1.3- Benzodioxole ring

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). 

The benzodioxole ring system is distributed widely in nature and is found in numerous natural products such as safrole and piperonal, as well as a multitude of alkaloids. 1,2-Dioxolanes are intermediates in the arachidonic acid cascade, which is the biochemical pathway from essential fatty acids to prostaglandins and similar hormones. The endoperoxide PGH2 (121) is believed to be formed on initial oxidation of arachidonic acid (120). PGH2 has a half-life of 4-5 minutes and is transformed enzymatically into prostaglandins, prostacyclin and the thromboxanes. These compounds are mediators for the control of platelet aggregation, blood vessel dilation and smooth muscle contraction. 

This section describes the application of Bioster database to medicinal chemistry problems. In the first example, the database was helpful in finding replacements for the pharmacologically unfavorable benzodioxole ring. Next, an earlier analysis is updated by tabulated examples of phenol bioisosteres. Finally, selected examples from a fragment query for a-ketoamide bioisosteres are presented. 

Figure 4.4 Replacing the benzodioxole ring by a benzothiadiazole ring results in affinity increases in two endothelin ETa receptor antagonist series [49],...

METHOD 8 Check this outi This uses benzene or 1,3-benzodioxole (forX) as the starting material [24]. This method is better suited for speed makers because the AICI3 catalyst can tear up that methylenedioxy ring structure of the X molecule precursor. Chloroacetone can be easily purchased. 

These little beauties are like bromine quarterbacks in that they take the ball (Br) and hand it off to the receiver (1,3-benzodioxole). The great thing about these two species is that they are so bulky that the only place on the benzene ring that they can hand off their Br atom with any efficiency is at the least hindered 5 carbon... 

But the name currently in vogue for this two-ring systemis 1,3-benzodioxole. As a prefix it becomes 1,3-benzodioxol-5-yl-something, and so J would be called l-(l,3-benzodioxol-5-yl)-2-aminobutane. This is the source of the code name BDB. And the N-methyl homologue, the alpha-ethyl analogue of MDMA, is named MBDB, or METHYL-J, and is with its own separate entry in this footnote. 

Fluoride-induced deprotection in the unusual substrate 176 was accompanied by 0-0 cleavage in the dioxetane ring to give benzodioxole 177 (Equation 51) <1997TL8947>. 

This interaction orients the rest of the diketopiperazine core toward the mobile H-loop where it forms a pi-stacking interaction above and below the plane of the ring with Phe786 and Phe820, respectively. The interaction with Gln817 orients the benzodioxol substituent into the same hydrophobic pocket utilized by the ethoxyphenyl of sildenafil and vardenafil. A recent review of the SAR of a large number of PDE5 inhibitors from... 

Figure 5.26 summarizes our synthesis of 141. Friedel-Crafts acylation of neat A with 3-chloropropanoyl chloride and boron trifluoride etherate gave B. Ring closure of B to C was effected with potassium carbonate in ethanol. Then, C was converted to 1,3-benzodioxole E via D. The reason for this conversion was to make later deprotection easy. 

The anomeric effect is not limited to six-membered ring compounds. In five-membered rings the anomeric effect can affect both ring and substiment conformation. The 1,3-dioxole ring adopts a puckered conformation as a result of an anomeric effect. Similar effects are observed, although attenuated, in l,3-benzodioxoles. °... 

Alternatively, C-ring formation has been achieved by connecting the atoms Cl 1 and C12 of the erythrinane core. This route principally involves the generation of angularly arylated hydroindoles, their N-alkylation with an appropriate C2-unit followed by the final cyclization step. Thus the hydroindole 93, accessible from 5-(nitromethyl)-l,3-benzodioxole (91) and the oxoheptenoic acid ester 92, has been reacted in a hetero Michael addition with phenyl vinylsulfoxide providing the required N-substimted precursor 94. The latter in turn has been cyclized in a Pummerer reaction to... 

Scheme 3.18 Asymmetric intramolecular addition/ring opening reaction of 3-(2-borylphenyOcydobutanones. (SEGPHOS 5,5 -bis(dipheylphosphino)-4,4 -bi-1,3-benzodioxole.)...

Figure 10. Ring-puckering quantum states of 1,3-benzodioxole in different flapping and electronic states.

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