o-Formylation of electron-rich phenols with dichloromethyl methyl ether and TiCl4

Article abstract of DOI:10.1016/S0040-4039(03)01168-7

o-Formylation of electron-rich phenols is accomplished with dichloromethyl methyl ether and TiCl₄. The reaction gives excellent yields, good regioselectivity, and does not leading to diformylation.

Full text of DOI:10.1016/S0040-4039(03)01168-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4961–4963
o-Formylation of electron-rich phenols with dichloromethyl
methyl ether and TiCl4
Oscar Garc´ıa,a Ernesto Nicola´sa,* and Fernando Albericioa,b,
*
aDepartament of Organic Chemistry, University of Barcelona, E-08028 Barcelona, Spain
bBarcelona Biomedical Research Institute, Barcelona Science Park, University of Barcelona, Josep Samitier 1,
E-08028 Barcelona, Spain
Received 6 April 2003; revised 10 May 2003; accepted 11 May 2003
Abstract—o-Formylation of electron-rich phenols is accomplished with dichloromethyl methyl ether and TiCl4. The reaction gives
excellent yields, good regioselectivity, and does not leading to diformylation. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
The application of one of the most common formyla-
tion methods, the Vilsmeier–Haack reaction (DMF,
POCl3), and the Duff reaction (hexamethylenetetramine
in strong acid medium) in attempts to obtain 2 did not
afford the desired product with good purity or regio-
selectivity. This result was consistent with one of our
earlier findings, when Vilsmeier–Haack conditions were
applied to 3,5-dimethoxyphenol gave a mixture of the
2- and 4-formyl derivatives together with a small
amount of the 2,4-diformyl derivative.5 Moreover, the
Vilsmeier–Haack reaction employs harsh conditions
and the outcome strongly depends on the stirring con-
ditions, with efficient mechanical stirring giving the best
results.
In solid-phase chemistry,1 the lability of most of the
acid-labile handles can be fine-tuned by the introduc-
tion of electron-donating substituents into a phenyl
ring.2 The way that these building blocks are function-
alized is usually through an aldehyde function, which
can undergo reduction or aminative reduction to afford
the corresponding alcohol or amine functions. The
handles are bifunctional spacer molecules and so a
phenol function can serve as an anchor to the solid
support. Furthermore, formyl-substituted phenols bear-
ing electron-donating substituents are important com-
pounds and/or interesting intermediates in other fields
of organic chemistry.3 A number of methods have been
described in the literature for the formylation of phe-
nols, but most of these give only low yields, leading to
diformylation, and/or lack regioselectivity.
In one of our current programmes, we became inter-
ested in preparing 2-formyl-3,5-dimethoxyphenol (1)
from 3,5-dimethoxyphenol, 2-formyl-3,5,6-trimethyl-
phenol (2) from 2,3,5-trimethylphenol, and 2-formyl-
3,4,5-trimethoxyphenol (3) from 3,4,5-trimethoxyphe-
nol. The formyl derivatives are useful in their own right
as direct handle precursors (e.g. 1 is the precursor of
the o-backbond amide linker (BAL) handle4) or inter-
mediates for benzopyran- or benzofuran-based handles.
Given the problems outlined above, it was decided to
investigate formylation with dichloromethyl methyl
ether in the presence of titanium(IV) chloride—a
method first described by Gross et al.6 and further
7
developed by Cresp et al. An assessment of this reac-
tion when applied to polysubstituted aromatic rings is
presented.
Keywords: benzofuran; benzopyran; handle; linker; protecting group;
solid phase.
* Corresponding authors: Tel.: +34-93-402-9057; fax: +34-93-339-
7878 (E.N.); Tel.: +34-93-403-7088; fax: +34-93-403-7126 (F.A.);
e-mail: nicolas@qo.ub.es; albericio@pcb.ub.es
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01168-7

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O. Garc´ıa et al. / Tetrahedron Letters 44 (2003) 4961–4963
2. Results and discussion
such as (3,4-dihydro-2-methyl-5,6,7-trimethoxy-2H-1-
benzopyran-2-yl)acetic acid to give 5 (81% yield after
As mentioned in the introduction, the Vilsmeier–Haack
conditions applied to 3,5-dimethoxyphenol to obtain 1
led to a mixture of 4-formyl-3,5-dimethoxyphenol
(52%), 2-formyl-3,5-dimethoxyphenol (1) (11%), and
column chromatography purification).11
3. Experimental protocols
2,4-diformyl-3,5-dimethoxyphenol
(1%).5
More
recently, Landi and Ramig described the lithiation of
3,5-dimethoxyphenol with triisopropylsilyl chloride and
n-butyllithium, followed by reaction with DMF to
afford regioselectively the 4-formyl derivative (74%).8
Reaction of 3,5-dimethoxyphenol with TiCl4 (2.2
equiv.) followed by addition of dichloromethylmethyl
ether led regioselectively to the 2-formyl (1) in prefer-
ence over the 4-formyl derivative (91:9 at −60°C, 75%
yield; 82:18 at 0°C, 94% yield, and 80:20 at 25°C). The
pure 2-formyl-3,5-dimethoxyphenol (1) was obtained
with an overall yield of 65% from the crude obtained at
0°C after column chromatography.
3.1. General procedure for the formylation reaction
Reagents were used as received without further purifi-
cation. Dichloromethane (DCM) was passed through
an alumina column, stored over CaH2 under an Ar
atmosphere, and protected from the light.
A solution of the appropriate phenol (20–150 mmol) in
DCM (1.5 mL/g phenol) was purged with N2, cooled
with an ice bath, and TiCl4 (2.2 equiv. to obtain 1 and
2 and 5 equiv. to obtain 3–5) was added dropwise over
15–30 min. The reaction mixture was left to react for
30–60 min. Dichloromethyl methyl ether (1 equiv.) was
added over 15 min and the mixture left to react for a
further 1–2 h. The reaction was quenched by the addi-
tion of saturated NH4Cl solution and the mixture was
left to stand for 1 h. The organic phase was separated
and washed with 0.1 N HCl, saturated NaHCO3 solu-
tion, and brine. The solution was dried over MgSO4,
filtered, and the solvent evaporated under reduced pres-
sure. The purified products were homogeneous by
HPLC (Nucleosil C18, 250×40 mm, 10 mm; linear gradi-
ent of CH3CN (+0.036% TFA) into H2O (+0.045%
TFA) at 1.0 mL/min flow rate; 220 nm), and were
characterised using different physical techniques.
When similar conditions were applied to 2,3,5-
trimethylphenol a mixture of 2- and 4-formyl-3,5,6-
trimethylphenol (7:3, at 0°C, 93% yield) was obtained.
Separation of the two isomers was easily achieved by
crystallization from ethanol/water (2-formyl derivative
(2), 71% overall yield; 4-formyl derivative, 15% overall
yield). Application of the same conditions to 3,4,5-
trimethoxyphenol led exclusively to the 2-formyl-3,4,5-
trimethoxyphenol (3) in high yield; the 2,6-diformyl
derivative was not detected as in the previous cases.
The regioselectivity of this reaction can be interpreted
in terms of coordination of the Ti with oxygen atoms
from both the phenol and the ether. Such coordination
would favour the regioselectivity and should also
increase the electrophilicity of the dichloromethyl
methyl ether and therefore the reaction rate.9 The
higher regioselectivity of the reaction of 3,5-
dimethoxyphenol to give 1 when compared to 2,3,5-
trimethylphenol to give 2 can be explained by the fact
that the TiCl4 will also coordinate with a methoxy
group at position 3 or 5, thus partially blocking susbsti-
tution at position 4.
3.2. Physical data
3.2.1. 2-Formyl-3,5-dimethoxyphenol (1). From 3,5-
dimethoxyphenol: mp: 63–66°C; IR (KBr): 2977, 1615,
1505, 1458, 1225, 1159, 1115, 1048 cm−1; MS (CI,
1
NH3): m/e=183 (M++1, 100%); H NMR (300 MHz,
CDCl3): l=3.81 and 3.83 (2s, 6H, 2×OCH3), 5.88 (d,
J=2.25, 1H, arom.), 5.99 (d, J=2.25, 1H, arom.), 10.07
(s, 1H, CHO), 12.49 (s, OH) ppm; 13C NMR (75 MHz,
CDCl3): l=55.60 and 55.63 (2×CH3, OCH3), 90.48 and
92.88 (2×CH, arom.), 105.97 (C2, arom.), 163.50,
166.27 and 168.07 (C1, C3, C5, arom.), 191.74 (CHO)
ppm; HPLC: 13.2 min (from 3:7 to 1:0 over 30 min).
This hypothesis is supported by the fact that when
similar conditions (2.2 equiv. of TiCl4) were applied to
2,3-dihydro-2,2-dimethyl-4,5,6-trimethoxybenzofuran
to give 4, more than 25% of the starting compound
remained unreacted. However, almost quantitative
yields (73% after column chromatography purification)
were obtained when 5 equiv. of TiCl4 and 4 equiv. of
dichloromethyl methyl ether were used. The need for
the larger amounts of reagents can be explained by
coordination of the TiCl4 with two contiguous methoxy
groups.10 Similar large excesses have to be used for the
formylation of other methoxy-rich aromatic systems
3.2.2. 2-Formyl-3,5,6-trimethylphenol (2). From 2,3,5-
trimethylphenol: mp: 75–76°C; IR (KBr): 2963, 1636,
1445, 1400, 1345, 1308, 1262, 1099, 1022 cm−1; MS (CI,
NH3): m/e=165 (M++1, 100%), 182 (M++18, 37%), 199
1
(M++35, 10%); H NMR (300 MHz, CDCl3): l=2.11,
2.25 and 2.50 (3s, 3×3H, 3×CH3), 6.51 (s, 1H, arom.),
1
10.20 (s, 1H, CHO), 12.28 (s, OH) ppm; H NMR (200
MHz, CD3OD): l=1.85, 2.02 and 2.29 (3s, 3×3H,
3×CH3), 6.34 (s, 1H, arom.), 10.0 (s, 1H, CHO) ppm;
13C NMR (75 MHz, CDCl3): l=10.35 (CH3-C6), 17.59
and 20.61 (2×CH3, CH3-C3 and CH3-C5), 116.27 (C2,
arom.), 122.82 (CH, arom.), 123.38 (C6, arom.), 138.42
(C3, arom.), 147.26 (C5, arom.), 161.37 (C1, arom.),
194.63 (CHO) ppm; HPLC: 19.27 min (from 3:7 to 1:0
over 30 min).

O. Garc´ıa et al. / Tetrahedron Letters 44 (2003) 4961–4963
4963
3.2.3. 4-Formyl-3,5,6-trimethylphenol. From 2,3,5-
Acknowledgements
trimethylphenol: mp: 123–125°C; IR (KBr): 2925,
1650, 1565, 1499, 1428, 1306, 1264, 1103, 1034 cm−1;
MS (CI, NH3): m/e=165 (M++1, 35%), 182 (M++18,
100%); 1H NMR (300 MHz, CDCl3): l=2.19, 2.53
and 2.54 (3s, 3×3H, 3×CH3), 6.05 (s, 1H, OH), 6.54
(s, 1H, arom.), 10.49 (s, 1H, CHO) ppm; 13C NMR
(75 MHz, CDCl3): l=11.16 (CH3-C2), 15.80 (CH3-
C3), 20.79 (CH3-C5), 115.85 (CH, arom.), 121.69
(C2, arom.), 126.50 (C4, arom.), 141.30 and 142.93
(2×C5, C3 and C1, arom.), 151.71 (C1, arom.), 192.96
(CHO) ppm; HPLC: 10.89 min (from 3:7 to 1:0 over
30 min).
We are grateful to the University of Barcelona for a
predoctoral fellowship (O.G.). This work was partially
supported by CICYT (BQU2000-0235), Generalitat de
Catalunya (Grup Consolidat and Centre de Refere`n-
cia en Biotecnologia).
References
1. (a) Lloyd-Williams, P.; Albericio, F.; Giralt, E. Chemical
Approaches to the Synthesis of Peptides and Proteins; CRC:
Boca Raton, FL, 1997; (b) Solid-Phase Synthesis. A
Practical Guide; Kates, S. A.; Albericio, F., Eds.; Marcel
Dekker: New York, 2000.
2. Albericio, F.; Giralt, E. In Houben-Weyl. Methods of
Organic Chemistry. Vol. E 22. Synthesis of Peptides and
Peptidomimetics; Goodman, M.; Felix, A.; Moroder, L.;
Toniolo, C., Eds.; Georg Thieme: Stuttgart, 2001; pp.
685–709.
3. Solladie´, G.; Girardin, A.; Lang, G. J. Org. Chem. 1989,
54, 2620–2628.
4. Boas, U.; Brask, J.; Christensen, J. B.; Jensen, K. J. J. Comb.
Chem. 2002, 4, 223–228.
5. Albericio, F.; Kneib-Cordonier, N.; Biancalana, S.; Gera,
L.; Masada, R. I.; Hudson, D.; Barany, G. J. Org. Chem.
1990, 55, 3730–3743.
6. Gross, H.; Rieche, A.; Mattey, G. Chem. Ber. 1963, 96,
308–319.
7. Cresp, T. M.; Sargent, M. V.; Elix, J. A.; Murphy, D. P.
H. J. Chem. Soc., Perkin Trans. 1 1973, 340–345.
8. Landi, J. J.; Ramig, K. Synth. Commun. 1991, 21, 167–171.
9. The reaction could take place through the following
mechanism:
3.2.4. 2-Formyl-3,4,5-trimethoxyphenol (3). From 3,4,5-
trimethoxyphenol: mp: 55–57°C; IR (KBr): 1638,
1490, 1368, 1299, 1248, 1204, 1150, 1106 cm−1; MS
(CI, NH3): m/e=213 (M++1, 100%); 1H NMR (300
MHz, CDCl3): l=3.77, 3.88 and 4.02 (3s, 9H, 3×
OCH3), 6.17 (s, 1H, arom.), 10.02 (s, 1H, CHO),
12.08 (s, OH) ppm; 13C NMR (75 MHz, CDCl3):
l=56.18, 61.12 and 61.99 (3×CH3, OCH3), 95.18
(CH, arom.), 108.35 (C2, arom.), 133.81 (C4, arom.),
155.43 (C3, arom.), 161.06 and 162.02 (C1 and C5,
arom.), 192.60 (CHO) ppm; HPLC: 11.85 min (from
0:1 to 1:0 over 30 min).
3.2.5. 2,3-Dihydro-2,2-dimethyl-4,5,6-trimethoxybenzo-
furan-7-carbaldehyde (4). From 2,3-dihydro-2,2-
dimethyl-4,5,6-trimethoxybenzofuran: mp: 64–65°C;
IR (KBr): 2975, 2939, 1684, 1594, 1457, 1416, 1358,
1200, 1047 cm−1; MS (CI, NH3): m/e=267 (M++1,
1
100%); H NMR (300 MHz, CDCl3): l=1.52 (s, 6H,
2×CH3), 3.02 (s, 2H, CH2), 3.80, 3.94 and 4.03 (3s,
3×3H, 3×OCH3), 10.17 (s, 1H, CHO) ppm; 13C NMR
(75 MHz, CDCl3): l=28.19 (2×CH3), 40.33 (CH2),
59.65, 61.25 and 62.13 (3×CH3, 3×OCH3), 89.39 (C2,
arom.), 109.93 (C7, arom.), 112.77 (C4%, arom.),
138.10 (C5, arom.), 154.10 (C6, arom.), 155.84 (C7%,
arom.), 157.01 (C4, arom.), 189.90 (CHO) ppm;
HPLC: 11.77 min (from 3:7 to 1:0 over 30 min).
3.2.6. (8-Formyl-3,4-dihydro-2-methyl-5,6,7-trimethoxy-
2H-1-benzopyran-2-yl)acetic acid (5). From (3,4-dihy-
dro-2-methyl-5,6,7-trimethoxy-2H-1-benzopyran-2-yl)-
acetic acid: oil; IR (KBr): 3280, 2942, 1739, 1683,
1586, 1464, 1399, 1283 cm−1; MS (CI, NH3): m/e=
325 (M++1, 9%). 1H NMR (300 MHz, CDCl3): l=
1.42 (s, 3H, CH3), 1.83–1.97 (m, 2H, CH2-C3),
2.60–2.81 (m, 4H, CH2), 3.85, 4.01 and 4.07 (3s, 9H,
3×OCH3), 10.23 (CHO) ppm; 13C NMR (75 MHz,
CDCl3): l=16.33 (CH2, C4), 21.77 (CH3), 30.58
(CH2, C3), 47.82 (CH2-C2), 60.77, 61.11 and 62.44
(3×CH3, OCH3), 75.43 (C2, arom.), 110.05 (C8,
arom.), 113.48 (C5%, arom.), 138.47 (C6, arom.),
149.52, 152.30 and 157.69 (3×Cq, C7, C8% and C5,
arom.), 170.50 (COOH), 188.96 (CHO) ppm; HPLC:
9.34 min (from 3:7 to 1:0 over 30 min).
10.
11. Solladie´ et al. have also reported excellent yields for the
formylation of pentamethylchromans, systems similar to 5
(see Ref. 3).