Efficient Procedure for Preparing Salicyl Alcohols

Article abstract of DOI:10.1023/A:1012708319679

A new convenient procedure was developed for selective ortho-hydroxymethylation of phenols by reaction of paraformaldehyde with a mixture of phenol and orthoboric acid. The method is general for phenols containing no strong electron-withdrawing substituents; it allows preparation of o-hydroxybenzyl alcohols of high purity in a high yield.

Full text of DOI:10.1023/A:1012708319679

Russian Journal of Applied Chemistry, Vol. 74, No. 1, 2001, pp. 103 105. Translated from Zhurnal Prikladnoi Khimii, Vol. 74, No. 1,
001, pp. 100 102.
Original Russian Text Copyright
2
2001 by Belyanin, Filimonov, Krasnov.
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Efficient Procedure for Preparing Salicyl Alcohols
M. L. Belyanin, V. D. Filimonov, and E. A. Krasnov
Siberian State Medical University, Tomsk, Russia
Tomsk Polytechnic Institute, Tomsk, Russia
Received February 21, 2000
Abstract A new convenient procedure was developed for selective ortho-hydroxymethylation of phenols
by reaction of paraformaldehyde with a mixture of phenol and orthoboric acid. The method is general for
phenols containing no strong electron-withdrawing substituents; it allows preparation of o-hydroxybenzyl
alcohols of high purity in a high yield.
Salicyl (o-hydroxybenzyl) alcohol and its deriva-
tives are of interest as intermediates in synthesis of
many organic compounds: phenylchromones [1], iso-
flavones [2], etc.
successfully performed selective o-hydroxymethyla-
tion of a series of phenols 1a 1k and obtained the
corresponding salicyl alcohols 2a 2k (Table 1).
1
The structures of 2a 2k were proved by the H
NMR (Table 2) and IR spectra and by comparison
with the authentic samples. The IR spectra of 2a 2k
contain two strong absorption bands at 3475 3440
and 3240 3165 cm 1 characteristic of the intramolec-
ular hydrogen bond and of O H stretching vibrations,
Salicyl alcohol is an aglycone of a number of gly-
cosides found in Salicaceae. Some of them exhibit
antihelminth [3] and antiviral [4] activity.
One of the most widely used routes to salicyl alco-
hol is hydroxymethylation with formaldehyde or com-
pounds generating it of phenyl metaborate PhOB=O
and also characteristic absorption bands (C O) at
1
1
015 1045 cm :
(exists as trimers [5]). The initial metaborate is pre-
R1
R1
pared by refluxing equimolar amounts of phenol and
boric acid in aprotic aromatic solvents (toluene, xyl-
ene) with azeotropic distillation of the released water
R2
R3
OH
R2
R3
OH
OH
CH O
2
H BO
3 3
[5 9]. The yield of the crude target product, according
to patents [6 8], depends on the initial phenol and
does not exceed 65%; attempts to reproduce the syn-
thesis of salicyl alcohol described in the patent re-
sulted in a yield as low as 35% [5]. The conversion
of phenol was incomplete, and polycondensation
products formed, complicating purification of the
target product [5].
R4
a 1j
HO
R4
1
2a 2j
OH
OH
CH3
HO
CH3
Another route is hydroxymethylation of phenol in
the presence of a 1.5-fold excess of arylboronic acids
2
k
1
2
3
4
2
3
3
4
ArB(OH) . The reaction involves intermediate forma-
where R = R = R = R = H (a); R = R = R = H,
2
1
1
2
4
2
tion of cyclic esters of hydroxybenzyl alcohol and
arylboronic acid. The desired alcohol is released by
treatment of these esters with propylene glycol or
hydrogen peroxide [10].
R = CH (b); R = R = R = H, R = CH (c); R =
3 3
3
1
4
1
2
R = H, R = CH(CH ) , R = CH (d); R = R =
3
2
3
4
3
2
1
2
4
3
4
R = H, R = OCH (e); R = R = R = H, R = Cl
3
1
4
3
1
2
(f); R = R = R = H, R = F (g); R = R = R = H,
3
1
1
2
4
3
R = Ph (h); R = R = R = H, R = OCOPh (i);
A simpler route to salicyl alcohols is reaction of
paraformaldehyde with a mixture of phenol and excess
boric acid in benzene under conditions of continuous
azeotropic distillation of water, without preparing
phenyl metaborate in advance. By this method we
3
4
2
R = R = R = H, R = OCOPh (j).
ortho-Hydroxymethylation of phenols 1a 1k by
the suggested procedure occurs at lower temperature
(up to 81 C), takes longer time, and requires a larger
1
070-4272/01/7401-0103$25.00 2001 MAIK Nauka/Interperiodica

104
BELYANIN et al.
Table 2. Synthesis of o-hydroxybenzyl alcohols 2a 2k by
reaction of phenols 1a 1k with paraform
unsuitable for preparing salicyl alcohols with substitu-
ents sensitive to bases. It was found that the boric acid
esters formed under conditions of our procedure can
be successfully saponified by keeping the reaction
mixture in water without adding alkali. This approach
allowed us to perform for the first time direct selective
hydroxymethylation of phenols 1i and 1j containing
phenyl benzoate moieties. The resulting alcohols 2i
and 2j (Table 1) are synthetic equivalents of difficult-
ly accessible dihydroxybenzyl alcohols.
Com-
pound
Yield,
%
,
h
mp,
C
2
2
a
b
22
37
53
48
84 85 (C H ) (85 86 [11])*
6
6
25 27 (hexane) (5 [6],
3 34 [11])
102 103 (C H ) (104 105
3
2
c
29
63
6
6
[11])
The relatively low yield of 2j is due to the fact that
reaction of phenol 1j with paraform yields, according
2
2
2
2
2
d
e
f
g
h
13
21
53
38
46
61
40
54
34
68
83 84 (hexane) (86 [12])
79 80 (CHCl ) (80 81 [11])
3
1
92 93 (C H ) (92 93 [11])
to the H NMR spectrum, a mixture of 2j and its iso-
6
6
69 70 (C H ) (68 70 [13])
mer, 2-hydroxymethyl-3-benzoyloxyphenol, insepara-
ble by chromatography. In other words, hydroxymeth-
ylation occurs at both o-positions of the phenolic
hydroxyl in 1j. We were able to isolate only a portion
of 2j by single recrystallization of the mixture from
benzene.
6
6
162 163 (C H CH ) (164
6
5
3
165 [13])
2
2
2
i
j
k
52
33
49
60
35
56
114 115 (C H )
6
6
125 126 (C H )
6 6
144 145 (water)
It should be noted that pyrocatechol monobenzoate
appeared to be almost inert in hydroxymethylation
(110 h). This is probably due to a strong intramolec-
ular hydrogen bond blocking the phenolic hydroxyl
in the o-position relative to the benzoate group.
*
In parentheses are published data.
excess of boric acid (up to 1.5 mol) than hydroxy-
methylation of aryl metaborates [5 9]. Also, fresh
portions of paraform should be added at regular inter-
vals to compensate for its removal with the distillate.
Nevertheless, there are important advantages: com-
plete conversion of the initial phenol, absence of
oligomeric products, and higher yield and purity of
the target alcohols 2a 2k.
Reaction of bisphenol 1k containing two equivalent
phenolic hydroxyls with paraform yields bis(hydroxy-
methyl) derivative 2k within 49 h. At a shorter reac-
tion time, the reaction mixture contained, according to
TLC, unchanged 1k, the monohydroxymethylation
product, and alcohol 2k; the latter is formed even in
early stages of the reaction. Thus, hydroxymethylation
of phenol 1k occurs nonselectively at both phenyl
rings.
It is important for practice that in hydroxymethyla-
tion of phenyl metaborate the resulting salicyl alcohol,
as a rule, is isolated by treatment of the reaction mix-
ture with alkali [5 7, 9], which makes this procedure
Table 2. 1H NMR spectra of salicyl alcohols 2a 2k in DMSO-d6
Compound
, ppm
2
2
2
2
a
b
c
d*
4.70 (s, 3H, CH OH), 6.70 7.18 (m, 4H, Ar), 8.80 (s, 1H, ArOH)
2
2.13 (s, 3H, CH ), 4.63 (s, 2H, CH OH), 6.52 6.95 (m, 3H, Ar)
3
2
2.18 (s, 3H, CH ), 4.43 (s, 2H, CH ), 4.89 (s, 1H, CH OH), 6.61 7.07 (m, 3H, Ar), 9.03 (s, 1H, ArOH)
3 2 2
1.10 1.20 (d, 6H, CH CH CH ), 2.02 (s, 4H, ArCH , CH CH CH ), 3.28 (m, 1 H, OH), 5.04 (s, 2H,
3
3
3
3
3
CH ), 6.65 7.02 (m, 2H, Ar)
2
2
2
2
2
2
2
2
e*
f
g
h
3.10 (s, 1H, OH), 3.60 (s, 3H, OCH ), 4.63 (s, 2H, CH ), 6.53 6.66 (m, 3H, Ar)
4.74 (s, 2H, CH ), 5.20 (s, 1H, CH OH), 6.98 7.54 (m, 3H, Ar), 9.90 (s, 1H, ArOH)
4.50 (s, 2H, CH ), 4.80 (s, 1H, CH OH), 6.70 7.26 (m, 3H, Ar), 9.40 (s, 1H, ArOH)
4.80 (s, 2H, CH ), 5.34 (s, 1H, CH OH), 7.05 7.84 (m, 8H, Ar), 9.78 (s, 1H, ArOH)
2 2
4.74 (s, 2H, CH ), 5.30 (s, 1H, CH OH), 7.08 8.36 (m, 8H, Ar), 9.73 (s, 1H, ArOH)
5.20 (s, 2H, CH OH), 6.91 8.33 (m, 8H, Ar), 9.06 (s, 1H, ArOH)
1.81 (d, 6H, CH CCH ), 4.76 (s, 4H, CH OH), 5.26 (s, 2H, CH OH), 6.90 7.46 (m, 6H, Ar), 9.39 (s, 2H,
3 2
2
2
2 2
i
2 2
j**
k
2
3
3
2
2
ArOH)
*
In CDCl . ** In pyridine-d .
3
5
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 74 No. 1 2001

EFFICIENT PROCEDURE FOR PREPARING SALICYL ALCOHOLS
105
Phenols with electron-withdrawing substituents in
CONCLUSIONS
1) Reaction of paraform with phenols in the pres-
ence of excess boric acid under conditions of continu-
ous azeotropic distillation of water results in selective
o-hydroxymethylation of the substrates with complete
conversion of the initial phenols and formation of
salicyl alcohols.
the ring (NO , CHO, COOH) remain inert under the
2
(
reaction conditions and do not give the corresponding
salicyl alcohols.
The positive effect reached in hydroxymethylation
of phenols in the presence of excess boric acid can
be explained as follows. In the case of equimolar
amounts of phenol and boric acid [5 9], the presuma-
ble precursors of salicyl alcohol are cyclic borates [5].
We can assume with confidence that under the reac-
tion conditions these cyclic borates are in equilibrium
with free alcohol 2a which enters further side trans-
formations (dehydration, condensation with formalde-
hyde, etc.). Then excess boric acid under the sug-
gested conditions decreases the concentration of free
salicyl alcohol owing to shift of the equilibrium. Also,
it is significant that the reaction is performed at a
lower temperature (81 C) than suggested in the liter-
ature (90 95 C) [5 9]. It is known that salicyl alcohol
is thermally unstable, and at temperatures above
(2) A general procedure was developed for prepar-
ing salicyl alcohols from phenols containing no strong
electron-withdrawing substituents.
(3) The suggested procedure allowed for the first
time preparation of the synthetic equivalents of dihy-
droxybenzyl alcohols.
ACKNOWLEDGMENTS
The study was financially supported by the Project
of the Ministry of Education of the Russian Federa-
tion Basic Research in the Field of Chemical Tech-
nologies (project no. 98-8-3.1-127).
1
00 C it rapidly forms polymeric products [14].
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EXPERIMENTAL
1
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spectra, on a Bruker AC 200 spectrometer (200 MHz,
1
2. Buruli, C., Desider, N., and Stein, M.L., Eur. J. Med.
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6
The reaction progress was monitored and the prod-
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5
3
The typical procedure of hydroxymethylation of
phenols 1a 1k with paraform in the presence of boric
acid was as follows. A mixture of 40 mmol of approp-
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6
7
8
(
60 mmol) of paraform in 70 ml of benzene was re-
fluxed in a flask equipped with a Dean Stark trap
with continuous azeotropic distillation of water until
the initial phenol was completely converted (TLC).
Every 4 h, a fresh 0.45-g (15-mmol) portion of para-
form was added. After reaction completion, excess
benzene was distilled off under reduced pressure.
To the residue 30 ml of water was added, and the
mixture was allowed to stand for 5 h to ensure hydrol-
ysis of the intermediate boric acid ester of the salicyl
alcohol. The product was extracted with ether (three
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4
0-ml portions), and the combined ether extracts were
washed with watedr (20 ml). The solvent was re-
moved, and alcohols 2a 2k were purified by recrys-
tallization.
1
4. Vul’fson, N.S., Preparativnaya organicheskaya khi-
miya (Synthetic Organic Chemistry), Moscow: Gos-
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RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 74 No. 1 2001