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Hydrogen Bonding in Organic Synthesis. IV.
A Simple, High-Yield Methylenation of Catechols

J.H. Clark. H.L. Holland, J.M. Miller
Tetrahedron Letters, pp. 3361-3364 (1976)

The methylenedioxy group is of special interest in chemistry because it occurs in many natural products1. and has been suggested as a protecting group in catechols2. However, attempts to carry out the methylenation of catechols have generally afforded low yields of products though many attempts at improvement have been made.

Bonthrone and Cornforth have shown3 that the use of a dipolar aprotic solvent such as dimethylsulphoxide may considerably enhance the rate of reaction and the product yield although this method suffered from the somewhat tedious procedure of slow addition of a mixture of solid sodium hydroxide and the catechol under a nitrogen atmosphere. Since then, a number of workers have reported the high-yield methylenation of several substituted catechols using dimethylsulphoxide (DMSO) or N,N-dimethylformamide (DMF) as solvent in the presence of a bronze4, nickel oxide5 or cupric oxide6 catalyst. More recently, Bashall and Collins have shown7 that high yields of methylenated catechols may be obtained in the absence of a dipolar aprotic solvent by using a phase transfer catalyst under reflux conditions, although this process still required the use of strong base and the method of slow addition of the reactants under a nitrogen atmosphere during a period of some 3 hours.

We now wish to report a simple method for the high-yield methylenation of catechols which requires neither the use of strong base nor any special precautions such as a nitrogen atmosphere or controlled addition of reagents. The reaction of a catechol with dihalogenomethane in DMF in the presence of an excess of potassium or caesium fluoride provides a high yield of the corresponding methylenedioxy compound in a relatively short period of time.

In a recent communication8 we reported a number of rapid and high-yield H-bond assisted condensations between halogenoakanes and aromatics capable of acting as H-bond electron acceptors with fluoride. We believe that these reactions and those described here are accelerated by the formation of an H-bond between the fluoride anion and the aromatic molecule which directs electrons from the electron-rich fluoride anion to the organic part of the complex.

We have shown, by observing the large shift in the electron acceptor stretching band in the IR, that 1,2-dihydroxyaromatics are capable of behaving as H-bond electron acceptor sites and producing strong H-bonds (ΔH0 = 62 kJ mol-1)9 with fluoride.

The various methylenations that were attempted10 are shown along with recovered yields and extent of intermolecular reaction3 in the table. Products were identified by routine analysis and by comparison with authentic samples.

ReactantsProduct
Isolated
Yield
Reaction
Time
Dimers and
Polymers*
Catechol/KF/CH2Br2Benzo-1,3-dioxole
84%
60 min
>10%
Catechol/CsF/CH2Br2Benzo-1,3-dioxole
86%
30 min
8%
Catechol/CsF/CH2Cl2 Benzo-1,3-dioxole
98%
90 min
trace
2,3-Dihydroxynaphthalene/KF/CH2Br2Naphtho[2,3-d][1,3]dioxole
70%
70 min
>20%
2,3-Dihydroxynaphthalene/CsF/CH2Br2Naphtho[2,3-d][1,3]dioxole
88%
30 min
<10%
2,3-Dihydroxynaphthalene/CsF/CH2Cl2 Naphtho[2,3-d][1,3]dioxole
98%
90 min
trace
3-Methylcatechol/KF/CH2Br23-Methyl-benzo-1,3-dioxole
81%
60 min
-
3,4-Dihydroxybenzaldehyde/KF/CH2Br2 Piperonal
90%
70 min
-

* Determined by recovery of residue from separation.

On shaking anhydrous caesium fluoride (7.6 g, 0.05 mol) with a solution of catechol (1.1 g, 0.01 mol) in anhydrous DMF (30 g), the mixture became warm and the IR of the mixture showed a new strong broad band at ca 2500 cm-1 due to vs(O-HF) which represents a shift Δvs(OH) of some 1100 cm-1 indicative of a strong H-bond. Dichloromethane (0.935 g, 0.011 mol11) was added to the cooled solution and the mixture heated at 110-120C for 1.5 h (100% reaction by 1H-NMR analysis). The cooled reaction mixture was then separated by ether extraction followed by washing the ethereal extracts with water (to remove DMF) and with cold dilute akali. Drying and evaporation followed by extraction of the pure product with hot pentane or by steam-distillation afforded benzo-1,3-dioxole (1.19 g, 0.0098 mol, 98%). Analysis of the residue showed only a trace (<1%) of dimer (m/e 244).

To date, the ionizing base for catechols has always been an alkoxide, alkali hydroxide or carbonate. Our method offers an alternative route to methylenation involving the use of an alkali metal fluoride and DMF via an H-bonding mechanism. The method is fast, efficient, provides high recoverable yields and avoids strongly basic conditions. Furthermore, it would seem that by using caesium fluoride and dichloromethane, intermolecular condensations may be kept to a minimum. These results offer further striking evidence for the potential general significance of the method of H-bond assisted reactions to synthetic chemistry.

References

  1. F. M. Dean, "Naturally Occurring Oxygen Ring Compounds", Butterworths, London, 1963.
  2. J. F. McOmie, "Protective Groups in Organic Chemistry", Plenum, London, 1973.
  3. W. Bonthrone and J. W. Cornforth, J. Chem. Soc. [C], 1202 (1969)
  4. H. Fujita and M. Yamashita, Bull. Chem. Soc. Japan, 46, 355 (1973)
  5. H. Fujita and M. Yamashita, Yukui Gosei Kagako Kyokai Shi, 31, 932 (1973)
  6. I. R. C. Bick and R. A. Russell, Aust. J. Chem., 22, 1563 (1969)
  7. A. P. Bashall and J. F. Collins, Tet. Lett., 40, 3489 (1975)
  8. J. H. Clark and J. M. Miller, J. Chem. Soc. Chem. Commun., 229 (1976)
  9. J. H. Clark and J. M. Miller, J. Amer. Chem. Soc., submitted for publication.
  10. We have attempted to extend this reaction procedure to the preparation of the polycyclic compounds hydrastine and bicuculline using the corresponding di- and tetra-hydroxy compounds as starting materials. To date, our reactions have only provided break-down products although reaction monitoring by thin layer chromatography and by 1H-NMR analysis has revealed the presence of the desired products during the course of the reactions. We believe that by carefully controlling the conditions of these reactions it may be possible to prepare reasonable quantities of these materials. Work is continuing in this direction.
  11. A 10 mole% excess of dihalogenomethane was used in all the reactions described to allow for minor dehydrohalogenation processes which may occur in the presence of fluoride/DMF.