Regioselective synthesis of 6-substituted 2-hydroxybenzaldehyde: Efficient synthesis of the immunomodulator tucaresol and related analogues

Article abstract of DOI:10.1039/a701102d

Two new improved procedures have been developed for the preparation of the immunostimulant tucaresol 1 [4-(2-formyl-3-hydroxyphenoxymethyl)benzoic acid]. These approaches, which start from resorcinol or 2,6-dimethoxybenzaldehyde, are practical and therefore amenable to scale-up. In the case of the second approach, the multi-step synthesis reported in the literature has been reduced to three steps. Furthermore, unlike the reported method, our synthesis is versatile for the preparation of tucaresol analogues. The method is general and applicable for the preparation of 6-substituted 2-hydroxybenzaldehydes.

Full text of DOI:10.1039/a701102d

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Regioselective synthesis of 6-substituted 2-hydroxybenzaldehyde:
efficient synthesis of the immunomodulator tucaresol and related
analogues
Boulos Zacharie,* Giorgio Attardo, Nancy Barriault and Christopher Penney
BioChem Therapeutic Inc., 275 Armand-Frappier Blvd., Laval, Québec, Canada H7V 4A7
Two new improved procedures have been developed for the preparation of the immunostimulant tucaresol
1 [4-(2-formyl-3-hydroxyphenoxymethyl)benzoic acid]. These approaches, which start from resorcinol or
2,6-dimethoxybenzaldehyde, are practical and therefore amenable to scale-up. In the case of the second
approach, the multi-step synthesis reported in the literature has been reduced to three steps. F urthermore,
unlike the reported method, our synthesis is versatile for the preparation of tucaresol analogues. The
method is general and applicable for the preparation of 6-substituted 2-hydroxybenzaldehydes.
Schiff-base formation between T-cells and antigen presenting
cells has been described as essential to the enhancement of the
immune response.1 Recently, it was reported that a substituted
benzaldehyde, tucaresol 1, can mimic this physiological sig-
nal to T-cells by Schiff-base formation with cell surface
amino groups.2 The resultant induction of cytokines such as
interleukin-2 and interferon-γ was shown to translate into a
therapeutic effect in various viral and tumor models. Sub-
sequently, tucaresol was selected for clinical evaluation in AIDS
and cancer patients.
formyl group directed by the 2,6-disubstituted ether. The sec-
ond approach requires selective deprotection of the methyl
function of the commercially available 2,6-dimethoxy-
benzaldehyde, without affecting the formyl moiety.
Our first approach was to use the ability of certain 1,3-
substituents on aromatic systems to direct metallation at a pos-
ition ortho to these groups using organolithium reagents. This
phenomenon is of synthetic interest since electrophilic attack
on aryllithium intermediates represents a useful method for
the functionalization of aromatic compounds.4 Accordingly,
factors which control regioselectivity and efficiency of lithiation
of aromatic substrates have been the subject of many studies
in recent years.4 Numerous functional groups are known to
promote ortho-lithiation.5 However, with many of these groups,
problems are encountered with lack of discrimination between
non-equivalent ortho positions or between the ring positions
and other acidic sites within the substrate.6
H3C
CH3
N
N
N
O
O
N
N
O
NH
OH
NH
NH
NH2
OTHP
OTHP
OH
BCH–1393
CHO
R
ii
i
OH
CHO
OH
R
R
4 R = OMe
9 R = F
3 R = OMe
8 R = F
R = OMe
R = F
O
OH
O
CH3
iii
O
1
2
OH
OH
OMe
As part of our immunomodulator research program, we
identified a small molecule non-toxic T-cell (CTL) stimulant;3
6-N,N-dimethylaminopurin-9-ylpentyloxycarbonyl--arginine
(BCH-1393). Thus, tucaresol 1 was required for comparative
studies. The preparation described in the literature involves a
multi-step synthesis with low overall yield. The key reported
step is the ozonolysis of 4-hydroxy-2-methylbenzofuran 2 at
65 ЊC with stirringand exclusion of moisture. Thisisawkward for
large-scale synthesis. Furthermore, compound 2 is not a versa-
tile intermediate for the preparation of analogues of tucaresol,
because of the limited number of derivatives that can be syn-
thesized from the benzofuran ring. We therefore developed two
short routes for the preparation of 2,6-disubstituted benzalde-
hydes and in particular 2-hydroxy-6-alkoxybenzaldehyde.
CHO
CHO
OH
CHO
iv
v
1
OMe
R
5 R = OMe
10 R = F
vi
O
O
CHO
R
CO2H
vii
CHO
R
CO2R′
6 R = OMe
11 R = F
7 R = OMe
12 R = F
Results and discussion
Scheme 1 Reagents and conditions: i, 3,4-dihydro-2H-pyran, PPTS;
ii, BuLi, Et2O, DMF; iii, Hϩ; iv, LiCl, DMF, D; v, AlBr3–benzene;
vi, Cs2CO3, 4-bromomethyl benzoate; vii, NaOH
Two distinct approaches were considered for the preparation of
tucaresol: the first route is a regioselective introduction of the
J. Chem. Soc., Perkin Trans. 1, 1997
2925

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As a model compound, we selected O-THP protected 3-
methoxyphenol 3 (Scheme 1). An early investigation 6 revealed
that ortho-lithiation of 1,3-di-OMe or 1,3-di-OTHP benzene
gave selective metallation at the common ortho site.6 Encour-
aged by these results, we investigated the reaction between BuLi
and the protected phenol 3 in the presence of DMF as electro-
phile and ether solvent. We found that lithiation of 3 occurred
with high regioselectivity between the two ortho directing
groups to give 4 in high yield (95%). Scheme 1 summarizes these
results. The OTHP group from the aldehyde 4 was deprotected
with catalytic PTSA to afford the phenol 5. This latter inter-
mediate was successfully benzylated using methyl or tert-butyl
4-bromomethylbenzoate,7 and caesium carbonate in DMF. This
procedure offered a more practical work-up to that reported
in the literature (alkyl halide, ButOK, DMSO2 or alkyl halide,
K2CO3).
In order to complete the synthesis of tucaresol, selective
demethylation of compound 6 was necessary. Previous work
has demonstrated that alkyl aryl ethers are cleaved under neu-
tral conditions using lithium halide in aprotic solvents.8 The
reaction is facilitated by the presence of electron-withdrawing
substituents in the ortho-positions.9 We therefore investigated
the reaction between the aldehyde 5 or 6 with lithium chloride
or bromide in boiling DMF under the standard conditions.9
However, decomposition of starting material took place.
In an effort to replace the methoxy group, we examined the
ortho-directing ability of the OTHP substituent relative to other
ortho-directing substituents in the metallation with BuLi. An
attractive alternative was the methoxymethyl group (MOM)
since it is known to efficiently direct ortho-metallation.10 To our
knowledge, formylation of 1,3-di-O-substituted phenols bear-
ing two different acid sensitive, strong ortho-directing groups
has not been reported. The results are described in Scheme 2.
Thus, resorcinol was selectively monoprotected as the meth-
oxymethyl ether by reaction with chloromethyl ether in acetone
in the presence of caesium carbonate.11 The resulting aryl ether
was treated with tetrahydropyran to afford quantitatively the
bis protected phenol 13. Lithiation of this compound was con-
ducted in a similar manner as described above. Again, a signifi-
cant degree of regioselective control of metallation between the
protected hydroxy groups was obtained (the ratio of aldehydes
14:15 is 93:7). The product yield remained high.
The next step was investigation of selective hydrolysis condi-
tions for the removal of the THP moiety in the presence of the
MOM protecting group. Under neutral conditions, a mild and
efficient procedure was developed to give the phenol 16 using
an excess of LiCl in DMF at 75 Њ (Scheme 2). This method is
general and has been applicable to a variety of aliphatic and
aromatic compounds bearing THP ethers in the presence of
the MOM group.12 Selective deprotection in acidic medium was
also successful. The best conditions employed aqueous HCl
acid adsorbed on silica gel or catalytic amount of PTSA in
dichloromethane to afford compound 16 (Scheme 2). The latter
was converted in two steps to tucaresol 1 by the same procedure
described above.
Our approach to the synthesis of tucaresol 1 demonstrates
that the ortho directing abilities of OTHP and OMOM groups in
a 1,3-disubstituted benzene permit high regiocontrol of metal-
lation. Both groups are convenient for protecting phenols
but are acid labile. The ability to control the removal of the
THP substituent in the presence of the MOM group make
this procedure attractive for the synthesis of differentially
functionalized resorcinol and particularly 6-substituted 2-
hydroxybenzene derivatives. Our method also constituted an
alternative to other electrophilic substitutions4a especially if
ortho substitution is desired.
As an extension of this approach, the preparation of ana-
logues of 1 was undertaken. These compounds cannot be
obtained by the original synthesis. Fluorotucaresol 12 was
chosen as a synthetic target since the introduction of fluorine
into biologically active molecules often induces new pharmaco-
logical properties.13 Previous studies14 reported that lithiation
of 3-fluoroanisole occurred in the doubly activated 2 position at
Ϫ78 ЊC. At this temperature, benzyne formation is minimized.14
In contrast to these results, Kirk16 showed that fluorine com-
petes significantly with the methoxy group as an ortho director.
For example, the lithiation of 3-dimethyl-tert-butylsilyl ethers
of fluorophenols proceeded exclusively ortho to fluorine and
not in the doubly activated 2-position. Therefore, we examined
the metallation of 3-fluorophenol O-protected by THP 8.
Scheme 1 summarizes our results. Treatment of compound 8 in
THF at Ϫ78 ЊC in the presence of DMF gave exclusively the
formyl product 9 in high yield. In contrast to the previous
observation of Kirk, our results demonstrate that the steric
bulk of the THP group does not predominate and coordination
by oxygen is important. The synthesis of fluorotucaresol 12 was
completed in a similar manner as described for tucaresol 1
(Scheme 1).
OH
OMOM
i
OH
OTHP
13
ii
OMOM
OMOM
CHO
OMOM
CHO
+
iii
Our second approach was based on the use of commercially
available benzaldehyde derivatives protected at the 2- and/or 6-
positions. We first examined the demethylation of 2,6-
dimethoxybenzaldehyde. As noted above, attempts to remove
the methyl group of 5 and 6 using lithium halides in boiling
DMF were unsuccessful. It was decided to shorten the reaction
time from 12 to 6 h in order to minimize product decom-
position. Thus, treatment of 2,6-dimethoxybenzaldehyde with
lithium chloride in DMF at reflux for 6 h removed only one
methyl group to give the phenol 5. Upon application of further
heat, this compound started to decompose. Efforts were then
directed to other dealkylating reagents. Boron trichloride is
known to demethylate methoxy groups that are ortho to a car-
bonyl moiety.16 This dealkylation occurred if a six-membered
ring is formed due to the complexation of the boron atom and
the two oxygens of the carbonyl and the methoxy group.16 The
stronger the complex, the easier the demethylation. Unfortun-
ately, this dual complex is not possible when the carbonyl func-
tion is ortho to both methoxy groups and only monodemethyl-
OH
OTHP
OTHP
CHO
15
14
(93:7)
16
iv
OMOM
CHO
OH
CHO
v
vi
O
O
OMe
OH
O
O
1
17
Scheme 2 Reagents and conditions: i, chloromethyl methyl ether; 3,4-
dihydro-2H-pyran, PPTS; ii, BuLi, Et2O, DMF; iii, LiCl–DMF (75 ЊC)
or cat. PTSA or 5% HCl adsorbed on SiO2; iv, Cs2CO3, 4-bromomethyl
(or tert-butyl) benzoate; v, Hϩ; vi, NaOH
2926
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
ation was observed in the case of 2,6-dimethoxybenzaldehyde.16
Aluminium halides have proven successful as ether cleavage
reagents.17,18 Therefore, treatment of a solution of 2,6-dimeth-
oxybenzaldehyde or the aldehyde 5 in benzene with aluminium
chloride or bromide at ambient temperature for a few hours
afforded 2,6-dihydroxybenzaldehyde.19,20 The latter was select-
ively mono benzylated with methyl 4-bromomethylbenzoate
then hydrolysed, as described before, to give tucaresol 1. The
major advantage of this procedure lies in the facile synthesis of
compound 1 in three steps starting from commercially available
material. A similar approach starting from the commercially
available aldehyde 5 was also successful. Protection of the 2-
hydroxy function as acetate then demethylation of the ether
followed by alkylation and alkaline hydrolysis gave tucaresol 1
in good yield.
In summary, we have developed two simple, practical, and
general procedures for the preparation of 2-hydroxy-6-alkoxy
substituted benzaldehyde. The success of our first strategy relies
on the highly regioselective ortho 2-lithiation of both OTHP
and OMOM groups in 1,3-disubstituted benzenes. Selective
hydrolysis conditions for the removal of the THP in the pres-
ence of the MOM protecting group make this procedure
attractive for use in the functionalization of polysubstituted
aromatic compounds. Of particular interest, the second
approach involved the selective alkylation of 2,6-dihydroxy-
benzaldehyde which was readily available by treating 2,6-
dimethoxybenzaldehyde or 2-hydroxy-6-methoxybenzaldehyde
with aluminium halides. Both synthetic routes have been
employed to supply gram quantities of tucaresol and offer the
advantage of practical and general routes for the preparation of
analogues. Biological data of analogues and structure–activity
relationships will be reported in due course.
ArH), 6.70–6.60 (1H, m, ArH), 5.42–5.35 (1H, m, CH-O),
3.94–3.82 (1H, m, 6-H), 3.68–3.55 (1H, m, 6-H) and 2.10–1.50
(6H, m, 3 × CH2).
1-Methoxymethoxy-3-tetrahydropyran-2-yloxybenzene 13.23
A solution of resorcinol (3.30 g, 30.00 mmol) in acetone (30 ml)
was treated with caesium carbonate (8.88 g, 27.24 mmol) at 0 ЊC
under argon. To the resulting white suspension was added
dropwise chloromethyl methyl ether (2.07 ml, 27.24 mmol) and
the mixture was maintained at 0 ЊC for 1.5 h. Insoluble material
was filtered off and the filtrate was evaporated under reduced
pressure. The crude material was purified by silica gel column
chromatography using an EtOAc–hexanes gradient. Appro-
priate fractions were combined to give the following. 3-
Methoxymethoxyphenol23 (2.1 g, 50%) as a colourless oil, bp
105 ЊC, 1.7 mmHg, TLC Rf 0.50 (D); δH (300 MHz; CDCl3)
7.22–7.08 (1H, m, ArH), 6.70–6.48 (3H, m, ArH), 5.85 (1H, s,
OH), 5.16 (2H, s, CH2-O) and 3.55 (3H, s, O-CH3).
3-Methoxymethoxyphenol was THP-protected according to
the procedure described above, starting with the monoprotected
phenol 3 (1.5 g, 9.73 mmol) to give 13 (2.19 g, 95%) as a colour-
less oil, bp 103 ЊC, 2 mmHg TLC Rf 0.44; δH (300 MHz; CDCl3)
7.28–7.13 (1H, m, ArH), 6.80–6.66 (3H, m, ArH), 5.50–5.40
(1H, m, CH-O), 5.15 (2H, s, CH2-O), 3.94–3.82 (1H, m, 6-H),
3.68–3.55 (1H, m, 6-H), 3.50 (3H, s, O-CH3) and 2.10–1.52 (6H,
m, 3 × CH2) (Found: C, 62.11; H, 6.54. C8H10O3 requires C,
62.33; H, 6.54%).
Lithiation of 1,3-di-O-substituted phenols
General procedure. A solution of diprotected phenol (2.02
mmol) in dry ether (10 ml) at 0 ЊC was treated dropwise with
butyllithium (1.6  solution in hexanes; 2.42 mmol). Stirring
was continued at room temperature for 2 h under a flow of
argon. To this pale yellow solution was added dry DMF (6.05
mmol) after which the mixture was stirred for 2 h. The reaction
was quenched with brine and extracted with diethyl ether (3 25
ml). The combined extracts were dried (Na2SO4), filtered and
evaporated. The residue was purified by silica gel column chro-
matography using an EtOAc–hexanes gradient.
6-Methoxy-2-tetrahydropyran-2-yloxybenzaldehyde 4. Start-
ing with phenol 3 (0.42 g, 2.02 mmol) we obtained the aldehyde
4 (0.36 g, 76%) as a white solid, mp 72–74 ЊC; TLC Rf 0.34;
δH (300 MHz; CDCl3) 10.58 (1H, s, CHO), 7.44 (1H, t, J 8.3,
ArH), 6.80 (1H, d, J 8.2, ArH), 6.58 (1H, d, J 8.2, ArH), 5.70–
5.50 (1H, m, CH-O), 3.89 (3H, s, OCH3), 3.87–3.82 (1H, m,
6-H ), 3.79–3.60 (1H, m, 6-H) and 2.01–1.86 (6H, m, 3 × CH2);
m/z (FAB, thioglycerol) 152 (MHϩ Ϫ THP, MHϩ Ϫ 85) (Found:
M Ϫ THP, 152.0463. C8H8O3 requires M, 152.0473).
Experimental
Melting points were taken on a Fisher-Johns melting apparatus
and are uncorrected. TLC was performed on Merck silica gel
GOF254 plates with solvent systems; (A) 5% EtOAc–hexanes;
(B) 15% EtOAc–hexanes; 25% EtOAc–hexanes; (D) 50%
1
EtOAc–hexanes; (E) EtOAc; (F ) 25% MeOH–EtOAc. H, 13C
and 19F NMR spectra were obtained on a Bruker DRX-400
or a Varian VXR-300 spectrometer. J Values are given in Hz.
Mass spectra were recorded on a Kratos MS-50 TA instru-
ment. All reagents were obtained from Aldrich Chemical Co.
(Milwaukee WI), except for 2-methoxy-6-hydroxybenzaldehyde
which originated from Lancaster (Windham).
Protection of the phenolic group with tetrahydropyran (THP)
General procedure. To a solution of monoprotected phenol
(40 mmol) and pyridinium toluene-p-sulfonate (PPTS, 16 mmol)
in dry dichloromethane (40 ml) was added 3,4-dihydro-2H-
pyran (44 mmol) under argon. The reaction mixture was stirred
at room temperature overnight after which it was evaporated
under reduced pressure. The residue was then partitioned
between 5% aqueous sodium hydrogen carbonate (60 ml) and
ethyl acetate (70 ml). The organic layer was separated, dried
(Na2SO4), filtered and evaporated. The remaining oil was puri-
fied by silica gel column chromatography to give the product.
1-Methoxy-3-tetrahydropyran-2-yloxybenzene 3.22 Starting
with 3-methoxyphenol (5 g, 40.32 mmol), we obtained 3 (5.10 g,
61%) as a colourless oil (this compound is volatile under
reduced pressure and some product was lost during evaporation
of solvents); TLC Rf 0.50 (B); δH (300 MHz; CDCl3) 7.28–7.15
(1H, m, ArH), 7.20–6.52 (3H, m, ArH), 5.50–5.40 (1H, m, CH-
O), 3.94–3.82 (1H, m, 6-H), 3.78 (3H, s, O-CH3), 3.68–3.55 (1H,
m, 6-H) and 2.10–1.52 (6H, m, 3 × CH2).
6-Fluoro-2-tetrahydropyran-2-yloxybenzaldehyde 9. In this
case the reaction temperature was maintained below Ϫ70 ЊC.
Starting with phenol 8 (1.54 g, 7.82 mmol) we obtained the
aldehyde 9 (1.65 g, 95%). This compound is volatile under high
pressure and some product can be lost during the evaporation;
TLC Rf 0.36; δH (300 MHz; CDCl3) 10.46 (1H, s, CHO), 7.50–
7.45 (1H, m, ArH), 7.00–6.50 (2H, m, ArH), 5.80–5.50 (1H, m,
CH-O), 3.96–3.90 (1H, m, 6-H), 3.76–3.60 (1H, m, 6-H) and
2.01–1.52 (6H, m, 3 × CH2).
6-Methoxymethoxy-2-tetrahydropyran-2-yloxybenzaldehyde
14 and 2-methoxymethoxy-4-tetrahydropyran-2-yloxybenzalde-
hyde 15. Starting with 13 (0.7 g, 2.94 mmol) we obtained 14 as
the major product (0.48 g, 62%); TLC Rf 0.22; δH (300 MHz;
CDCl3) 10.48 (1H, s, CHO), 7.44 (1H, t, J 8.3, ArH), 6.88 (1H,
d, J 8.3, ArH), 6.79 (1H, d, J 8.3, ArH), 5.50–5.40 (1H, m, CH-
O), 5.15 (2H, s, CH2-O), 3.94–3.82 (1H, m, 6-H), 3.68–3.55
(1H, m, 6-H), 3.50 (3H, s, OCH3) and 2.10–1.50 6H, m,
3 × CH2). A minor product 15 was also isolated (0.03 g, 4%);
TLC Rf 0.26; δH (300 MHz; CDCl3) 10.40 (1H, s, CHO), 7.80
(1H, d, J 8.3, ArH), 6.80 (1H, s, ArH), 6.70 (1H, d, J 8.4, ArH),
5.55–5.45 (1H, m, CH-O), 5.17–5.09 (2H, m, CH2-O), 3.92–3.82
(1H, m, 6-H), 3.69–3.60 (1H, m, 6-H), 3.50 (3H, s, O-CH3) and
2.05–1.50 (6H, m, 3 × CH2).
1-Fluoro-3-tetrahydropyran-2-yloxybenzene 8. Starting with
3-fluorophenol (4 ml, 44.20 mmol) we obtained 8 (0.62 g, 72%)
as a low-melting solid, mp 48–50 ЊC; TLC Rf 0.57 (A); δH (300
MHz; CDCl3) 7.27–7.15 (1H, m, ArH), 6.88–6.75 (2H, m,
J. Chem. Soc., Perkin Trans. 1, 1997
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Cleavage of the tetrahydropyran (THP) group
dried and evaporated. The crude product was purified by silica
General procedure. Method A: deprotection under neutral
conditions.—The protected phenol (2.12 mmol) was dissolved in
DMF (15 ml) and LiCl (6.35 mmol) was added to the solution.
The clear solution was stirred for 6 h at 75 ЊC after which it was
filtered to remove insoluble material and then evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography using a EtOAc–hexanes gradient.
Method B: deprotection under acidic conditions.—(1) The
protected phenol (2.12 mmol) was dissolved in THF (25 ml)
containing aq. HCl (1 , 5 ml). The reaction mixture was stirred
at room temperature for 5 h, dried (Na2SO4), filtered and evap-
orated to dryness. This gave the phenolic derivative in high
yield. This compound was used in the next step without further
purification.
(2) The protected phenol (6.24 mmol) was dissolved in
dichloromethane (60 ml) and toluene-p-sulfonic acid (PTSA,
2.5 mmol) was added to the solution. After being stirred for
3 h at room temperature the yellow mixture was extracted with
5% aq. sodium hydrogen carbonate (2 × 10 ml), dried (Na2SO4),
filtered and evaporated to give the expected phenol deriv-
ative in high yield. This compound was used in the next step
without further purification.
gel column chromatography using an EtOAc–hexanes gradient.
Methyl 4-(2-formyl-3-methoxyphenoxymethyl)benzoate 6.
Starting with the phenol 5 (0.32 g, 2.12 mmol) we obtained 6
(0.56 g, 89%) as a white solid, mp 122–123 ЊC; TLC Rf 0.39;
δH (300 MHz; CDCl3) 10.58 (1H, s, CHO), 8.03 (2H, d, J 8.2,
ArH), 7.52 (2H, d, J 8.0, ArH), 7.44 (1H, m, ArH), 6.60 (1H, d,
J 8.3, ArH), 6.55 (1H, d, J 8.3, ArH), 5.20 (2H, s, CH2-O), 3.90
(3H, s, OCH3) and 3.88 (3H, s, OCH3); m/z (FAB, thioglycerol)
301 (MHϩ) (Found: MHϩ, 301.1092. C17H17O5 requires M,
301.1076).
Methyl 4-(2-formyl-3-fluorophenoxymethyl)benzoate 11.
Starting with the phenol 10 (0.87 g, 6.24 mmol) we obtained 11
(1.61 g, 90%) as a white solid, mp 111–113 ЊC; TLC Rf 0.35 (D);
δH [(300 MHz; CDCl3)] 10.48 (1H, s, CHO), 8.16 (2H, d, J 8.3,
ArH), 7.6 (2H, d, J 8.2, ArH), 7.55–7.50 (1H, m, ArH),
6.82–6.77 (2H, m, ArH), 5.29 (2H, s, CH2-O) and 3.98 (3H, s,
OCH3); m/z (FAB, thioglycerol) 289 (MHϩ) (Found: MHϩ,
289.0869. C16H14FO4 requires M, 289.0876).
Methyl 4-(2-formyl-3-methoxymethoxyphenoxymethyl)benz-
oate 17. Starting with the phenol 16 (0.24 g, 1.31 mmol) we
obtained 17 (0.37 g, 86%) as a white solid mp 90–92 ЊC; TLC Rf
0.40 (D); δH (300 MHz; CDCl3) 10.58 (1H, s, CHO), 8.10 (2H,
d, J 8.2, ArH), 7.55 (2H, d, J 8.1, ArH), 7.43 (1H, t, 8.3, ArH),
6.82 (1H, d, J 8.3, ArH), 6.60 (1H, d, J 8.3, ArH), 5.30 (2H, s,
CH2-O), 5.22 (2H, s, CH2-O), 3.98 (3H, s, OCH3) and 3.55 (3H,
s, OCH3); m/z (FAB, thioglycerol) 331 (MHϩ) (Found: MHϩ,
331.1168. C18H19O6 requires M, 331.1181).
2-Hydroxy-6-methoxybenzaldehyde 5.18 Method A or B-1.
Starting with aldehyde 4 (0.5 g, 2.12 mmol) we obtained 5 (0.31
g, 98%) as a white solid, mp 73–75 ЊC; TLC Rf 0.22; δH (300
MHz; CDCl3) 11.98 (1H, s, OH), 10.97 (1H, s, CHO), 7.44
(1H, t, J 8.3, ArH), 6.54 (1H, d, J 8.0, ArH), 6.40 (1H, d, J 8.1,
ArH) and 3.89 (3H, s, OCH3).
2-Fluoro-6-hydroxybenzaldehyde 10.24 Method B-2. Starting
with aldehyde 9 (1.4 g, 6.24 mmol) we obtained 10 (0.86 g, 98%)
as a white solid. This compound is volatile under high pressure
and some of this material can be lost during the evaporation;
TLC Rf 0.65; δH (300 MHz; CDCl3) 11.30 (1H, br s, OH), 10.18
(1H, s, CHO), 7.43 (1H, m, ArH) and 6.67 (2H, m, ArH).
Hydrolysis of 4-(3-substituted 2-formylphenoxymethyl)benzoic
esters
General procedure. To a suspension of the ester (1.86 mmol)
in ethanol (95%; 20 ml) was added aq. NaOH (1 , 20 ml).
The reaction mixture was stirred at room temperature for 2 h
after which the pale yellow solution was cooled at 0 ЊC and
acidified with concentrated hydrochloric acid. A white solid was
precipitated from the reaction mixture after 2 h at room tem-
perature. This was filtered off, washed with water (1 ml) and
dried to give the corresponding acid.
4-(2-Formyl-3-methoxyphenoxymethyl)benzoic acid 7. Start-
ing with ester 6 (0.56 g, 1.86 mmol) we obtained the acid 7 (0.48
g, 90%) as a white solid, mp 203–205 ЊC; TLC Rf 0.40 (F );
δH [300 MHz; (CD3)2SO] 10.62 (1H, s, CHO), 8.15 (2H, d, J 8.2,
ArH) 7.60 (2H, d, J 8.2, ArH), 7.46 (1H, t, J 8.4, ArH), 6.64 (d,
2H, d, J 8.2, ArH), 5.26 (2H, s, CH2-O) and 3.92 (3H, s, OCH3);
δC(300 MHz; CD3OD) 170.13, 160.95, 159.60, 144.85, 132.13,
131.73, 131.43, 128.51, 128.08, 107.81, 106.54, 103.14, 71.51
and 56.93; m/z (FAB, thioglycerol) 287 (MHϩ) (Found: MHϩ,
287.0913. C16H15O5 requires M, 287.0919).
4-(2-Formyl-3-fluorophenoxymethyl)benzoic acid 12. Starting
with the ester 11 (0.62 g, 2.17 mmol) we obtained the acid 12
(0.54 g, 91%) as a white solid, mp 198–200 ЊC; TLC Rf 0.30 (E);
δH (300 MHz; CDCl3) 10.55 (1H, s, CHO), 8.16 (2H, d, J 8.3,
ArH), 7.59 (2H, d, 8.2, ArH), 7.51–7.45 (1H, m, ArH), 6.82–
6.77 (2H, m, ArH) and 5.28 (2H, s, CH2-O); δC[300 MHz;
(CD3)2SO] 167.30, 163.75, 160.91, 160.31, 141.35, 137.01,
136.84, 130,49, 129.90, 129.70, 127.40, 113.70, 109.04, 108.77
and 69.93; δF [400 MHz; (CD3)2SO, CFCl3 as a reference]
δ Ϫ115 (dd, J 8.5); m/z (FAB, thioglycerol) 275 (MHϩ) (Found:
MHϩ, 275.0734. C15H12FO4 requires M, 275.0720).
Cleavage of the tetrahydropyran (THP) group in the presence of
the MOM group
2-Hydroxy-6-methoxymethoxybenzaldehyde 16.2 A solution
of the aldehyde 14 (0.15 g, 0.56 mmol) in methylene dichloride,
was added to a stirred mixture of 10% aq. HCl adsorbed on
silica (ca. 2 g). The reaction mixture was stirred at ambient
temperature for 8 h, after which solid sodium hydrogen car-
bonate was added to it; stirring was continued for 5 min after
which the mixture was filtered. The solid material was washed
with dichloromethane, and the combined filtrate and washings
were evaporated. This gave 16 (0.1 g, 97%) as a viscous oil which
solidified with time, mp 48–50 ЊC;2 TLC Rf 0.34; δH (300 MHz;
CDCl3) 11.92 (1H, s, OH), 10.39 (1H, s, CHO), 7.42 (1H, t, J
8.2, ArH), 6.66 (2H, d, J 8.4, ArH), 5.20 (2H, s, CH2-O) and
3.50 (3H, s, OCH3). The material was used in the next step
without further purification.
Compound 16 was also prepared by selective deprotection of
the THP group using PTSA as described in method B-2 above.
In this case starting with 14 (0.3 g, 1.13 mmol) and PTSA (0.071
g, 0.28 mmol) in dichloromethane (30 ml) we obtained 16
(0.2 g, 97%). The material was used in the next step without
further purification.
General procedure for benzylation of 2-substituted
6-hydroxybenzaldehyde 5
The phenol derivative (2.12 mmol) was dissolved in anhydrous
DMF (15 ml) and caesium carbonate (2.54 mmol) was added
to the solution under nitrogen. To this solution, methyl or tert-
butyl 4-bromomethylbenzoate (2.14 mmol) was added after
which the reaction mixture was stirred at room temperature
overnight. Insoluble material was removed by filtration and the
filtrate evaporated under reduced pressure. The residue was dis-
solved in dichloromethane (60 ml) and the solution washed
with brine and 5% aqueous sodium hydrogen carbonate (30 ml),
4-(2-Formyl-3-hydroxyphenoxymethyl)benzoic acid, tucaresol
1:2 deprotection of the MOM group
Hydrochloric acid (3 , 45 ml) was added dropwise to a solu-
tion of the aldehyde 17 (1 g, 303 mmol) in ethanol (45 ml). The
reaction mixture was stirred at 60 ЊC for 1.5 h after which the
precipitated solid was filtered off. This was washed with cold
water (5 ml), dried and recrystallised from ethanol–water (2:1)
to give the corresponding phenol derivative (0.82 g, 94%), mp
123–125 ЊC; TLC Rf 0.50 (D); δH (300 MHz; CDCl3) 11.95
2928
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
2 K. Geoffrey, EP 0054 924 A2.
3 B. Zacharie, L. Gagnon, G. Attardo, T. Connolly and C. L. Penney,
J. Med. Chem., in the press.
(1H, s, OH), 10.40 (1H, s, CHO), 8.10 (2H, d, J 8.1, ArH), 7.55
(2H, d, J 8.1, ArH), 7.40 (1H, t, J 8.2, ArH), 6.60 (1H, d, J 8.4,
ArH), 6.40 (1H, d, J 6.4, ArH), 5.18 (2H, s, CH2-O) and 3.99
(3H, s, OCH3); m/z (FAB, thioglycerol) 287 (MHϩ) (Found:
MHϩ, 287.0925. C16H15O5 requires M, 287.0920). The ester
(0.65 g, 2.27 mmol) was hydrolysed according to the procedure
described above to give 1 (0.55 g, 89%) as a white solid, mp 240–
242 ЊC; TLC Rf 0.40 (F ); δH [300 MHz; (CD3)2SO] 11.75 (1H, br
s, OH), 10.35 (1H, s, CHO), 7.94 (2H, d, J 8.03, ArH), 7.53 (2H,
d, J 8.12, ArH), 7.48 (1H, t, J 8.34, ArH), 6.68 (1H, d, J 8.40,
ArH), 6.52 (1H, d, J 8.40, ArH) and 5.28 (2H, s, CH2-O);
δC[300 MHz; (CD3)2SO] 167.24, 162.65, 162.38, 161.15, 141.53,
138.92, 130.42, 129.67, 127.40, 110.83, 109.50,103.56 and 69.44
(Found: C, 65.99; H, 4.29. C15H12O5 requires C, 66.17; H,
4.44%).
4 For a review see (a) V. Snieckus, Chem. Rev., 1990, 90, 879; (b) G. W.
Klumpp and M. J. Sinnige, Tetrahedron Lett., 1986, 27, 2247.
5 A. I. Meyers and W. B. Avila, Tetrahedron Lett., 1980, 21, 3335.
6 (a) M. R. Winkle and R. C. Ronald, J. Org. Chem., 1982, 47, 2101;
(b) H. W. Gschwend and H. R. Rodriguez, Org. React (NY), 1979,
26, 1.
7 Prepared according to the procedure that we developed to convert
carboxylic acids into esters using EEDQ: see: B. Zacharie, T.
Connolly and C. L. Penney, J. Org. Chem., 1995, 60, 7072.
8 M. Y. Bhatt, Synthesis, 1983, 249.
9 A. M. Bernard, M. R. Ghiani, P. P. Piras and A. Rivoldini,
Synthesis, 1989, 287.
10 (a) M. R. Winkle and R. C. Ronald, J. Org. Chem., 1982, 47, 2101;
(b) R. C. Ronald and M. R. Winkle, Tetrahedron, 1983, 39, 2031.
11 Our procedure offers a much simpler and more satisfactory work-up
to that reported in the literature (MOMCl, NaH, THF–DMF ).
12 B. Zacharie, unpublished results. During the writing of this
manuscript, a method for deprotection of THP ethers to give their
corresponding alcohols using an excess of LiCl in hot H2O–DMSO
was reported (see: G. Maiti and S. C. Roy, J. Org. Chem., 1996, 61,
6038).
13 (a) J. T. Welch, Tetrahedron, 1987, 43, 3123; (b) J. Mann, Chem. Soc.
Rev., 1987, 16, 381.
14 A. Adjare and D. D. Miller, Tetrahedron Lett., 1984, 25, 5597.
15 D. C. Furlano, S. N. Calderon, G. Chen and K. L. Kirk, J. Org.
Chem., 1988, 53, 3145.
16 F. M. Dean, J. Goodchild, L. E. Houghton, J. A. Martin, R. B.
Morton, B. Parton, A. W. Price and N. Somvichien, Tetrahedron
Lett., 1966, 4153.
17 T. Harayama, K. Katsuno, H. Nishioka, M. Fujii, Y. Nishita,
H. Ishii and Y. Kaneko, Heterocycles, 1994, 39, 613.
18 R. Adams and J. Mathieu, J. Am. Chem. Soc., 1948, 70, 2120.
19 This compound was prepared in literature by a different route:
J. R. Merchant and A. J. Mountwala, J. Org. Chem., 1958, 23, 1774.
20 The literature procedure was modified, R. W. Wagner and J. S.
Lindsey, Tetrahedron, 1994, 50, 11097.
21 K. Tadashi, K. Hiroyuki and F. Yukio, Synthesis, 1988, 12, 1005.
22 H. Takamitsu, T. Eiji, M. Takashi and S. Keisuke, J. Am. Chem.
Soc., 1994, 116, 1004.
23 R. Aldered, R. Johnston, D. Levin and J. Neilan, J. Chem. Soc.,
Perkin Trans. 1, 1994, 1823.
Preparation of 2,6-dihydroxybenzaldehyde20
To a solution 2,6-dimethoxybenzaldehyde (0.456 g, 2.28 mmol)
or 2-hydroxy-6-methoxybenzaldehyde (0.424 g, 2.28 mmol) in
benzene (25 ml) was added aluminium bromide (1.8 g, 6.84
mmol or 1.21 g, 4.56 mmol, respectively) at room temperature.
The complex which formed was precipitated as a red gum. After
the mixture had been stirred for 3 h, crushed ice, 3  hydro-
chloric acid (15 ml), and ether (30 ml) were added to it. The
aqueouslayer wasseparated and extracted with ether (2 × 30ml).
The ether extracts were combined and extracted with 1  aq.
NaOH (5 ml). The alkaline solution was cooled in ice–water
and concentrated hydrochloric acid (2 ml) was added to it. The
crude yellow product was purified by column chromatography
(silica gel, EtOAc–hexanes 1:1) to yield a pale yellow solid
(0.18 g, 58%), mp 157–158 ЊC;20,21 TLC Rf 0.50 (D); δH [300
MHz; (CD3)2SO] 10.24 (1H, s, CHO), 7.37 (1H, t, J 8.0, ArH)
and 6.36 (2H, d, J 8.1, ArH); m/z (EI) 138 (MHϩ) (Found: MHϩ,
138.0317. C7H6O3 requires M, 138.0318).
Acknowledgements
We appreciate the thoughtful reading of the manuscript by
Drs T. Bowlin, S. Abbott and Mr T. Connolly. We also thank
Ms L. Marcil and Ms S. A. MacLellan for secretarial and tech-
nical assistance.
References
Paper 7/01102D
Received 17th February 1997
Accepted 8th May 1997
1 (a) G. M. Shearer, Nature, 1995, 377, 16; (b) S. Rhodes, H. Chen,
S. R. Hall, J. E. Beesley, D. C. Jenkins, P. Collins and B. Zheng,
Nature, 1995, 377, 71.
J. Chem. Soc., Perkin Trans. 1, 1997
2929