Hydrogenation of substituted aromatic aldehydes: Nucleophilic trapping of the reaction intermediate, application to the efficient synthesis of methylene linked flavanol dimers

Article abstract of DOI:10.1016/j.tetlet.2005.05.132

The synthesis of dimeric flavanols is the consequence of the possible trapping of the reaction intermediates generated in the course of the reductive hydrogenation of substituted benzaldehydes. The scope of this reaction is investigated.

Full text of DOI:10.1016/j.tetlet.2005.05.132

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5177–5180
Hydrogenation of substituted aromatic aldehydes:
nucleophilic trapping of the reaction intermediate, application to
the efficient synthesis of methylene linked flavanol dimers
Franc¸ois-Didier Boyer and Paul-Henri Ducrot*
´ ´
Unite de Phytopharmacie et Mediateurs Chimiques, INRA, Route de Saint-Cyr 78026 Versailles Cedex, France
Received 11 April 2005; revised 24 May 2005; accepted 27 May 2005
Available online 15 June 2005
Abstract—The synthesis of dimeric flavanols is the consequence of the possible trapping of the reaction intermediates generated in
the course of the reductive hydrogenation of substituted benzaldehydes. The scope of this reaction is investigated.
Ó 2005 Elsevier Ltd. All rights reserved.
Dimeric flavanols linked through a methylene bridge
and related unsymmetrical diaromatic methylene have
been recently described as natural substances from Gly-
cosmis montana1 (1, 2), Agrimonia pilosa2 (3) or pro-
duced by fermentation of cacao liquor3 (4) (Fig. 1).
Moreover, this type of linkage has also been found to
be a significant transformation pathway for flavanols
during red wine ageing.4,5 Polymerizations of (+)-cate-
chin with formaldehyde,6 acetaldehyde,7–10 furfural11
phloroglucinol-aldehyde12–15 or with tartaric and gly-
oxylic acid16–19 leading to such compounds have there-
fore been extensively studied but the procedures
described, designed to have a biomimetic significance,
gave in all cases only moderate yields of dimeric com-
pounds beside complex mixtures of higher oligomers.
The proposed mechanism9,18,19 of the formation of these
flavanol derivatives however suggests the formation of
an aldehydic intermediate, which reacts with another
aromatic compound (namely another flavanol mole-
cule), leading to a bis-benzylic alcohol, which is presum-
ably reduced in situ to furnish the corresponding
pseudo-dimeric flavanol linked through a methylene or
methine bridge.
OH
HO
R2
R2
O
OH
O
OR1
OH
H2C
R1O
HO
OH
OH
1: R1 = Me, R2 = OH
4: R1 = H, R2 = H
OH
OR1
MeO
R2
OH
O
OH
HO
HO
OH
HO
CH2
O
O
OH
OH
R2
HO
OH
OH
OR1
OH
H2C
3
HO
O
OH
OH
2: R1 = Me, R2 = OH
Based on the mechanistic features arising from these
condensation reactions already reported in the literature
and on our own observation that the reduction of aro-
Figure 1.
matic aldehydes upon hydrogenation (H2, Pd/C) could
lead, depending on the substitution pattern of the aro-
matic ring, a complex mixture of compounds resulting
Keywords: Flavanol; Catechin; Hydrogenation.
*
Corresponding author. Tel.: +33 1 30 83 36 41; fax: +33 1 30 83 31
19; e-mail: ducrot@versailles.inra.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.132

5178
F.-D. Boyer, P.-H. Ducrot / Tetrahedron Letters 46 (2005) 5177–5180
The starting point of our work has indeed been the
observation that the hydrogenation of very simple com-
pounds such as 5a or 5b (Table 1, entries 1 and 2) could
either be a quite quantitative process (5b) or lead to the
formation of a complex mixture of products, MS analy-
sis of which reveals the presence of oligomeric com-
pounds. In the case of 5a, the formation of such
compounds can be explained by the known high nucleo-
philic potency of phloroglucinol derivatives. These
observations prompted us to assume the reaction path-
way described on Scheme 1 to be feasible, assuming that
the less the aldehyde will be easily reduced, the more the
nucleophilic trapping pathway would be effective. The
major problem relied however on the possibility of man-
aging the ability of the aldehyde to be reduced versus the
nucleophilic potency of the aromatic nucleophile used.
Nu
H
[Pd]
O
[Pd]
[Pd]
NuH
Nu'H
Ar
Ar
Ar
O
O
H2
H2
Nu'
Nu
CH3
Ar
Nu
Ar
Ar
Scheme 1.
from polycondensation side reactions, we present here
new reaction conditions allowing the palladium interme-
diate generated in the hydrogenation process to be
trapped by an aromatic nucleophilic species (Scheme
1). Reaction conditions have been optimized (mainly
concentration of starting material and nucleophile) in
order to minimize direct reduction of the carbonyl group
and formation of double condensation products.
We therefore tried this reaction on various aromatic
aldehydes (Fig. 2) with Pd on charcoal (10%) as catalyst
either in the presence of hydrogen or not and using either
phloroglucinol 8 or catechin 9 as aromatic nucleophilic
Table 1. Hydrogenation/nucleophilic addition sequence on aldehydes 5a–h–7

F.-D. Boyer, P.-H. Ducrot / Tetrahedron Letters 46 (2005) 5177–5180
OBn
5179
reaction pathway, but the nucleophilic addition was
however in most cases predominant. It is important to
note that the substitution pattern of the aromatic ring
obviously influences the course of the reaction and that,
in the case of the very reactive aldehyde 5c (entry 12),
the double addition compound may become the major
product of the reaction, even with very bulky nucleo-
philes such as catechin 9 (as already known for catechin,
exhibiting two nucleophilic sites at C-6 and C-8, the
most reactive site is C-8 and the proportions of regio-
isomers formed in the course of the reactions reported
in Table 1 are always in favour of the product where
the methylene is linked to the C-8 of 9).
O
R6
O
H
OBn
6
R5
R4
1
2
BnO
O
H
5
4
R2
3
OBn
R3
OBn
5a : R2=R4=R6=OH; R3=R5=H
5b : R2=R6=OMe; R3=R4=R5=H
5c : R3=R5=OMe; R2=R4=R6=H
5d : R4=NO2; R2=R3=R5=R6=H
5e : R2=R6=R3=R4=R5=H
6
O
H
5f : R2=R3=OH; R4=R5=R6=H
5g : R3=R4=OH; R2=R5=R6=H
7
Figure 2.
In the case of aldehyde 620 as starting material, the main
problem raised from the high reactivity of this com-
pound, thus forcing us to decrease the concentration of
substrate to alleviate side reactions. However, even at
the lowest concentration tested and in the absence of
other nucleophile (entry 14), the product of the hydroge-
nation of the carbonyl group (ArCH3) acted as a nucleo-
phile and the dimeric compound 1021 was obtained in
50% yield. At an intermediate concentration (4 10À2 M,
entry 15), the production of dimeric compound 10 raised
up to 75%. In the presence of an excess of another nucleo-
phile, the best results were also obtained at 4 10À2 M. In
these optimized conditions and in the presence of 9 or 8
as nucleophile (5 equiv; entries 16 and 17), aldehyde 6
nicely reacted to afford the desired pseudo-dimers (11,
12) and 13, respectively,21 (Scheme 2); in these condi-
tions, the formation of 10 was not observed.
species in order to be able to have access to compounds
related to natural products 3 and 1 (or 2), respectively.
Results are gathered in Table 1 and in Scheme 2.
The best way of preventing the direct reduction of the
carbonyl group was in fact to perform the reaction in
the absence of hydrogen (conditions C, entries 18–20).
However, for the three aldehydes tested in these condi-
tions, results were somehow disappointing, since indeed,
for 5a, no reaction occurred at all and for 5b and 5c, be-
side a large amount of degradation products, the only
compound obtained corresponded to a double addition
of a nucleophile. Noteworthy, when the aldehyde is ste-
rically highly hindered (5b) and although the yield was
low, the bulky phloroglucinol was replaced in the second
addition reaction by methanol (used as solvent) as the
nucleophilic species.
Noteworthy also, homobenzylic aldehyde 7, which is
not supposed to be reduced in these hydrogenation con-
ditions, nevertheless reacted in our conditions with
phloro- glucinol as nucleophilic species. But, on the
In the presence of hydrogen, the direct reduction of the
carbonyl group occurred in some cases as an important
OH
OH
OH
OH
HO
CH3
O
OH
CH2
HO
OH
table 1, entry 14, 15
O
OH
6
OH
OH
HO
HO
OH
O
OH
CH2
HO
OH
10
O
OH
HO
OH
11
OH
OH
CH2
HO
HO
OH
OH
table 1, entry 17
11:12 = 2: 3
table 1, entry 16
6
OH
O
HO
OH
O
OH
O
OH
OH
H2C
13
HO
HO
OH
OH
OH
12
OH
Scheme 2.

5180
F.-D. Boyer, P.-H. Ducrot / Tetrahedron Letters 46 (2005) 5177–5180
´
17. Es-Safi; Le Guerneve, C.; Cheynier, V.; Moutounet, M.
J. Agric. Food. Chem. 2000, 48, 4233–4240.
other hand, the same conditions tested on various ace-
tophenones unfortunately gave no satisfactory results.
´
18. Es-Safi; Le Guerneve, C.; Cheynier, V.; Moutounet, M.
Tetrahedron Lett. 2000, 41, 1917–1921.
In conclusion, the most important feature of the reac-
tion described in this paper is not only to give a general
access to the methylene linked flavanol pseudo-dimers,
which play an important role in the quality of various
food products and for which already reported prepara-
tion procedures are available, but also to allow the prep-
aration of unsymmetrical diaromatic methylenes such as
13 using very easily carried out reaction conditions.
Such compounds are currently tested for their antioxi-
dant activities, which will be reported in due course.
19. Fulcrand, H.; Cheynier, V.; Oszmianski, J.; Moutounet,
M. Phytochemistry 1997, 46, 223–227.
´
20. Boyer, F. D.; Es-safi, N. E.; Beauhaire, J.; Le Guerneve, C.;
Ducrot, P. H. Bioorg. Med. Chem. Lett. 2005, 15, 559–562.
21. Compound 10: 13C NMR (75 MHz, CD3OD) d = 155.73
(C), 154.07 (C), 153.07 (C), 152.65 (2C), 151.70 (C), 146.77
(C), 146.40 (C), 146.10 (C), 145.99 (C), 132.79 (C), 130.66
(C), 120.56 (CH), 119.78 (CH), 116.42 (CH), 116.10 (CH),
115.68 (CH), 115.09 (CH), 108.22 (C), 106.80 (C), 105.09
(C), 101.92 (C), 101.80 (C), 96.97 (CH), 84.29 (CH), 92.46
(CH), 69.00 (CH), 68.04 (CH), 28.81 (CH2), 28.64 (CH2),
1
18.15 (CH2), 8.59 (CH3). H NMR (300 MHz, CD3OD)
References and notes
d = 6.90–6.89 (br s, 1H), 6.82–6.66 (m, 5H), 6.12 (s, 1H),
4.75 (d, J = 8.1 Hz, 1H), 4.57 (d, J = 6.9 Hz, 1H), 4.11 (q,
J = 7.8 Hz, 1H), 3.91 (q, J = 7.5 Hz, 1H), 3.65 (s, 2H), 2.91
(dd, J = 16.2, 5.4 Hz, 1H), 2.78 (dd, J = 15.6, 4.8 Hz, 1H),
2.59–2.46 (m, 2H), 1.90 (s, 3H). ESI MS m/z (%) 607
(MH+) (100). Product ions [607]: 455, 317, 303. Ratio 11/
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155.42 (C), 154.93 (C), 152.73 (C), 146.33 (C), 145.92
(C), 130.69 (C), 120.55 (CH), 116.12 (CH), 115.68 (CH),
106.28 (C), 106.22 (C), 101.71 (CH), 97.49 (CH), 96.52
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1H), 6.95–6.90 (m, 2H), 6.19 (s, 1H), 5.97 (s, 2H), 4.82 (d,
J = 7.8 Hz, 1H), 4.21–4.18 (m, 1H), 3.72 (s, 2H), 3.09–3.02
(m, 1H + 1OH), 2.65 (dd, J = 15.6, 8.1 Hz, 1H). ESI MS
m/z (%) 429 (MH+) (100), 411 (10), 277 (80). Product ions
[429]: 411, 303, 289, 277, 151.
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