Simple, short and efficient procedure for the preparation of hydroxyl- and hydroxymethyl-substituted 2,6-dichlorobenzaldehydes

Article abstract of DOI:10.1055/s-2004-829154

Hydroxyl- and hydroxymethyl-substituted 2,6-dichlorobenzaldehydes 1-4 have been obtained by lithiation of the corresponding TIPS-protected dichlorophenols or dichlorobenzylic alcohols followed by reaction with DMF and subsequent deprotection of the hydroxy group. Yields are high and formation of regioisomers is not observed.

Full text of DOI:10.1055/s-2004-829154

2062
PRACTICAL SYNTHETIC PROCEDURES
Simple, Short and Efficient Procedure for the Preparation
of Hydroxyl- and Hydroxymethyl-Substituted
2,6-Dichlorobenzaldehydes
S
ubstituted 2,6-
h
D
ichloroben
o
zaldehydes mas von Hirschheydt,* Edgar Voss
PSP
Roche Diagnostics GmbH, Nonnenwaldstr. 2, 82372 Penzberg, Germany
Fax +49(8856)604445; E-mail: Thomas.von_Hirschheydt@roche.com
Received 23 December 2003; revised 19 April 2004
No26
Abstract: Hydroxyl- and hydroxymethyl-substituted 2,6-dichlorobenzaldehydes 1–4 have been obtained by lithiation of the corresponding
TIPS-protected dichlorophenols or dichlorobenzylic alcohols followed by reaction with DMF and subsequent deprotection of the hydroxy
group. Yields are high and formation of regioisomers is not observed.
Key words: aldehydes, lithiation, protection groups, steric hindrance, regioselectivity
Scheme 1
2,6-Dichlorosubstitution is
a
common motif in
pharmaceuticals1 and therefore 2,6-dichlorobenzalde-
hydes are valuable building blocks. Additional hydroxyl
groups decrease the lipophilicity and thus increase the sol-
ubility of a drug candidate and provide the possibility of
further derivatization.
2,6-Dichloro-4-hydroxybenzaldehyde (1) and 2,6-dichlo-
ro-3-hydroxybenzaldehyde (2) are already known in the
literature (Figure 1). Compound 1 can be prepared by ei-
ther a Reimer–Tiemann reaction2 or by a bromination/
Grignard sequence.3 The Reimer–Tiemann procedure
does not allow an economical preparation due to very low
yields (3–10%). In addition, the required use of chloro-
form causes substantial ecological problems. The reaction
via a bromination/Grignard reaction sequence requires
four steps, including stoichiometric bromination with bro-
mine and the use of carcinogenic chloromethyl methyl
ether to protect the phenol. In addition, the total yield is
only 40%. A third method, which is very similar to that we
present in this paper, has been described by Bringmann et
al.4 after the filing of our patent application.5 In addition,
we show that our method is not limited to the synthesis of
1 but allows for a broader application (Scheme 1).
Figure 1 2,6-Dichloro-substituted benzaldehydes 1–4 prepared
Compound 2 has been synthesized from 3-hydroxyben-
zaldehyde,6 but this requires the use of highly toxic chlo-
rine gas and leads to side products due to overreaction. To
the best of our knowledge, the corresponding hydroxy-
methyl-substituted 2,6-dichlorobenzaldehydes 3 and 4
have not been reported in the literature so far.
Aromatic 1,3-dichloro substitution is a known motif for
directed lithiation.7 Unfortunately the lithiation of 3,5-
dichloroanisole, which would be a cheap precursor for 1,
leads to two regioisomers.8,9 Moreover, it might be diffi-
cult to find suitable conditions for the cleavage of the
methoxy group to obtain the free hydroxyl function. The
use of a bulky silyl protection group (e.g. TIPS) should
avoid both disadvantages: the bulk of the TIPS group is
known to direct metalation away from the silyl group10
and the silyl ether can easily be cleaved under acidic con-
ditions.
SYNTHESIS 2004, No. 12, pp 2062–2065
Advanced online publication: 13.07.2004
DOI: 10.1055/s-2004-829154; Art ID: T14103SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
4
The silyl ethers were prepared from the phenols (or ben-
zylic alcohols) with triisopropylsilyl trifluoromethane-

PRACTICAL SYNTHETIC PROCEDURES
Substituted 2,6-Dichlorobenzaldehydes
2063
Scale-Up
sulfonate (TIPSOTf) and 2,6-lutidine in CH2Cl2 at 0 °C
almost quantitatively. Lithiation of the protected phenols
with n-BuLi in anhydrous THF under nitrogen at –78 °C
and subsequent reaction with DMF followed by hydroly-
sis with aqueous HCl gave the corresponding aldehydes in
yields above 90%. In both cases formation of regioiso-
mers was not observed. Cleavage of the silyl ether already
occurred under the acidic workup conditions in the case of
1 (98% yield) or was achieved following a protocol by
Sinhababu et al.11 using NaF/HBr in DMF in the case of 2
(78% yield), respectively. The products could be purified
by washing with n-hexane and/or by recrystallization.
To a solution of 3,5-dichlorophenol (200 g, 1.23 mol) and 2,6-luti-
dine (330 mL, 2.83 mol) in anhyd CH2Cl2 (3 L) was added triiso-
propylsilyl triflate (400 g, 1.305 mol) was added at 0 °C within 1 h
and the mixture was stirred for additional 3 h at this temperature.
After hydrolysis with H2O (1 L), the organic layer was washed with
brine, dried (MgSO4) and evaporated to dryness (70 °C/80 mbar).
The residue was taken up in petroleum ether and filtered through sil-
ica gel to yield 360 g (92%) of the title compound as a colorless oil.
2,6-Dichloro-4-hydroxybenzaldehyde (1)
A solution of n-BuLi (2.5 M in hexane, 9.4 mL, 23 mmol) was add-
ed to a stirred solution of 3,5-dichlorotriisopropylsilyloxybenzene
(7.49 g, 23 mmol) in anhyd THF (30 mL) under N2 keeping the tem-
perature below –67 °C. After stirring for 45 min at –78 °C, anhyd
DMF (2.14 g, 29 mmol) was added keeping the temperature below
–65 °C. The mixture was allowed to warm up to –10 °C. After hy-
drolysis with NaCl-saturated 2 N HCl (25 mL), the layers were sep-
arated and the organic layer was dried (MgSO4) and evaporated to
dryness. To the residue was added hexane (20 mL) and the precipi-
tate (4.37 g, quant) was filtered off and washed with hexane (5 mL);
mp 229–230 °C (Lit.2a mp 223.5–224.5 °C).
1H NMR (250 MHz, DMSO-d6): d = 6.94 (s, 2 H, CH), 10.25 (s, 1
H, CH=O), 11.46 (br s, 1 H, OH).
13C NMR (62.9 MHz, DMSO-d6): d = 117.0 (CH), 120.7, 137.8,
162.1 (C), 187.2 (CH=O).
The same reaction sequence as described above is suitable
for the preparation of the corresponding benzylic alcohols
3 and 4 with the exception that the cleavage of the silyl
ether in both cases had to be done in an additional step
with Bu4NF in THF at room temperature or HCl in EtOH
at 85 °C, respectively (Scheme 2). The overall yield of 3
was 72% on a multigram scale. In the case of 4, the yield
of the formylation was very high (92% yield) whereas the
deprotection of the hydroxyl group using Bu4NF/THF
was not satisfactory (32%).12 Again in both cases 3 and 4,
the formation of regioisomers was not observed.
HRMS (EI): m/z calcd for C7H4Cl2O2: 189.9583; found: 189.9582.
Scale-Up
To a solution of 3,5-dichlorotriisopropylsilyloxybenzene (360 g,
1.11 mol) in anhyd THF (2.6 L) was added n-BuLi (440 mL of a 2.7
M solution in hexane) under N2 keeping the temperature below
–65 °C. After stirring for 2 h at –70 °C, anhyd DMF (120 mL, 1.55
mol) was added keeping the temperature below –65 °C. The mix-
ture was allowed to warm up to r.t. overnight. After the addition of
4 M HCl (700 mL), the mixture was stirred vigorously for 1 h at r.t.
Then the phases were separated (addition of solid NaCl may be nec-
essary) and the organic layer was dried (Na2SO4) and was concen-
trated in vacuo. Recrystallization of the precipitate from toluene–
THF yielded 154 g (70%) of the title compound. A small amount of
2,6-dichloro-4-triisopropylsilyloxybenzaldehyde was isolated from
the mother liquor by column chromatography on silica gel (isohex-
ane–EtOAc, 20:1).
Scheme 2
In summary, a simple, short and efficient route to hydrox-
yl- and hydroxymethyl-2,6-dichlorobenzaldehydes is de-
scribed, which gives the products without undesired
regioisomers in high yields.
Petroleum ether used refers to the fraction boiling at 60–90 °C. All
reagents and solvents were purchased from commercial suppliers
and were used as received without further purification. NMR spec-
tra were recorded on a Bruker Avance DPX 250 or a Bruker Avance
DPX 400, respectively. NMR shifts were reported relative to a TMS
internal standard or relative to the residual solvent, respectively.
HRMS were obtained on a MAT 95 XL spectrometer at 70 eV using
perfluorokerosine (PFK) as reference. Melting points are uncorrect-
ed.
1H NMR (250 MHz, CDCl3):13 d = 1.05–1.17 (m, 18 H, CH3), 1.19–
1.39 (m, 3 H, CH), 6.88 (s, 2 H, CH), 10.41 (s, 1 H, CH=O).
13C NMR (62.9 MHz, CDCl3): d = 12.7 (CH), 17.9 (CH3), 121.5
(CH), 123.4, 138.9, 160.4 (C), 187.9 (CH=O).
2,4-Dichlorotriisopropylsilyloxybenzene
An analogous reaction to that described above, but starting with 2,4-
dichlorophenol gave the title compound as a colorless oil in quanti-
tative yield.
1H NMR (250 MHz, CDCl3): d = 1.07–1.18 (m, 18 H, CH3), 1.20–
1.40 (m, 3 H, CH), 6.82 (d, J = 8.8 Hz, 1 H, CH), 7.07 (dd, J = 8.8
Hz, J = 2.5 Hz, 1 H, CH), 7.34 (d, J = 2.5 Hz, 1 H, CH).
3,5-Dichlorotriisopropylsilyloxybenzene
To a stirred solution of 3,5-dichlorophenol (4.08 g, 25 mmol) and
2,6-lutidine (6.70 g, 62.5 mmol) in anhyd CH2Cl2 (75 mL) was add-
ed TIPSOTf (9.96 g, 32.5 mmol) at 0 °C and the mixture was stirred
for 2 h at this temperature. After hydrolysis with H2O (15 mL), the
organic layer was washed with brine, dried (MgSO4) and evaporat-
ed to dryness. Chromatography of the crude product on silica gel us-
ing isohexane as eluent gave the title compound as a colorless oil in
quantitative yield.
1H NMR (250 MHz, CDCl3):13 d = 1.03–1.15 (m, 18 H, CH3), 1.16–
1.35 (m, 3 H, CH), 6.73–6.80 (m, 2 H, CH), 6.92–6.98 (m, 1 H, CH).
13C NMR (62.9 MHz, CDCl3): d = 12.7 (CH), 18.0 (CH3), 119.0,
121.6 (CH), 135.2, 157.4 (C).
13C NMR (62.9 MHz, CDCl3): d = 13.0 (CH), 18.0 (CH3), 120.8
(CH), 125.9 (C), 126.2 (C), 127.6, 130.1 (CH), 151.0 (C).
2,6-Dichloro-3-triisopropylsilyloxybenzaldehyde
A solution of n-BuLi (2.5 M in hexane, 3.1 mL, 7.8 mmol) was add-
ed to a stirred solution of 2,4-dichlorotriisopropylsilyloxybenzene
(2.5 g, 7.8 mmol) in anhyd THF (10 mL) under N2 keeping the tem-
perature below –70 °C. After stirring for 45 min at –78 °C, anhyd
DMF (0.72 g, 9.8 mmol) was added keeping the temperature below
–68 °C. The mixture was allowed to warm up to –10 °C. After hy-
Synthesis 2004, No. 12, 2062–2065 © Thieme Stuttgart · New York

2064
T. von Hirschheydt, E. Voss
PRACTICAL SYNTHETIC PROCEDURES
drolysis with NaCl-saturated 2 N HCl (25 mL), the layers were sep-
arated and the organic layer was dried (MgSO4) and evaporated to
dryness. The obtained yellow oil (2.56 g) was a 9:1 mixture of the
title compound and 2, and was used without further purification.
1H NMR (400 MHz, DMSO-d6): d = 1.09 (d, J = 7.5 Hz, 18 H,
CH3), 1.35 (sept, J = 7.5 Hz, 3 H, CH), 7.23 (d, J = 9.0 Hz, 1 H,
CH), 7.46 (d, J = 9.0 Hz, 1 H, CH), 10.33 (s, 1 H, CH=O).
of Bu4NF (1.3 mL, 1 M in THF, 1.3 mmol) was added at r.t. and
stirred overnight. After concentration in vacuo, 134.0 mg of 2,6-
dichloro-4-hydroxymethylbenzaldehyde was isolated by column
chromatography on silica gel (isohexane–EtOAc, 2:1) as a colorless
solid; mp 109–110 °C.
1H NMR (250 MHz, CDCl3): d = 1.99 (t, J = 4.4 Hz, 1 H, OH), 4.74
(d, J = 4.4 Hz, 2 H, OCH2), 7.40 (s, 2 H, CH), 10.48 (s, 1 H, CH=O).
13C NMR (100.6 MHz, DMSO-d6): d = 12.5 (CH), 18.0 (CH3),
124.3 (CH), 125.9, 126.2 (C), 130.5 (CH), 132.2, 151.4 (C), 190.3
(CH=O).
13C NMR (62.9 MHz, CDCl3): d = 63.4 (OCH2), 127.5 (CH), 129.2,
137.4, 147.9 (C), 188.7 (CH=O).
HRMS (EI): m/z calcd for C8H6Cl2O2: 203.9739; found: 203.9740.
2,6-Dichloro-3-hydroxybenzaldehyde (2)
Scale-Up
To a solution of a 9:1 mixture of 2,6-dichloro-3-triisopropylsilyl-
oxybenzaldehyde and 2 (2.56 g, see above) in DMF (25 mL) were
added NaF (660 mg, 15.7 mmol) and aq 48% HBr (0.26 mL) and
the mixture was stirred overnight at r.t.. All volatiles were removed
in vacuo and the residue was treated with H2O (20 mL) and extract-
ed with EtOAc (3 × 20 mL). The combined organic layers were
dried (Na2SO4) and evaporated to dryness; yield: 1.26 g (84%); light
yellow solid.
1H NMR (400 MHz, DMSO-d6): d = 7.19 (d, J = 8.8 Hz, 1 H, CH),
7.38 (d, J = 8.8 Hz, 1 H, CH), 10.33 (s, 1 H, CH=O), 10.90 (s, 1 H,
OH).
To a solution of 2,6-dichloro-4-(triisopropylsilyloxymethyl)benzal-
dehyde (65 g, 0.18 mol) in EtOH (1100 mL) at 50 °C was added
0.25 N HCl (180 mL) and the mixture was stirred for 6 h at 85 °C.
The EtOH was removed in vacuo whereupon the product precipitat-
ed. EtOAc–petroleum ether (2:1, 700 mL) was added and the organ-
ic layer was washed with H2O and aq NaCl and dried (Na2SO4). The
solution was reduced to about 100 mL and warm petroleum ether
(200 mL) was added and shortly warmed up to 50 °C. After stand-
ing at r.t. overnight, the precipitate was filtered off and washed with
petroleum ether–EtOAc (15:1); yield: 24.3 g (66%). Purification of
the mother liquor by column chromatography yielded another 4 g
(11%) product.
13C NMR (100.6 MHz, DMSO-d6): d = 121.1 (CH), 121.9, 123.8
(C), 130.1 (CH), 131.6, 153.5 (C), 190.4 (CH=O).
2,4-Dichloro(triisopropylsilyloxymethyl)benzene
An analogous reaction to that described above, but starting with 2,4-
dichlorobenzyl alcohol gave the title compound as a colorless oil in
quantitative yield.
1H NMR (400 MHz, CDCl3): d = 1.1 (d, J = 7 Hz, 18 H, CH3), 1.15–
1.29 (m, 3 H, CH), 4.83 (s, 2 H, OCH2), 7.28 (dd, J = 8.4, 2.0 Hz, 1
H, CH), 7.32 (d, J = 2.0 Hz, 1 H, CH), 7.59 (d, J = 8.4 Hz, 1 H, CH).
HRMS (EI): m/z calcd for C7H4Cl2O2: 189.9583; found: 189.9586.
3,5-Dichloro(triisopropylsilyloxymethyl)benzene
An analogous reaction to that described for 3,5-dichlorotriisopro-
pylsilyloxybenzene, but starting with 3,5-dichlorobenzyl alcohol
gave the title compound as a colorless oil in quantitative yield.
1H NMR (250 MHz, CDCl3): d = 0.96–1.25 [m, 21 H, 3 CH(CH3)2],
4.78 (s, 2 H, OCH2), 7.23 [s, 2 H, CH).
13C NMR (62.9 MHz, CDCl3): d = 12.1 (CH), 18.1 (CH3), 64.0
(OCH2), 124.2, 127.0 (CH), 134.9, 145.3 (C).
13C NMR (100.6 MHz, CDCl3): d = 12.4 (CH), 18.4 (CH3), 62.5
(OCH2), 127.4, 128.5, 128.9 (CH), 132.0, 133.1, 138.1 (C).
2,6-Dichloro-3-(triisopropylsilyloxymethyl)benzaldehyde
An analogous reaction to that described above, but starting with 2,4-
dichloro(triisopropylsilyloxymethyl)benzene yielded 92% of the ti-
tle compound as a colorless oil that solidifies on standing overnight.
1H NMR (400 MHz, CDCl3): d = 1.03–1.15 (m, 18 H, CH3), 1.15–
1.29 (m, 3 H, CH), 4.88 (s, 2 H, OCH2), 7.44 (d, J = 8.4 Hz, 1 H,
CH), 7.80 (d, J = 8.4 Hz, 1 H, CH), 10.50 (s, 1 H, C=O).
13C NMR (100.6 MHz, CDCl3): d = 12.3 (CH), 18.4 (CH3), 62.3
(OCH2), 129.8 (CH), 130.4 (Carom), 131.6 (CH), 133.4, 135.0, 140.3
(Carom), 189.5 (C=O).
2,6-Dichloro-4-(triisopropylsilyloxymethyl)benzaldehyde
An analogous reaction to that described for 2,6-dichloro-4-hy-
droxybenzaldehyde, but starting with 3,5-dichloro(triisopropylsil-
yloxymethyl)benzene and hydrolyzing with ice water instead of aq
HCl yielded the title compound as a colorless oil that solidified on
cooling in an ice bath (eluent: isohexane–EtOAc, 20:1).
1H NMR (250 MHz, CDCl3): d = 1.03–1.28 [m, 21 H, 3 CH(CH3)2],
4.82 (s, 2 H, OCH2), 7.37 (s, 2 H, CH), 10.48 (s, 1 H, CH=O).
13C NMR (62.9 MHz, CDCl3): d = 12.0 (CH), 18.1 (CH3), 63.6
(OCH2), 126.8 (CH), 128.6, 137.2, 149.0 (C), 188.8 (CH=O).
2,6-Dichloro-3-hydroxymethylbenzaldehyde (4)
An analogous reaction to that described above using Bu4NF/THF at
r.t., but starting with 2,6-dichloro-3-(triisopropylsilyloxymeth-
yl)benzaldehyde yielded 32% of the title compound as a colorless
solid; mp 93–95 °C.
1H NMR (400 MHz, CDCl3): d = 4.82 (s, 2 H, OCH2), 7.41 (d,
J = 8.4 Hz, 1 H, CH), 7.67 (d, J = 8.4 Hz, 1 H, CH), 10.48 (s, 1 H,
C=O).
Scale-Up
To a solution of 3,5-dichloro(triisopropylsilyloxymethyl)benzene
(70 g) in anhyd THF (220 mL) was added n-BuLi (131 mL, 1.6 M
in hexane) was added under N2 keeping the temperature below
–70 °C. After stirring for 45 min at –75 °C, anhyd DMF (28 mL,
0.36 mol) was added keeping the temperature below –65 °C. The
mixture was stirred for an additional 30 min at –75 °C and then was
allowed to warm up to 0 °C within 3 h. After 2 h at 0 °C, ice water
(150 mL) and Et2O (150 mL) were added. The phases were sepa-
rated and the aqueous layer extracted with Et2O (100 mL). The
combined organic layers were washed with aq NaCl, dried
(Na2SO4) and evaporated to dryness; yield: 73 g (95%); light brown
oil, that solidified on cooling in an ice bath.
13C NMR (100.6 MHz, CDCl3): d = 61.7 (OCH2), 129.5 (CH),
130.5 (C), 132.1(CH), 134.2, 135.2, 139.1 (C), 189.2 (C=O).
HRMS (EI): m/z calcd for C8H6Cl2O2: 203.9739; found: 203.9743.
References
(1) Examples from the patent literature, especially in the field of
kinase inhibitors, are legion by now. In addition, the
Derwent World Drug Index is a (commercial) source of
2,6-Dichloro-4-hydroxymethylbenzaldehyde (3)
2,6-Dichloro-4-(triisopropylsilyloxymethyl)benzaldehyde
mg, 1.2 mmol) was dissolved in anhyd THF (20 mL) and a solution
(426
Synthesis 2004, No. 12, 2062–2065 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Substituted 2,6-Dichlorobenzaldehydes
2065
information for marketed and development drugs. It contains
well over 100 examples of compounds with 2,6-
dichlorophenyl substitution.
(7) (a) Kress, T. H.; Leanna, M. R. Synthesis 1988, 803.
(b) Saednya, A.; Hart, H. Synthesis 1996, 1455.
(8) Pascal, R. A. Jr.; Chen, Y.-C. J. J. Org. Chem. 1985, 50, 408.
(9) We have found that the lithiation of 3,5-dichloroanisole in
THF at –78 °C and subsequent reaction with DMF leads to a
2:1 mixture of 2,4-dichloro-6-methoxybenzaldehyde and
2,6-dichloro-4-methoxybenzaldehyde, which had to be
separated by tedious column chromatography.
(10) Landi, J. J. Jr.; Ramig, K. Synth. Commun. 1991, 21, 167.
(11) Sinhababu, A. K.; Kawase, M.; Borchardt, R. T. Synthesis
1988, 710.
(2) (a) Baldwin, J. J.; Engelhardt, E. L.; Hirschmann, R.;
Lundell, G. F.; Ponticello, G. S.; Ludden, C. T.; Sweet, C. S.;
Scriabine, A.; Share, N. N.; Hall, R. J. Med. Chem. 1979, 22,
687. (b) Knuutinen, J. S.; Kolehmainen, E. T. J. Chem. Eng.
Data 1983, 28, 139.
(3) Katsurda, M.; Kawata, S.; Kyomura, N.; Shiga, Y.; Fukuchi,
T.; Yamada, R. PCT Int. Appl. WO 2001044154, 2001;
Chem. Abstr. 2001, 135, 46183.
(4) Bringmann, G.; Menche, D.; Mühlbacher, J.; Reichert, M.;
Saito, N.; Pfeiffer, S. S.; Lipshutz, B. H. Org. Lett. 2002, 4,
2833.
(5) Brandt, M.; Fertig, G.; Krell, H.-W.; von Hirschheydt, T.;
Voss, E. PCT Int. Appl. WO 2003087026, 2003 (priority
date 18.04.2002); Chem. Abstr. 2003, 139, 337979.
(6) Gust, R.; Schoenenberger, H. Eur. J. Med. Chem. 1993, 28,
103.
(12) Other desilylating agents should easily overcome this
disadvantage.
(13) The bulk of the TIPS group hinders the rotation of the
phenolic C–O bond and causes a symmetry breakdown on
1H NMR timescale. Therefore a spin system of higher order
was observed.
Synthesis 2004, No. 12, 2062–2065 © Thieme Stuttgart · New York