Actually, Osmium was correct, there’s far more of interest about rearrangements, a matter very important to the bees. In particular the previous paper published by the same group is very important in gaining understanding:
Synthesis of New Analogues of Furapiole, a Potent Insecticide Synergist
C DEVAKUMAR & S K MUKERJEE
The synthesis of seven new analogues of furapiole (6,7-dihydro-4-methoxy-6-methylfuro [2; 3,f]-1,3-benzodioxole) is described. The methoxy analogue has been obtained by Vilsmeier formylation of furapiole followed by Baeyer-Villiger oxidation and methylation. The angular analogue has been prepared from dillapiole in four steps. 4-Allyloxy-2-hydroxyacetophenone when refluxed in DMA-PTS medium gives the coumaran derivative which on Dakin oxidation followed by methylation furnishes 4,5-dihydro-5-methylfuro [3,2,e]-1,3-benzoidioxole. The synthesis of other analogues is best accomplished from the appropriate o-allylsesamols through Hydrogen bromide addition followed by Adams method of cyclisation of the intermediates. Bioassay studies have shown these as highly-potent pyrethrum synergists.
Furapiole is a new potent synergist for pyrethrum and carbamate insecticides. Its formation from dillapiole mediated by Hydrogen bromide involves an unusual selective demethylative cyclisation. In an earlier communications, we have postulated a mechanism for this reaction and supported with studies on a large number of structural variants.
The unusually high biological activity of furapiole is not easily understandable even though a great deal of structure-activity relationship (SAR) studies have been made on its derivatives and open chain analogues Since furapiole is the first example of a methylenedioxy-alpha-methyldihydrobenzofuran in literature, it was of interest to synthesise its novel analogues. In this paper, we report the syntheses and synergistic efficacy of some of its analogues.
The synthesis of 6,7-dihydro-4, 8-dimethoxy-6-methylfuro [2,3-f]-1,3-benzodioxole was accomplished from furapiole. Bromination of furapiole gave the bromofurapiole in a quantitative yield. Attempts to convert bromofurapiole into 6,7-dihydro-4,8-dimethoxy-6-methylfuro [2,3-f]-1,3-benzodioxole by direct methoxylation using sodium methoxide either in dimethylformamide containing Cu2I2 or by the recent procedure of Marchand et al employing Cu2Cl2-pyridine-methanol under reflux, failed. In an indirect approach, Vilsmeier formylation of furapiole using N-methylformanilide-POCl3 complex gave the formylfurapiole in 60% yield. The presence of formyl group in formylfurapiole was indicated by its IR absorption at 1670 cm -1 and a one-proton singlet at 6 10.0 in its PMR spectrum in which the chemical shifts of OCH3 and - OCH2O- protons appeared downfield by <5 0.1 in comparison to those in furapiole. Baeyer-Villiger oxidation of the aldehyde by performic acid afforded the phenol in 50% yield, methylation of which furnished the analogue in a quantitative yield. The PMR spectrum showed a six-proton singlet at 5 3.90 for the two methoxyls in accordance with the structure.
The syntheses of the analogues were achieved by elaboration of dihydrofuran ring from the corresponding benzodioxoles. The synthetic approach as outlined involved Hydrogen bromide addition to the corresponding o-allylsesamols to give the o-(2'-bromopropyl)-sesamols as intermediates followed by Adams method of base catalysed cyclisation of the latter to the dihydrofurans. While the known allylphenols were prepared by the reported procedure, the new phenols were obtained by Claisen migration of the corresponding allyloxybenzodioxoles . Attempts to induce direct cyclisation of the phenols by Adams method did not succeed due to the facile fission of methylenedioxy group under Hydrogen bromide-AcOH treatment. However, the methylenedioxy group was stable up to 2 hr in the presence of dry Hydrogen bromide in non-polar solvents such as chloroform [Chloroform] and the indirect route was, therefore, preferred. The bromophenols thus obtained, on refluxing with acetone-potassium carbonate [K2CO3] furnished the required analogues respectively in 80-85% yields. The usual method of heating with pyridine, on the other hand, gave mixtures containing o-(1-propenyl)-phenols due to dehydrobromination in addition to the desired cyclised products.
A combination of the above two approaches enabled the synthesis of the angular methoxy analogue. While the treatment of dillapiole with dry Hydrogen bromide gave a mixture of furapiole and the bromopropyl derivative in chloroform [CHCl3], it exclusively led to the bromopropyl derivative in DIMETHYLFORMAMIDE medium. Formylation of the bromopropyl derivative as in the case of furapiole gave the bromoaldehyde in about 40% yield. Performic acid oxidation of bromoaldehyde gave the formyl ester which on refluxing with acetone-POTASSIUM CARBONATE underwent ester cleavage and intra-molecular cyclisation with the side chain, leading to the formation of .the analogue The PMR spectrum of analogue showing two singlets of three protons each at 53.75 and 3.93 established the angular fusion of fur|n ring.
4,5-Dihydro-5-methylfuro [3,2-e]-1,3-benzodioxole was synthesised. o-Hydroxyallylacetophenone on refluxing in N,N-dimethylaniline containing p-toluenesulfonic acid underwent a single-pot Claisen rearrangement and cyclisation to the coumaran in 60% yield. Dakin oxidation of the coumarin gave the catechol in about 30% yield. The poor yield of the catechol was due to the formation of a mixture of polar products. A re-scanning of literature at this point revealed that 5-hydroxy-2,3-dihydrobenzofurans of this type are highly unstable in the presence of alkaline hydrogen peroxide [H2O2], their most characteristic reaction being facile oxidation to quinones with the fission of the heterocyclic ring. Methylenation of 2, 3-Dihydro-4,5-dihydroxy-2-methylbenzofuran with CH2Cl2 and KF in anhydrous dimethylformamide [DMF] medium gave the analogue in 60% yield. A comparison of its PMR spectrum with that of 6,7-Dihydro-6-methylfuro[2,3-f]-1, 3-benzodizole revealed the presence of double doublets for two ortho-protons at <56.45 and 6.55 in 2, 3-Dihydro-4,5-dihydroxy-2-methylenzofuran in contrast to double singlets at 6.2 and 6.4 for two p-protons in 6,7-Dihydro-6-methylfuro[2,3-f]-1, 3-benzodizole.
The bioassay studies of the compounds as pyrethrum synergists against red flour beetles (Tribolium casteneum Herbst) using our earlier techniques have shown that the linear analogues are highly active, the respective factors of synergism being 5.2,6.3 and 4.6. It implies that furo [2,3-f]-l,3-benzodioxoles are per se better pyrethrum synergists than simple 1,3-benzodioxoles, and additional methoxy substituents have an enhancing effect on this ring system as observed in other cases.
Experimental Procedure
8-Bromo-4-methoxy-6-methyl-6,7-dihydrofuro [2,3-f]-2,3-benzodioxole
Bromine (0.1 ml) in chloroform [CHCl3] (20 ml) was added dropwise to a solution of furapiole (415 mg) in chloroform [CHCl3] (20ml) till the pale yellow colour of bromine persisted. After 1 hr, the solvent was evaporated and the residue (560 mg) crystallised from methanol to give colourless needles
8-Formyl-4-methoxy-6-methyl-6,7 dihydrofuro[2,3-f]-1,3-benzodioxole
N-Methylformanilide (11.2g) was mixed dropwise with phosphoryl trichloride [POCl3] (11.5g) in dry chlorobenzene (10 ml) at 0°.after keeping for 1 hr, the mixture was added to furapiole (10.6g) in chlorobenzene (20 ml) at 0°, stirred at 20° for 6 hr and heated at 60-70° for 8 hr. It was then poured into ice-water (100 ml), the organic layer washed free of acid and dried over anhydrous sodium sulfate [Na2SO4]. Dilution of the organic layer with hexane followed by chilling precipitated the aldehyde which was recrystallised from hexane-benzene (95:5) as light yellow needles (7.1 g), m.p. 101-2°
6,7-Dihydro-4-methoxy-6-methylfuro[2,3]-1,3-benzodioxol-8-ol
Baeyer-Villiger oxidation of 8-Formyl-4-methoxy-6-methyl-6,l dihydrofuro[2,3-f]-l,3-benzodioxole (4.72g) with performic acid using the procedure described for sesamol gave the phenol which was crystallised from cyclohexane as white plates (2.35 g), m.p. 89-90°
6,7-Dihydro-4,8-dimethoxy-6-methylfuro-[2,3-f]-l3-benzodioxole
Methylation of the above phenol (1.12g) with methyl iodide [MeI] (1.5 ml) in dry acetone (50 ml) containing anhydrous potassium carbonate [K2CO3] (1.4g) under reflux for 4 hr furnished the methoxyfurapiole (1.12 g) which was recrystallised from methyl alcohol [MeOH] as white needles, m.p. 47°
6-(2'-Bromopropyl)-4,5-dimethoxy-1,3-benzodioxole
Dillapiole [4,5-Dimethoxy-6-(2'-propenyl)-1,3-benzodioxole] (1.1 g, 0.05 mol) in dry dimethylformamide (100 ml) was saturated with dry Hydrogen bromide at 0°. After keeping for 2 hr, it was poured into ice-cold water (300 ml), extracted with Chloroform, washed the org. layer with H2O till neutral, dried over anhydrous sodium sulfate [Na2SO4] and evaporated to furnish the bromopropyl derivative (14.9 g). It was passed through a short column of silica gel (100 g) using hexane-benzene (4:1) as eluent to give 6-(2'-Bromopropyl)-4,5-dimethoxy-1,3-benzodioxole as a light brown oil
6-(2'-Bromopropyl)-4,5-dimethoxy-7-formyl-1,3-benzodioxole
Vilsmeier formylation of 6-(2'-Bromopropyl)-4,5-dimethoxy-1,3-benzodioxole (0.025 mole) by the procedure described for 8-Formyl-4-methoxy-6-methyl-6,1 dihydrofuro[2,3-f]-1,3-benzodioxole furnished the bromoaldehyde in 40% yield. It was recrystallised from n-hexane as pale yellow needles, m.p. 91°
6-{2'-Bromopropyl)-4,5-dimethoxy-7-formyloxy-1,3-benzodioxole
The above aldehyde (6.62 g) was oxidized with performic acid at - 5° for 16 hr as described earlier for 6,7-Dihydro-4-methoxy-6-methylfuro[2,3]-1,3-benzodioxol-8-ol. The formic acid solution of the product was poured into ice-water, extracted with diethyl ether, dried over anhydrous Na2SO4 and solvent removed to furnish the formyl ester (2.1 g) as a reddish brown oil. Its purity was ascertained by TLC
5,6-Dihydro-7,8-dimethoxy-5-methylfuro-[2,3-e]-1,3-benzodioxole
The formyl ester (1.04g) was refluxed in dry acetone (50 ml) containing anhyd. potassium carbonate (0.5 g) on a water bath for 6-8 hr. The completion of the reaction was monitored by TLC. The usual work-up gave a residue (650 mg) which was purified on a column of silica gel (20g) using hexane-benzene (3:1) as eluent to give 5,6-Dihydro-7, 8-dimethoxy-methylfuro[2,3-e]-1,3-benzodioxole as white needles, m.p. 39-40° (2-Allyl-4,5-methylenedioxyphenol) and 6-allyl-2,3-methylene-dioxyphenol) were prepared as described earlier.
o-Allylphenols
These were prepared by the Claisen rearrangement of 5-allyloxy-6-methoxy-1,3-benzodioxole and 6-allyloxy-4,5-dimethoxy-1,3-benzodioxole as reported earlier. The corresponding allyloxybenzodioxoles (10 mmol) in N,N-dimethylaniline (20 ml) were refluxed for 2 hr, cooled and poured into ice-cold dil. HCl (100 ml, 1:1). Usual work-up followed by vacuum distillation gave pale yellow viscous liquids (yield 55%).
4-(2'-Propenyl)-6-methoxy-1,3-benzodioxol-5-ol: b.p. 115-16°/1 mm
4-(2'-Propenyl)-6,7-dimethoxy-1,3-benzodioxol-5-ol: b.p. 124-25°/1mm
Reaction of o-allylphenols with Hydrogen bromide-AcOH A typical example is described below:
Aqueous Hydrogen bromide (48%, 0.2 ml) was added to a solution of the phenol (100 mg) in glacial acetic acid (1 ml) till the whole mixture became turbid. The mixture was warmed on a water-bath for 30-45 min at 50-60°, diluted with water (10 ml) and fractionated into phenolic and neutral portions. The latter portion amounted to hardly 5% while the phenolic part was mostly polymeric in nature and contained only traces of the starting phenol. Variation in reaction period and temperature also did not help in inducing cyfclisation of allylphenols. For example, the phenol could be recovered as such following the above treatment at 0° for 1 hr as well as keeping the reaction mixture at room temperature for 1/2 hr.
Reaction of o-allylphenols with dry Hydrogen bromide
A solution of appropriate o-allylphenol (1 mmol) in dry chloroform (15 ml) at 0° was saturated with hydrogen bromide. After keeping for 2 hr, the reaction-mixture was pouted into ice-water (50 ml), the chloroform layer washed with water till neutral, dried sodium sulfate (Na2SO4) and evaporated to furnish the corresponding o-(2'-bromopropyl)phenol in > 96% yield as a dark brown liquid. They.were used as such without further purification in the following reaction.
Preparation of furapiole analogues
o-(2'-Bromopropyl)phenols (1 mmol each) were refluxed separately in dry acetone (50 ml containing anhydrous potassium carbonate (140 mg, 1 mmol) on a water-bath for 5-8 hr and worked-up as described in the case of 6,7-Dihydro-4-methoxy-6-methylfuro[2,3]-1,3-benzodioxol-8-ol to furnish the corresponding furapiole analogues in 80-85% yields.
6,7-Dihydro-6-methylfuro[2,3-f]-1,3-benzodixole: Colourless oil
4,5-Dihydro-7-methoxy-5-methylfuro [3,2-e]-1,3-benzodioxole: Pale yellow oil
4,5-Dihydro-7,8-dimethoxy-5-methylfuro [3,2-e]-1,3-benzodioxole: It was crystallised from MeOH as white plates, m.p. 38-39°
5,6-Dihydro-5-methylfuro[2,3-f]-1,3-benzodioxole Colourless oil
5-Acetyl-2,3-dihydro-4-hydroxy-2-methylbenzofuran:
4-Allyloxy-2-hydroxyacetophenone (3.8 g) was refluxed in dry N,N-dimethylaniline (40 ml) fortified with anhydrous p-toluenesulfonic acid (3g) for 4 hr and 90% of the aniline distilled off. The residue after cooling to room temperature was poured inter ice-water (50 ml) containing concentrated HCl (10 ml), and worked-up as usual to give 5-Acetyl-2,3-dihydro-4-hydroxy-2-methylbenzofuran as a colourless viscous oil which solidified immediately into white plates (2.3 g), m.p. 44-45°
2,3-Dihydro-4,5-dihydroxy-2-methylbenzofuran
A solution of 5-Acetyl-2,3-dihydro-4-hydroxy-2-methylbenzofuran (1.92 g) in aq. NaOH (10 ml, 1 N) was treated with aqueous H2O2 (10 ml, 6%) at 0° under nitrogen atmosphere. The initial precipitate formed gradually went into solution and after 45 min the reaction mixture was quenched with 2N HCl (10 ml), cooled and the dark coloured precipitate (0.65 g) filtered. It was purified by repeated crystallisation from acetone-hexane (1:3) to give 2,3-Dihydro-4,5-dihydroxy-2-methylbenzofuran as cream coloured plates (330 mg), m.p. 125-6°; gave positive colour reaction with FeCl3
4,5-Dihydro-5-methylfuro [3,2-e]-1,3-benzodioxole
Methylenation of 2,3-Dihydro-4,5-dihydroxy-2-methylbenzofuran (250 mg) in dry dimethylformamide (10 ml) containing anhydrous KF (450 mg) with CH2Cl2 (0.1 ml) by the general procedure gave a pale yellow oil (150 mg) which was chromatographed over silica gel (3 g) using hexane-C6H6 (4:1) as eluent to give 4,5-Dihydro-5-methylfuro [3,2-e]-1,3-benzodioxole as a colourless oil (95 mg)
References .
1 Mukerjee S K, Walia S, Saxena, V S & Tomar S S; Agric Biol Chem, 46 (1982) 1277.
2 Walia S, Saxena V S & Tomar S S, Indian J Ent, (in press)
3 Devakumar C & Mukerjee S K, Indian J Chem, 25B (1986) 368.
4 Devakumar C, Saxena V S & Mukerjee S K (under communication)
5 Devalcumar C. Saxena V S & Mukerjee S K, Agric Biol Chem. 49 (1985)725. ,
6 McKillop A, Howarth B D & Kobylecki R J, Synth Commun. 4 (1974) 35.. ..
7 Manchand P S, Townsend J M, Belica P S & Wong H S. Synthesis, (1980) 410.
8 Arnold R T & Burdwell F, J Am Chem Soc, 64 (1942) 2983.
9 Baker. W & Savage R I, J Chem Soc, (1938) 1602.
10 Baker, W & Lothian O M, J chem Soc, (1935) 628.
11 Coffey S Rodd’s Chemistry of Carbon Compounds. Vol. 4, Part A (Elsevier Publishing Company, London) 1973, 169.
12 Clark J H, Holland H L & Miller J M, Tetrahedron Lett , (1976) 3361.