Improved selective reduction of 3-formylchromones using basic alumina and 2-propanol

Article abstract of DOI:10.1081/SCC-120023445

Treatment of formylchromones, dissolved in 2-propanol with basic alumina at 75°C, selectively reduces the formyl group with good yields without any activation process of the alumina.

Full text of DOI:10.1081/SCC-120023445

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Improved Selective Reduction of 3-Formylchromones
Using Basic Alumina and 2-Propanol
Ramiro Araya-Maturana a , Jorge Heredia-Moya a , Hernán Pessoa-Mahana a & Boris Weiss-
López b
a Department of Organic and Physical Chemistry, Faculty of Chemical and Pharmaceutical
Sciences, University of Chile, Casilla, Santiago, Chile
b Department of Chemistry, Faculty of Sciences, University of Chile, Casilla, Santiago, Chile
Version of record first published: 17 Aug 2006.
To cite this article: Ramiro Araya-Maturana , Jorge Heredia-Moya , Hernán Pessoa-Mahana & Boris Weiss-López (2003):
Improved Selective Reduction of 3-Formylchromones Using Basic Alumina and 2-Propanol, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:18, 3225-3231
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 18, pp. 3225–3231, 2003
Improved Selective Reduction of
3-Formylchromones Using Basic Alumina
and 2-Propanol
1
Ramiro Araya-Maturana,1, Jorge Heredia-Moya,
*
Hernan Pessoa-Mahana,1 and Boris Weiss-Lopez2
1Department of Organic and Physical Chemistry,
Faculty of Chemical and Pharmaceutical Sciences, and
2Department of Chemistry,
Faculty of Sciences, University of Chile,
Casilla, Santiago, Chile
ABSTRACT
Treatment of formylchromones, dissolved in 2-propanol with basic
alumina at 75ꢀC, selectively reduces the formyl group with good
yields without any activation process of the alumina.
Key Words:
*Correspondence: Ramiro Araya-Maturana, Department of Organic and
Physical Chemistry, Faculty of Chemical and Pharmaceutical Sciences
University of Chile, Casilla, 233 Santiago 1, Chile; Fax: 56-2-6782868; E-mail:
raraya@ciq.uchile.cl.
3225
DOI: 10.1081/SCC-120023445
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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3226
Araya-Maturana et al.
The remarkable biological activities of 4-oxo-4H-1-benzopyranes
(chromones) prompted to several groups to synthesize a large variety
of 2- or 3-substituted derivatives.[1–8] The Vilsmeir–Haack reaction of
o-hydroxyacetophenones provides a facile entry into the field of
chromones yielding 4-oxo-4H-1-benzopyran-3-carboxaldehydes (3-
formylchromones),[9,10] a variety of 3-formylchromones has been
described by this method.
An attractive way to synthesize 3-substituted chromone derivatives
may be envisaged through selective functional group interconversion of
the formyl group. The requisite of this strategy is to posses synthetic
methods that allow the selective conversion of the aldehydic carbonyl
group in the presence of the other two electropositive centers (namely
C-2 and pyrone carbonyl carbon). Owing to the synthetic versatileness of
hydroxy group that permits the use of alcohols as building blocks besides
the reported antiallergic and antiasthma activities of 3-hydroxymethyl-
chromone moiety[6,11] we decide to study the reduction of 3-formyl chro-
mones. This reaction has been previously reported using different methods
with variable yields. The first of them, described thirty years ago,
utilized NaBH4 and AlCl3 to reduce selectively the formyl group of the
parent compound 3-formyl chromone in very low yield.[9a] However,
different authors have claimed that certain two substituted chromones
underwent reduction of both aldehyde carbonyl and a,b-ethylenic group
using sodiumborohydride-aluminumchloride as well as sodiumborohy-
dride, DIBAL-H in tetrahydrofuran and sodiumcyanoborohydride in
the presence of acid, and are inert to Meerwein–Pondorf–Verley homo-
geneous conditions using aluminium isopropoxide.[12] Because of the
difficulty in obtaining clean reduction of a,b-ethylenic aldehydes other
methods have been reported. For instance, 2-propanol on dried woelm
alumina has shown synthetic utility.[12] The yields obtained were about
50%. The drawbacks of this method, as pointed out by the authors, are
the high temperature (400ꢀC under vacuum) required for the alumina
activation and the relatively large amount of alumina (3–5 g/mmol of
carbonyl substrate) necessary for effective substrate reduction. Also has
been described that the parent 3-formylchromone and the two derivatives
6-methyl and 6-chloro-3-formylchromone, when dissolved in CH2Cl2 and
in contact with Brockman neutral alumina (dried at 120ꢀC under vacuum),
gives a mixture of at least six products one of them corresponding to
3-hydroxymethyl chromones with yields between 20–30%.[13]
As far as we know the best method reported at this time consists in
the treatment of formyl chromones with diborane giving the correspond-
ing 3-hydroxymethylchromone with high yield.[14] However, several sig-
nificant advantages of the alumina supported 2-propanol, such as the low

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Reduction of 3-Formylchromones
3227
Table 1. Results for the reduction of formylchromones.
R1
O
OH
R1
O
R2
R3
R2
R3
CHO
basic Al2O3
2-propanol
O
O
R4
R4
Compound
Product
R1
R2
R3
R4
Isolated yield (%)
1a
1b
1c
1d
2a
2b
2c
2d
H
OH
H
H
H
H
H
H
H
H
H
H
H
61
50
15
65
OH
OMe
H
cost of the 2-propanol, easy product isolation, the selectivity for carbonyl
reduction and the compatibility with many different types of functional
groups make that this method remain as attractive alternative.
We had observed that basic alumina can satisfactorily replace the
neutral dried alumina, without a previous drying process, in the reduction
of the parent 3-formylchromone therefore eliminating the main drawback
of this method. The yield is comparable to those with dried neutral
alumina. In this communication we report the potential utility of 2-
propanol/basic alumina for the selective reduction of carbonyl aldehyde
group of certain formyl substituted chromones.
Treatment of formyl chromones 1a–d dissolved in 2-propanol with
basic alumina at 75ꢀC, in about the same ratio reported for the neutral
dried alumina, allowed to obtain the 3-hydroxymethyl chromones in
good yields (50–60%), with the exception of compound 2C, because to
the free phenolyc hydroxyl group, as shown in Table 1, this kind of
compounds are the starting materials for the synthesis of a series of bis-
3-hydroxymethylchromoniloxy derivatives that present a high anti-
asthma activities.[15] Although this product is obtained in low yield
(15%) this methodology remains as a feasible alternative because the
synthesis of 2C has been only reported with 5% of yield.[11a] In Table 1
are summarized the results of reductions of 3-formylchromones.
EXPERIMENTAL
All melting points uncorrected were determined on a Kofler hot-
stage apparatus. Infrared spectra were recorded on a FT-IR Bruker

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3228
Araya-Maturana et al.
IFS 55 spectrophotometer for KBr disc and wave numbers are reported
in cmꢁ1. The 1H and 13C NMR spectra were performed on Bruker
AVANCE DRX 300 spectrometer operating at 300.13 MHz (1H) or
75.47 MHz (13C). Measurements were carried out a probe temperature
of 300K, using CDCl3 containing tetramethylsilane (TMS) as internal
standard. Microanalysis was performed using Fisons EA 1108 analyzer.
Basic alumina used was Panreac Montplet & Esteban for column
chromatography.
The formyl chromones used as substrates were synthesized through
Vilsmeier–Haack reaction, their physical and spectroscopic properties are
in accordance with the reported bibliography.
GENERAL PROCEDURE FOR
PREPARATION OF 1A–D
The experimental conditions utilized were similar to the report in
the literature.[9b] To a cooled dimethylformamide solution of o-hydroxy-
acetophenone, phosphorus oxychloride was added dropwise and then the
ice bath was removed. The stirring reaction mixture was kept at 75ꢀC
overnight and then treated with ice-water to give the corresponding 3-
formyl chromone derivative.
4-Oxo-4H-1-benzopyran-3-carboxaldehyde (1a). M.p. 149–151ꢀC
(Lit.[6] 151–152ꢀC). 1H NMR, ꢀ (CDCl3): 7.52 (ddd, 1H, J1 ¼ 7.9 Hz,
J2 ¼ 7.2 Hz, J3 ¼ 1.1 Hz, 6-H), 7.56 (dd, 1H, J1 ¼ 8.5 Hz, J2 ¼ 1.1 Hz,
8-H), 7.77 (ddd, 1H, J1 ¼ 8.5 Hz, J2 ¼ 7.2 Hz, J3 ¼ 1.7 Hz, 7-H), 8.32
(dd, 1H, J1 ¼ 7.9 Hz, J2 ¼ 1.7 Hz, 5-H), 8.57(s, 1H, 2-H); 10.40 (s,
1H, CHO).
5-Hydroxy-4-oxo-4H-1-benzopyran-3-carboxaldehyde (1b).[16] M.p.
157ꢀC. 1H NMR, ꢀ (CDCl3): 6.91 (dd, 1H, J1 ¼ 0.7 Hz, J2 ¼ 8.3 Hz,
6-H), 6.99 (dd, 1H, J1 ¼ 0.7 Hz, J2 ¼ 8.3 Hz, 8-H), 7.61 (dd, 1H,
J1 ¼ J2 ¼ 8.3 Hz, 7-H), 8.52 (s, 1, 2-H); 10.32 (s, 1H, CHO), 12.10
(s, 1H, OH).
6-Hydroxy-4-oxo-4H-1-benzopyran-3-carboxaldehyde (1c).[17] M.p.
235–238ꢀC (dec.). H NMR, ꢀ (CDCl3): 6.08 (s, 1H, OH), 7.30 (dd, 1H,
1
J1 ¼ 9.01 Hz, J2 ¼ 3.05 Hz, 7-H), 7.48 (d, 1H, J ¼ 9.01 Hz, 8-H), 7.69
(d, 1H, J ¼ 3.05 Hz, 5-H), 8.55 (s, 1H, 2-H); 10.39 (s, 1H, CHO).
6-Methoxy-4-oxo-4H-1-benzopyran-3-carboxaldehyde (1d). M.p.
163–165ꢀC (Lit.[9b] 164–166ꢀC). 1H NMR, ꢀ (CDCl3): 3.93 (3H, s, OCH3),
7.32 (dd, 1H, J1 ¼ 9.2 Hz, J2 ¼ 3.0 Hz, 7-H), 7.48 (1H, d, J ¼ 9.2 Hz, 8-H),
7.66 (1H, d, J ¼ 3.0 Hz, 5-H), 8.53 (1H, s, 2-H); 10.41 (1H, s, CHO).

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Reduction of 3-Formylchromones
3229
GENERAL PROCEDURE FOR REDUCTION OF
FORMYLCHROMONES
About 1 g of basic alumina and about 50 mg of the corresponding
formyl chromone (5% of alumina weight) dissolved in 10 mL of 2-pro-
panol were placed in a round-bottomflask containing a magnetic bar, the
mixture is stirred for 4 h at 75ꢀC. Vacuumfiltration through celite, and
rotatory evaporation of solvent give crude alcohols which may be
purified by column chromatography using ethyl acetate/hexane 1:1 as
eluent.
3-(Hydroxymethyl)-4-oxo-4H-1-benzopyrane (2a). M.p. 109–110ꢀC
(Lit.[6] 108–110ꢀC). 1H NMR, ꢀ (CDCl3): 3.00 (t, 1H, J ¼ 6.3 Hz,
CH2OH), 4.59 (dd, 2H, J1 ¼ 6.3 Hz, J2 ¼ 0.7 Hz, CH2OH), 7.43 (ddd,
1H, J1 ¼ 7.9 Hz, J2 ¼ 7.3 Hz, J3 ¼ 1.0 Hz, 6-H), 7.48 (1H, d, J ¼ 8.6 Hz,
8-H), 7.70 (ddd, 1H, J1 ¼ 8.6 Hz, J2 ¼ 6.9 Hz, J3 ¼ 1.6 Hz, 7-H), 7.95 (t,
1H, J ¼ 0.7 Hz, 2-H), 8.24 (dd, 1H, J1 ¼ 7.9 Hz, J2 ¼ 1.6 Hz, 5-H).
5-Hydroxy-3-(hydroxymethyl)-4-oxo-4H-1-benzopyrane (2b). M.p.
102–104ꢀC. 1H NMR, ꢀ (CDCl3): 4.58 (s, 2H, CH2OH), 5.12 (t, 1H,
J ¼ 0.8 Hz, CH2OH), 6.82 (dd, 1H, J1 ¼ 8 Hz, J2 ¼ 0.9 Hz, 6-H), 6.92
(1H, dd, J1 ¼ 8.4 Hz, J2 ¼ 0.8 Hz, 8-H), 7.55 (dd, 1H, J1 ¼ J2 ¼ 8.4 Hz,
7-H); 7.94 (t, 1H, J ¼ 0.8 Hz, 2-H), 12.25 (s, 1H, 5-H).
13C NMR, ꢀ (CDCl3): 58.3, 107.5, 111.15, 111.8, 122.09, 136.07,
154.0, 157.2, 160.98, 183.0. IR: 3415, 1651, 1271. Anal. calcd. for
C10H8O4: C, 62.50; H, 4.20. Found: C, 61.93; H, 4.28.
6-Hydroxy-3-(hydroxymethyl)-4-oxo-4H-1-benzopyrane (2c). M.p.
217–219ꢀC (Lit.[11] 215–218.5ꢀC). H NMR, ꢀ (DMSO-d6): 4.42 (d, 2H,
1
J ¼ 4.5 Hz, CH2OH), 5.17 (t, 1H, J ¼ 4.5 Hz, CH2OH), 7.29 (dd, 1H,
J1 ¼ 2.5 Hz, J2 ¼ 8.9 Hz, 7-H); 7.39 (d, 1H, J ¼ 2.5 Hz, 5-H), 7.58 (d,
1H, J ¼ 9 Hz, 8-H), 8.22 (s, 1H, 2-H), 10.08 (s, 1H, 6-OH).
3-(Hydroxymethyl)-6-methoxy-4-oxo-4H-1-benzopyrane (2d). M.p.
151–152ꢀC (Lit.[6] 150–153.5ꢀC). 1H NMR, ꢀ (CDCl3): 2.99 (t, 1H,
J ¼ 6.5 Hz, CH2OH), 3.91 (s, 3H, OCH3), 4.59 (d, 2H, J ¼ 5.6 Hz,
CH2OH), 7.29 (dd, 1H, J1 ¼ 9.3 Hz, J2 ¼ 3.0 Hz, 7-H), 7.42 (d, 1H,
J ¼ 9.2 Hz, 8-H), 7.57 (d, 1H, J ¼ 2.9 Hz, 5-H), 7.93 (s, 1H, 2-H).
ACKNOWLEDGMENTS
This work was supported by FONDECYT Grant Nꢀ 1000859,
J. H.-M. thanks DAAD for a fellowship.

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3230
Araya-Maturana et al.
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Received in the USA March 12, 2003

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