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One-Pot Synthesis of Substituted Catechols from the Corresponding Phenols.

Article in ChemInform · August 2005

DOI: 10.1016/j.tetlet.2005.03.082

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Trond Vidar Hansen Lars Skattebøl

University of Oslo University of Oslo
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One-pot synthesis of substituted catechols from the

corresponding phenols
Trond Vidar Hansen1,  and Lars Skattebøl2
1
School of Pharmacy, Department of Chemistry, University of Oslo,
P.O.B. 1068 Blindern, N-0316, Oslo, Norway. 2Department of Chemistry, University of
Oslo, P.O.B. 1033 Blindern, N-0315, Oslo, Norway.
_______________________________________________________________________
Abstract: Phenols are converted to salicylaldehydes with paraformaldehyde, MgCl2-Et3N
in THF, and when subsequently treated with aqueous NaOH and H2O2 afford the
corresponding catechols. The sequence is conveniently carried out as a one-pot
procedure.
_______________________________________________________________________

The catechol structural entity is present in a number of important naturally occurring

compounds and in other molecules with interesting biological activity. Hence synthetic
methods leading to substituted catechols are of considerable interest. Several methods of
preparation are known.1 The copper ion catalyzed substitution of 2-halophenols with
hydroxide ion can lead to the corresponding catechols in good yields, but the conditions
are quite harsh.2 The most versatile methods are probably the oxidation of
salicylaldehydes or acetophenone derivatives with either hydrogen peroxide or peracids,
the Dakin and Bayer-Villiger reactions, respectively.3,4 In the last two decades
fermentation methods have been introduced with considerable success.5 Benzene
derivatives are converted to the corresponding optical pure cyclohexadiene-1,2-diols,
which readily transform to catechols. In the present paper we describe an efficient one-
pot method for the conversion of phenols to catechols.

We have recently described a simple procedure for the selective ortho-formylation of

phenols that involves heating a mixture of the phenol, anhydrous MgCl2, triethylamine
and paraformaldehyde under reflux in acetonitrile or THF. For alkyl and halogen
substituted phenols excellent yields of salicylaldehydes were obtained.6 Moreover, we
have shown that the reaction products from this formylation reaction can without
isolation be reacted with (+)-(R, R)-1,2-diammoniumcyclohexane mono-(+)-tartrate salt,
thus giving rise to a convenient high yielding and one-pot method for the preparation of
salen ligands.7 A similar approach seemed feasible for the preparation of catechols,
hence, the formylation reaction is followed by the Dakin oxidation with H2O2 as a one-
pot procedure.

Keywords: ortho-formylation of phenols, Dakin reaction, substituted catechols


Corresponding author: E-mail: [email protected]. Fax: +47 22855947.

1
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OH OH OH
MgCl2, Et3N, (CH2O)n NaOH, H2O2
OH
O
R THF,  R R.T. R

Scheme R = F, Cl,
Br, Me

Accordingly, to the THF solution from the formylation reaction, aqueous NaOH was
added followed by 30% H2O2. After 4-8 h at room temperature the reaction was complete
and normal work-up furnished the crystalline catechol derivative. The reactions were
carried out with both 2-and 4-substituted phenols as starting materials. The catechols 1-8,
prepared by this method, are shown in the Figure. Except for compound 3, they are all
commercially available compounds that were identified by comparison with authentic
samples.8 The recorded yields are for recrystallized materials, based on the phenols, and
are not optimized. Experimental details for the preparation of 3 are given below and are
typical.9

F Cl Br Me
OH OH OH OH

OH OH OH OH

1: 66% 2: 58% 3: 55% 4: 66%

F Cl Br Me

OH OH OH OH
OH OH OH OH

5: 65% 6: 69% 7: 66% 8: 70%

Figure

Substituted phenols are readily available, and the present method appears to be a
convenient way of transforming them into the corresponding catechols.

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References and notes

1. Müller, E. In Houben-Weyl:Methoden der Organischen Chemie; O. Bayer, Ed.,

Georg Thieme Verlag; Stuttgart, 1976; Vol. VI/1c, 1, pp. 166–308.
2. For typical reaction conditions see: Allen, C. F. H; VanAllan, J. A. J. Org. Chem.
1949, 14, 798-801.
3. Surrey, A. R. Org. Synth. 1946, 26, 90-92.
4. (a) Hüe, R.; Jubier, A.; Andrieux, J.; Resplandy, A. Bull. Soc. Chim. Fr. 1970, 3617-
3624; (b) Hassall, C. H. Org. React. 1957, 9, 73-106.
5. (a) Bui, V. P.; Hudlicky, T.; Hansen, T. V.; Stenstrøm, Y. Tetrahedron Lett. 2002, 43,
2839-2841; (b) Endoma, M. A.; Bui, V. P.; Hansen, J.; Hudlicky, T. Org. Process
Res. Dev. 2002, 6, 525-532; (c) Bui, V. P.; Hansen, T. V.; Stenstrøm, Y.; Hudlicky,
T. Green Chem. 2000, 2, 263-265 and references therein.
6. Hofsløkken, N. U.; Skattebøl, L. Acta Chem. Scand. 1999, 53, 258-262.
7. Hansen, T. V.; Skattebøl, L. Tetrahedron Lett. 2005, 46, accepted.
8. a) Pearson, D. E.; Wysong, R. D.; Breder, C. V. J. Org. Chem. 1967, 32, 2358-2360;
b) Lorraine, M. D.; Brazwell, E. M.; Vander-Jagt, D. L.; Royer, R. E. Org. Prep.
Proc. Int. 1990, 22, 495-500; c) Klix, R. C.; Chain, M. H; Bhatia, A. V. Tetrahedron
Lett. 1995, 36, 6413-6414.
9. Preparation of 3: A mixture of 2-bromophenol (1.73 g, 10 mmol), MgCl2 (1.90 g, 20
mmol), Et3N (2.02 g, 20 mmol) and paraformaldehyde (0.90 g, 30 mmol) under argon
and in THF (15 ml) was heated under reflux for 3 h. The reaction mixture was cooled
to room temperature and sodium hydroxide (0.05N, 30 ml) was added dropwise.
When all components had dissolved, H2O2 (30%, 4 ml) was added dropwise. After 2
h, another portion of 30% H2O2 (4 ml) was added and the reaction mixture stirred for
another 4 h until complete conversion (TLC). The reaction mixture was acidified
(1.0N HCl, 25 ml) and extracted with CH2Cl2. The extract was washed with NaS2O4,
the solvent removed under reduced pressure and the residue dissolved in a small
amount of MeOH. Filtration and washing (CH2Cl2, 50 mL) through a plug of silica
followed by evaporation of the solvent gave a solid residue, that was recrystallized
from pentane to give 3-bromocatechol 3 as white crystals (1.03 g, 55%): mp 40-41
°C, lit.8a mp 40.5-41.5 °C; 1H NMR (300 MHz, CDCl3):  5.65 (bs, 2H), 6.72 (t, J =
7.8 Hz, 1H), 6.85 (dd, J = 1.5, 7.8 Hz, 1H), 6.98 (dd, J = 1.5, 7.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3):  109.5, 114.9, 121.9, 123.3, 140.3, 144.6; HRMS calcd. for
C6H5BrO2 (M+): 187.9473 found 187.9485.

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