, gives 2a as main product
(75%), whereas 5a is obtained in low amount (22%) in 6 h
(entry 1, Table 2). Increasing the amount of NaOiPr from 2 to
150 mol% resulted in a progressive enhancement of the
formation of desired 5a (38 to 85%, entries 2–7), whereas the
amount of 2a decreased from 47 to 6%. It is worth pointing
out that with 100 mol% of base at 0.1 M and at 0.05 M of 1a
no significant change of the distribution products has been
°
investigated and the data are summarized in Table 3. At 50 C
with D (0.5 mol%), complete conversion is achieved in 6 h,
°
affording 5a in 36% yield, while at 60 and 82 C, 5a is formed
in 52 to 74% yield, respectively (entries 1–3). Rising the
amount of D to 1 mol% at 50, 60 and 82 C, conducts to an
°
increase in the amount of 5a, which is obtained in 79–92%
yield, whereas at 1.5 mol% of D no significant improvements
were observed in the formation of 5a (entries 4–7).
°
The best selectivity for 5a is achieved at 60 C with 1 mol%
of D, also observing that complete conversion is attained in 1 h.
In order to broaden the scope of this reaction, the
reduction of flavanones[16] and ortho-hydroxychalcones bear-
ing different substituents on the phenyl ring was carried out
Table 2. Effect of the NaOiPr on the selectivity of the TH of 1a (0.1 M) with
catalyst D (0.5 mol%) in 2-propanol at reflux after 6 h.
°
using D (1.0 mol%) with NaOiPr (150 mol%) at 60 C in 1 h.
Thus, 1a and the flavanones 1b–e bearing electron donating
groups (Me, OMe) and 1f–j containing electron withdrawing
groups (F, Cl, Br) are reduced to ortho-hydroxy 1,3-propanols
5a–j and isolated in 80–88% yield (entries 1–13, Table 4). In
addition, the TH of ortho-hydroxychalcones 3a, 3e and 3i
leads to 5a, 5 e and 5 i (84-85%, entries 2, 7, 12), showing
similar reactivity of the corresponding flavanones. These
Entry NaOiPr
Conv.
[%][a]
2a
3a
4a
5a
[mol%]
[%][b]
[%][b]
[%][b]
[%][b]
1
2
0
2
99
93
91
94
98
97
99
75
47
40
36
23
21
6
0
0
0
0
0
0
0
2
8
0
0
0
0
8
22
38
51
58
75
76
85
3
4
5
40
100
100
150
5
6c
7c
[a] The conversion was determined by 1H-NMR measurements, [b] The
percentages of 2a, 3a, 4a and 5a were determined by 1H-NMR analysis on
the crude reaction products. 1a 0.05 M.
c)
Table 4. Synthesis of 1,3-diarylpropanols 5a-j from flavanones 1a-j and
ortho-hydroxychalcones 3a, 3e, 3i (0.05 M) via TH.
Table 3. Effect of temperature and loading of D in the TH of 1a (0.05 M) in
2-propanol in the presence of NaOiPr (150 mol%) after 6 h.
Entry
Substrate
R
Product
Yield [%][a]
1
2
3
4
5
6
7
8
1a
3a
1b
1c
1d
1e
3e
1f
1g
1h
1i
3i
1j
H
H
5a
5a
5b
5c
5d
5e
5e
5f
5g
5h
5i
5i
5j
87
85
86
82
83
86
84
83
82
88
80
84
84
Entry
D
T
Conv.
[%][a]
2a
3a
4a
5a
4-Me
2-OMe
3-OMe
4-OMe
4-OMe
2-F
3-F
4-F
4-Cl
4-Cl
[mol%] [ C]
[%][b]
[%][b]
[%][b]
[%][b]
°
1
2
3
4
5
6
7
0.5
0.5
0.5
1.0
1.0
1.0
1.5
50
60
82
50
60
82
60
99
99
99
99
99
99
99
0
0
7
0
0
4
0
1
1
1
0
0
0
0
52
46
17
20
7
3
8
36
52
74
79
92
92
91
9
10
11
12
13
[a] The conversion was determined by 1H-NMR measurements. [b] The
percentages of 2a, 3a, 4a and 5a were determined by 1H-NMR analysis on
the crude reaction products.
4-Br
[a] Isolated yield after flash column chromatography.
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results indicate that the nature and position of the aryl
substituent do not significantly affect the selectivity of the
TH, showing a broad substrate scope for this reaction. To
show the practical potential of this methodology, 1.84 g of
1,3-diarylpropanol 5a (81% yield) were obtained from 2.24 g
saturated ketone, (i. e. 1,3-diphenylpropanone), which is
finally enantioselectively reduced to (S)-5 k.
Accordingly, it is likely that the ruthenium catalyzed
conversion of flavanones to 1,3-diarylpropanols in basic 2-
propanol entails a retro oxa-Michael reaction to hydrox-
ychalcones, followed by a TH at the C=O bond affording the
°
(10 mmol) of flavanone 1a in 1 h at 60 C, using 1.0 mol% of
complex D in 2-propanol.
corresponding
allylic
alcohols.
Subsequent
Finally, the asymmetric TH version was envisaged for the
preparation of chiral 1,3-diarylpropanols, so the reduction of
1a was carried out using the chiral pincer ruthenium
complexes E31 and F,39 under the optimized catalytic con-
isomerization[28,44] gives the dihydrochalcones which are
reduced to 1,3-diarylpropanols via (asymmetric) TH.
In the TH the catalytically active ruthenium hydride is
formed by substitution of the chloride with the isopropoxide
followed by a β-H elimination. Nucleophilic attack of the
hydride to the ketone substrate gives a Ru-alkoxide which is
protonated by 2-propanol, affording the alcohol product and
Ru-OiPr which closes the catalytic cycle. The presence of the
NÀ H functionality strongly accelerates the catalytic process
via proton shuttling involving the NÀ H group, 2-propanol
and the ketone substrate.[45,46] The use of robust pincer
catalysts appears crucial with these substrates, since the
chalcones and their reduced products are present as phen-
oxides under basic catalytic conditions and therefore are apt
to coordinate to the metal center, hindering the catalytic
activity.
°
ditions (catalyst 1.0 mol%, NaOiPr 150 mol%, 60 C and 1 h)
(Figure 3).
Preliminary results show that complexes E and F contain-
ing the (S,R)-Josiphos[37] diphosphine, which are highly
efficient catalysts for the asymmetric TH of aryl-alkyl ketones
to (S)-alcohols,[39–41] are able to reduce 1a to a mixture of 4a
(69 and 64%) and (S)-5a (31 and 36%) with 70 and 92% ee,
respectively.Control experiments show that the TH of the
model chalcone 3 k with catalyst E, under the same
catalytic conditions, gives the corresponding (S)-1,3-diphe-
nylpropan-1-ol 5 k with 77 % ee, as confirmed by NMR and
HPLC measurements (Scheme 2).[42,43]This reaction gives
the saturated alcohol with an ee value close to that
found in the reduction of the flavanone 1 a to (S)-5 a and
in agreement with the data observed for the TH of the Conclusions
aryl-alkyl ketones with E, affording (S)-alcohols.[32] Inter-
estingly, the TH of the racemic allylic alcohol 3 k’ affords
(S)-5 k with 66 % ee. Since E catalyzes efficiently the
asymmetric TH at the C=O bond, while it displays poor
activity for the C=C reduction, it is likely that the
reaction occurs through a ruthenium-catalyzed allylic
alcohol isomerization[28] of rac-3k’ to the corresponding
In summary, we have reported that flavanones and ortho-
hydroxychalcones can been easily and selectively reduced to
ortho-hydroxy 1,3-diarylpropanols in a one-pot reaction using
robust pincer ruthenium complexes RuCl(CNNPh)(disphosphine)
with 2-propanol and in the presence of NaOiPr. This general
and straightforward procedure has allowed the synthesis of 1,3-
diarylpropanols containing electron donating and withdrawing
substituents at the phenyl ring under mild reaction conditions.
Interestingly, the use of pincer ruthenium catalysts bearing
(S,R)-Josiphos diphosphine allowed the conversion of flavanone
to the (S)-alcohol (36% conversion) with up to 92% ee. Further
studies are underway to broaden the scope of pincer ruthenium
catalysts in organic transformations.
Figure 3. Chiral pincer ruthenium catalysts E and F.
Scheme 2. Asymmetric TH of chalcone 3k and the allylic alcohol rac-3k’ to enantioenriched alcohol 5k with catalyst E.
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General Experimental Information
All reactions were carried out under an argon atmosphere using
standard Schlenk techniques. The solvent 2-propanol used in TH
has been carefully dried with sodium and distilled under argon
before use. Flavanones 1b–j and chalcones 3a, 3e, 3i were
prepared following the literature procedures,[16] while 1a was
purchased from Alfa Aesar. The ampy and CNN pincer ruthenium
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kept at the defined temperature (60 C) for 1 h. Reaction was
quenched by addition of an aqueous 0.1 M solution of HCl (5.0 mL)
and the resulting mixture was extracted with dichloromethane (3 x
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Keywords: alcohols · flavonoid · transfer hydrogenation ·
ketones · ruthenium
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Manuscript received: December 21, 2020
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