Synthesis of aromatic aldehydes by oxidative hydroxymethylation

Article abstract of DOI:10.1055/s-2004-829535

A new high yield method for the synthesis of aromatic aldehydes has been developed. The procedure is based on an acid catalyzed hydroxymethylation of an arene substrate by paraformaldehyde with concurrent selective oxidation of the intermediate aromatic carbinol by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to the aldehyde product.

Full text of DOI:10.1055/s-2004-829535

LETTER
1575
Synthesis of Aromatic Aldehydes by Oxidative Hydroxymethylation
Synthesis of
A
rom
l
atic
A
l
e
n
O
xidative
H
a
ydroxymethylatio
B
n
ranytska, Ronny Neumann*
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel
Fax +972(8)9344142; E-mail: Ronny.Neumann@weizmann.ac.il
Received 1 April 2004
with the associated halide waste or use often reagents with
formation of hazardous (in)organic waste.
Abstract: A new high yield method for the synthesis of aromatic
aldehydes has been developed. The procedure is based on an acid
catalyzed hydroxymethylation of an arene substrate by paraformal-
dehyde with concurrent selective oxidation of the intermediate aro-
matic carbinol by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to
the aldehyde product.
An alternative method for the preparation of aryl alde-
hydes would be to hydroxymethylate an arene with form-
aldehyde to yield an intermediate arylmethanol with in
situ oxidation of the arylmethanol by any number of meth-
ods, Scheme 1.
Key words: aldehydes, arenes, electrophilic aromatic substitutions,
oxidations, quinones
H+
[O]
+ HCHO
OH
R'
O
R'
R'
The discovery of new methods for the preparation of
chemicals is an important goal in the development of Scheme 1 Oxidative hydroxymethylation for synthesis of aryl alde-
hydes
modern methods for chemical synthesis. Of special signif-
icance are the use procedures that minimize amounts of
A major problem with this concept is the fact that normal-
ly the hydroxymethylation step requires the use of a Brøn-
sted acid catalyst such as sulfuric acid. Under these
conditions the intermediate arylmethanol reacts with the
arene substrate to yield condensation products, Scheme 2.
In the limited case of phenol and some of its alkylated de-
rivatives, the concept delineated in Scheme 1 has been re-
alized, mostly in the patent literature, since no Brønsted
acid is reportedly needed for the hydroxymethylation re-
action. Thus, salicylaldehyde products may be obtained
using for the arylmethanol oxidation step tin chlorides,10
chromium salts,11 peroxides and manganese com-
pounds,12 titanium or zirconium compounds,13 or clays
modified with trialkylamines14 as catalysts.
waste and by-products. In this context, the preparation of
rather simple aromatic aldehydes presents a surprisingly
difficult challenge. Perusal of basic organic textbooks will
show that many different approaches can be taken towards
the synthesis of aromatic aldehydes including: (a) direct
oxidation of methylaromatic substrates to aromatic alde-
hydes using stoichiometric reagents such as silver(II)
oxide, ceric ammonium nitrate, selenium dioxide, manga-
nese dioxide, chromyl chloride and periodic acid;1 (b)
chlorination/bromination of methylaromatic substrates in
the presence of peroxides and/or light as radical chain ini-
tiators followed by hydrolysis to the required aldehyde;
(c) oxidation of the methylaromatic substrates to the cor-
responding carboxylic acids with oxidants such as nitric
acid, chromic acid and derivatives and potassium
permanganate1 followed by halogenation to acyl halides
and catalytic hydrogenation to the corresponding aromat-
ic aldehydes using palladium-based catalysts;2 (d) haloge-
nation of arenes to the corresponding haloarenes followed
by carbonylation with carbon monoxide in the presence of
noble metal based catalysts (usually palladium) to yield
aromatic aldehydes;3 (e) formylation of arenes with vari-
ous reagents notably (i) aluminum chloride/gaseous hy-
drogen chloride/carbon monoxide (Gatterman–Koch
reaction),4 (ii) zinc cyanide/hydrogen chloride (Gatterman
reaction),5 (iii) phosphorous oxychloride disubstituted
formamides (Vilsmeier–Haack reaction),6 (iv) chloro-
form/sodium hydroxide (Reimer–Tiemann reaction),7 (v)
dichloromethyl methyl ether/aluminum chloride,8 and (vi)
formylfluoride/boron trifluoride.9 All these methods are
either multistage procedures, or use bromine/chlorine
H+
OH
R'
R'
R'
R'
Scheme 2 Formation of diarylmethanes under hydroxymethylation
conditions
Beyond the aforementioned case of oxidative hydroxy-
methylation for certain phenolic substrates there exists no
general method for preparation of aryl aldehydes from
arenes by the reaction pathway as delineated in Scheme 1.
Notably, in the one case where such a possibility has been
mentioned in the literature for the oxidative hydroxylation
of anisole the reaction yield is low, <25%, and required
high temperatures, ca. 350 °C.15
A high yield procedure for oxidative hydroxymethylation
would be an advantageous alternative to the classic
methods described above.1–9 Such a preliminary proce-
dure is now described as outlined in Scheme 3, wherein
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is used as
the oxidant for the intermediate aryl methanol.16 The 2,3-
SYNLETT 2004, No. 9, pp 1575–1576
2
2.
0
7.
2
0
0
4
Advanced online publication: 29.06.2004
DOI: 10.1055/s-2004-829535; Art ID: G10304ST
© Georg Thieme Verlag Stuttgart · New York

1576
O. Branytska, R. Neumann
LETTER
Table 1 Oxidative Hydroxymethylation of Arenes to Aryl Aldehydesa
Substrate
Isolated yield (%)
Product (purity, %)
1,2-Dimethoxybenzene
1,4-Dimethoxybenzene
Methoxybenzene
Ethoxybenzene
92
89
87
94
74
63
91
95
3,4-Dimethoxybenzaldehyde (95)
2,5-Dimethoxybenzaldehyde (99)
2- and 4-Methoxybenzaldehyde (99)b
2- and 4-Ethoxybenzaldehyde (99)c
4-Methoxy-1-naphthaldehyde (99)
Piperonal (98)
4-Methoxynaphthalene
1,3-Benzodioxole
Thiophene
Thiophene-2-carboxyaldehyde (98)
Benzothiophene-2-carboxyaldehyde (93)d
Benzothiophene
a Reaction conditions: 10 mmol arene, 100 mmol paraformaldehyde, 0.0025 mmol H2SO4, 20 mmol DDQ, 10 mL MeCN, 5 h, 80 °C.
b 75% 4-Methoxybenzaldehyde, 25% 2-methoxybenzaldehyde.
c 78% 4-Ethoxybenzaldehyde, 22% 2-ethoxybenzaldehyde.
d Ca. 7% benzothiophene-3-carboxyaldehyde.
tered and washed twice with EtOAc. The filtrate containing the aryl
H2SO4
+ HCHO
Cl
aldehyde products was purified by flash chromatography and the
product was analyzed by 1H NMR and GC. The GLC were carried
out with both FID and MS detectors using a Restek Rtx-5MS col-
umn (5% phenymethylsilicone, 30 m, 0.32 mm ID, 0.25 mm coat-
ing). The determination of the regioselectivity of the reactions and
the confirmation of the GC analysis was carried out by 1H NMR.
OH
HO
R'
R'
Cl
Cl
Cl
+
+
O
O
OH
OH
O
R'
R'
NC
CN
NC
CN
Acknowledgment
Scheme 3 Synthesis of aryl aldehydes by oxidative hydroxy-
methylation with DDQ as oxidant
This research was supported by the Israel Science Foundation and
the Helen and Martin Kimmel Center for Molecular Design. R. N.
is the Rebecca and Israel Sieff Professor of Organic Chemistry.
dichloro-5,6-dicyanohydroquinone (DDHQ) formed in
the reaction can be recovered and re-oxidized to DDQ
with nitric acid.17
References
(1) Haines, A. H. Methods for the Oxidation of Organic
Compounds; Academic Press: London, 1988.
(2) Rylander, P. N. Catalytic Hydrogenation in Organic
Syntheses; Academic Press: New York, 1979.
(3) Heck, R. F. Palladium Reagents in Organic Syntheses;
Academic Press: London, 1985.
(4) Crounse, N. N. Org. React. 1949, 5, 290.
In a typical procedure 10 mmol arene, 3 g (100 mmol)
paraformaldehyde, 0.25 mg (0.0025 mmol) H2SO4 and
4.54 g (20 mmol) DDQ were stirred in 10 mL acetonitrile
for 5 hours at 80 °C. The reaction mixture was cooled to
room temperature. The precipitate formed was filtered
and washed twice with EtOAc. The product from the
filtrate and wash was purified by flash chromatography.
The results for some exemplary substrates are presented in
Table 1.
(5) Truce, W. E. Org. React. 1957, 9, 37.
(6) Jutz, C. Adv. Org. Chem. 1976, 9, 225.
(7) Wynberg, H.; Meijer, E. W. Org. React. 1982, 28, 1.
(8) Reiche, A.; Gross, H.; Höft, E. Chem. Ber. 1960, 93, 88.
(9) Olah, G. A.; Kuhn, S. J. J. Am. Chem. Soc. 1960, 82, 2380.
(10) (a) Casnati, G.; Casiraghi, G.; Puglia, G.; Sartori, G.;
Terenghi, G. US Patent 4,151,201, 1979. (b) Casiraghi, G.;
Casnati, G.; Puglia, G.; Sartori, M. G.; Terenghi, G. J. Chem.
Soc., Perkin Trans. 1 1980, 1862. (c) Furukawa, Y.; Keishi,
K. US Patent 6,080,895, 2000.
(11) Matsuda, T.; Murata, T. US Patent 4,231,967, 1980.
(12) Lee, R. J.; Baranowski, L. J. US Patent 4,371,712, 1983.
(13) Virnig, M. J. US Patent 4,638,096, 1987.
(14) Bigi, F.; Conforti, M. L.; Maggi, R.; Sartori, G. Tetrahedron
2000, 56, 2709.
The method presented, although conceptually novel and
quite effective for arylethers and thiophenes still has two
limitations related to substrate scope. First, less reactive
arenes such as benzene require larger amounts of acid for
the hydroxymethylation reaction. Under such conditions
the in situ oxidation to the aryl aldehyde is less rate com-
petitive and mostly coupling products (Scheme 2) are still
formed. Second, for methylated substrates such as 4-
methoxytoluene, there is a competitive parallel oxidation
of the methyl moiety to aldehyde that reduces the reaction
yield. It should be noted that the procedure also requires a
disadvantageous excess of paraformaldehyde as a reagent.
(15) Jyothi, T. M.; Talawar, M. B.; Rao, B. S. Catal. Lett. 2000,
64, 151.
(16) (a) Becker, H. D.; Bjoerk, A.; Adler, E. J. Org. Chem. 1980,
45, 1596. (b) Khenkin, A. M.; Vigdergauz, I.; Neumann, R.
Chem.–Eur. J. 2000, 6, 875; and references therein.
(17) (a) Newman, M. S.; Khanna, V. K. Org. Prep. Proced. Int.
1985, 17, 422. (b) Kim, K. H.; Grunewald, G. L. Org. Prep.
Proced. Int. 1976, 8, 141.
In a typical oxidative hydroxymethylation procedure (Table 1) 10
mmol arene substrate, 3 g (100 mmol) paraformaldehyde, 0.25 mg
(0.0025 mmol) H2SO4 and 4.54 g (20 mmol) DDQ were stirred in
10 mL MeCN for 5 h at 80 °C. The reaction mixtures were then
cooled and the precipitate containing the DDHQ product was fil-
Synlett 2004, No. 9, 1575–1576 © Thieme Stuttgart · New York