Methylenation, of catechols

Methylenation of catechols is greatly improved with potassium or cesium fluoride in DMF and CH2CI2 or CH2Br2. 

Methylenation of catechols. Bashah and Collins have converted various <3-dihydroxyphenols into the methylenedioxy derivative by addition of a solution of the phenol in aqueous NaOH to a mixture of dibromomethane, water, and this phase-transfer catalyst. Reported yields are 76-86%. Classical methods require anhydrous conditions and aprotic solvents. 

Ready methylenation of catechols and 2-hydroxy-lhiophenols with methylene dibromide to produce derivatives (3 X = 0,S) has also been reported. PTC methods have been used to alkylate various nitrogen derivatives, such as indole and other heterocycles, some anilides and phenylhydrazones. ... 

Fig. 11 Plots of log EM vs number of bridge methylenes for the formation of catechol, resorcinol, and hydroquinone polymethylene ethers by intramolecular nucleophilic substitution in 99% Me2SO. (Reproduced with permission from Dalla Cort et al., 1980)...

Palladium-catalyzed approaches have been described and studied for the oxygenated series. Thus, treatment of 2,3-dibromo-l-propene 182 with the monoanion of catechol 181, generated with NaH, in the presence of Pd(PPh3)4 and anhydrous potassium carbonate, afforded 2,3-dihydro-2-methylene-l,4-benzodioxin 183 in 67% yield (Equation 31) <1998JA9283>. 

The kinetics and product distributions of ozonolysis of vinylcyclohexane and methylene cyclohexane have been investigated.162 Steric hindrance of the cyclic substituent largely offsets electronic effects hi determining the rate of reaction. The main products of ozonation of catechols were quinones, while catechol acetals gave rise to compounds with an opened benzene ring.163 The ozonolysis of azoles such as pyrroles, oxazoles, and imidazoles has been reviewed.164... 

It has also been suggested to manufacture heliotropin starting from catechol (J. Gen. Chem., USSR, 1938, 8, 1975). This method involves a 3-step process which comprises 1) the preparation of methylenedioxybenzene from catechol, 2) the conversion of methylenedioxybenzene with paraformaldehyde and hydrogen chloride to heliotropyl chloride and 3) the reaction of the latter with hexamethylenetetramine in ethanol to obtain heliotropin with an overall yield of 11—28 % based on catechol. An improvement in the yield of step 1), and thus overall yield, can be obtained by employing a process for preparation of methylenedioxybenzene from catechol as described in U.K. patent specification 1,097,270 which involves the reaction of catechol with a methylene dihalide under alkaline conditions in the presences of a highly polar, aprotic solvent. 

Twenty minutes after the addition of catechol and sodium hydroxide was complete, further portions of methylene chloride (20 w.) and sodium hydroxide (3 w.) were added at 125-130° C. The reaction was stirred at this temperature for a further 70 minutes and then the solids addition head was replaced by a Vigreux column and a constant take-off distillation head. Water (50 v.) was added and the methylenedioxy-benzene/water azeotrope was distilled off at 98-100° C., more water being added slowly to the reaction mixture as distillation proceeded. 

Recently the conditions have been defined under which trimerization of some phenol ethers is viable these require anodic oxidation in a flow cell with porous electrodes, using acetonitrile or trifluoroacetic acid-methylene chloride. Catechol derivative (48) and 1,2-methylenedioxybenzene were thus converted into trimers (49) and (50) respectively, in ca. 30% yield. 

The reaction itself works by the action of Na or K from NaOH or KOH which form what is called a catechoxide dianion with the two OHs of the catechol species. This makes the two ripe for an attack by a methylene halide which can be either DCM (methylene chloride, or dichloromethane), DBM (methylene bromide, or di-bromomethane) or DIM (methylene iodide, or diiodomethane). DCM is cheap and works pretty well, but DBM and DIM work better yet are more expensive. 

Nal, SiCl4, rt, 20-60 min, 78% yield. Cleavage results in subsequent formation of a diiodide, but this is not a general process. For the most part, ketals are cleaved to give the ketone, while catechol methylene acetals return the catechol. ... 

A relatively unique type of reactive metabolite is carbene, i.e., a divalent carbon, which is a proposed intermediate in the oxidation of methylene dioxy-containing compounds. A methylenedioxy group in aromatic compounds is subject to O-dealkylation, e.g., 3,4-methylenedioxyamphetamine, as shown in Figure 8.20. The process generates formic acid and the catechol metabolite as final products. However, in the course of the reaction, a... 

From Catechol. Several routes have recently been developed for the synthesis of heliotropin from catechol. In one such route, catechol is converted into 3,4-dihydroxymandelic acid with glyoxylic acid in an alkaline medium in the presence of aluminum oxide. 3,4-Dihydroxymandelic acid is oxidized to the corresponding keto acid (e.g. with copper-(II) oxide), which is decarboxylated to 3,4-dihydroxybenzaldehyde [176]. The latter product is converted into heliotropin, for example, by reaction with methylene chloride in the presence of quaternary ammonium salts [177]. 

With the exception of compound 75 none of these compounds were active. Since the exocyclic methylene analog 75 had activity we chose to prepare a simplified analog [Fig. (23)]. Thus, the catechol 66 was reacted with 79, K2CO3 and Nal in DMF for 16 h to give the exocyclic methylene compound 80 which lacked the C26 dimethyls. Compound 80 was inactive, which further emphasizes the importance of C26 dimethyls. 

Deoxygenation of carbonyl compounds (6, 98 7, 54 8, 79-80). This easily prepared borane is as effective as catechol borane for reduction of tosylhydrazones of carbonyl compounds to the corresponding methylene compounds. 

Bashall and Collins4S have treated catechol (9) with methylene dibromide under PTC conditions in the presence of Adogen. The 76% yield in this reaction is comparable to that obtained in DMSO,46 but PTC is much more convenient. In DMSO, addition of pelleted sodium hydroxide and catechol is required in the absence of air. 

The most common procedure is ozonolysis at -78 °C (P.S. Bailey, 1978) in methanol or methylene chloride in the presence of dimethyl sulfide or pyridine, which reduce the intermediate ozonides to aldehydes. Unsubstituted cydohexene derivatives give 1,6-dialdehydes, enol ethers or esters yield carboxylic acid derivatives. Oxygen-substituted C—C bonds in cyclohexene derivatives, which may also be obtained by Birch reduction of alkoxyarenes (see p. 103f.), are often more rapidly oxidized than non-substituted bonds (E.J. Corey, 1968 D G. Stork, 1968 A,B). Catechol derivatives may also be directly cleaved to afford conjugated hexa-dienedioic acid derivatives (R.B. Woodward, 1963). Highly regioselective cleavage of the more electron-rich double bond is achieved in the ozonization of dienes (W. KnOll, 1975). 

The two possible homologues, with either one or two methyl groups on the methylene carbon of the methylenedioxy group of MDA, are also known. The ethylidene compound (the acetaldehyde addition to the catechol group) has been encoded as EDA, and the acetone (isopropylidine addition to the catechol group) is... 

An even broader structural variety has been evidenced for ethylene-bridged PBs. As for methylene-bridged systems, the presence of n-donat-ing substituents at boron (such as catechol or pinacol) prevents intramolecular P-B interaction and leads to linear monomeric structures (compounds 40g and 40h).56 This is clearly apparent in solution from the 3IP and 11B NMR data, and was further confirmed crystallographi-cally for 40h (Figure 5). The environment around boron remains trigonal planar and the anti arrangement of the PCH2CH2B skeleton maintains the distal phosphorus and boron atoms far away from each other (4.231(2) A). 

Methylenedioxy (Benzodioxole) Ring Cleavage. Methylenedioxy-phenyl compounds, such as safrole or the insecticide synergist, piperonyl butoxide, many of which are effective inhibitors of CYP monooxygenations, are themselves metabolized to catechols. The most probable mechanism appears to be an attack on the methylene carbon, followed by elimination of water to yield a carbene. The highly reactive carbene either reacts with the heme iron to form a CYP-inhibitory complex or breaks down to yield the catechol (Figure 7.8). 

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