2,5-Dimethoxy-4-substituted

TABLE 1. Human hallucinogenic potencies of 2,5-dimethoxy-4-substituted phenylisopropylamines ... 

Raney Nickel W2 or W4, EtOH, 85-100% yield. Mono- and dimethoxy-substituted benzyl ethers and benzaldehyde acetals are not cleaved under these conditions, and trisubstituted alkenes are not reduced. 

DMA. None of the three possible tetramethoxy analogs has been investigated, and the pentamethoxy analog does not produce DOM-like stimulus effects. From these studies, it is apparent that the 2,4- and 2,5-dimethoxy substitution pattern plays an important role certain 2.6-dimethoxy derivatives are also active, depending upon what substituents are present at the 4-position. 

Oxidation of mono-iV -oxides 4H -imidazole (223) and (224) with Pb02 in methanol leads to the formation of stable a,a-dimethoxy-substituted nitroxyl radicals (271) and methoxy substituted imino nitroxyl radicals (INR) (272)-(274) (Scheme 2.101) (514). 

Oxidation of oxazolidine derivatives (275) gives isomeric pairs (A) and (B) of a-methoxy-substituted oxazolidine nitroxyl radicals (276a-d, f, g) and a,a-dimethoxy-substituted nitroxyl radical (276e) (Scheme 2.102) (515). 

Moreover, one should mention that in spite of similar electronic structures, PBN and the isoquinoline nitrone (278) react in a different way. Under no circumstances does PBN give an oxidative methoxylation product, whereas nitrone (278) reacts readily to form a,a-dialkoxy-substituted nitroxyl radical (280) (517). Perhaps this difference might be due to the ability to form a complex with methanol in aldo-nitrones with -configuration. This seems favorable for a fast nucleophilic addition of methanol to the radical cation (RC), formed in the oxidation step. The a-methoxy nitrone (279), obtained in the initial methoxylation, has a lower oxidation potential than the initial aldo-nitrone (see Section 2.4). Its oxidation to the radical cation and subsequent reaction with methanol results in the formation of the a,a-dimethoxy-substituted nitroxyl radical (280) (Scheme 2.105). 

In the 2,5-dimethoxy substituted series, when the 4-substituent is alkoxy, a methoxy group gives optimum activity. (Compare, for example, TMA-2 and MEM in Table 1.) The 4-ethoxy group does not lead to an increase in activity, despite increased lipophilicity. This is in sharp contrast to 3,4,5-substituted compounds (discussed below), where an analogous transformation leads to an activity increase of nearly an order of magnitude. 

The products of this catalytic enantioselective 1,4-addition still contain an enone moiety, prone to subsequent 1,4-addition [73]. An intriguing question regarding stereocontrol was posed would the stereoselectivity in the second addition step be governed by the catalyst or would there be a major effect from the stereocenters already present Sequential 1,4-addition to dimethoxy-substituted cyclohexadienone 66 (Scheme 7.18) using the copper catalyst based on (S, R, R)-ligand 18 both in the... 

Parke-Davis workers have performed SAR studies on endothelin receptor antagonists derived from a dimethoxy-substituted oxicam in the search of treatments for hypertension, congestive heart failure, renal failure, pulmonary hypertension, ischemia, and cerebral vasospasm <1998BMC1447>. Compound 295 displayed a 40-fold selectivity for endothelin receptor antagonist A (ETa) over endothelin receptor antagonist B (ETb) (Figure 26). 

Analogous reactions with perfluoro(isopropyl-l,3,5-triazine) and per-fluoro(diisopropyI-l,3,5-triazine) with CsF yielded adducts 116 and 117, respectively, which were detected by 19F-NMR. Use of potassium fluoride, either alone or associated with 18-crown-6, did not lead to the formation of the adducts. In contrast, from tris(perfluoroisopropyl)-l,3,5-triazine no adduct was detected. This is quite interesting because it would indicate the importance of the gem-difluoro substitution to stabilize the adduct,160 in analogy with the effect of gem-dimethoxy substitution.76... 

The meta-orientation of the two methoxyl groups does, however, greatly increase the susceptibility of the aromatic ring to electrophilic attack. This is one of the three possible meta-dimethoxy substituted amphetamines, and it is the best studied one in the pursuit of potential radio-halogen substituted brain blood-flow agents. This strategy is discussed under 1DNNA the other two meta-compounds are discussed under 3,4-DMA. 

Conformational analysis was carried out on the molecules shown in Figure 42 <2002CPL(363)18>. One group consists of thiophene-phenylene-thiophene (TPT) 178, dimethyl-substituted TPT (DMTPT) 179, and dimethoxy-substituted TPT (DMOTPT) 180, and the other group is composed of dihexyl-substituted bithiophene (DHBT) 175 and dicyclohexyl-substituted bithiophene (DCBT) 181. 

The dimethoxy-substituted benzhydryl chloride is also fully ionized in a SnCl4/EtOAc/CH2Cl2 solution [60], and the reactivity toward 2-methyl-l-pentene is identical with that in the BCI3/CH2Q2 solution (Fig. 19). AnPhCHCl is not fully ionized under these conditions, however, and... 

Table 5 lists the half-lives of recovery for some OP-inhibited AChEs. In general OP-AChE complexes from dimethoxy-substituted OPs (e.g., malathion) spontaneously dephosphorylate faster than diethoxy (e.g., parathion) or diisopropoxy (e.g., DPP) complexes. Eto pointed out in 1974 that the stability of a phosphorylated AChE may be predicted from the stability of the specific OP inhibitor itself. One possibility is that methyl groups have less steric hindrance and greater electronegativity than ethyl or isopropyl groups. 

This methodology has also been used to generate 3,3 -bipyridine, (4), (72%)24 and methyl-substituted 3,3 -bipyridines (84%).25 The 3,4,3, 4 -tetramethoxy-substituted bipyridine, which is a precursor to the natural tetrahydroxy bipyridine, Orelline, was similarly afforded in 80% yield through homocoupling of a dimethoxy-substituted iodopyridine.26... 

If is only a 3 - OH, however, activity is reduced at a-sites and almost eliminated at p-sites, thus affording selective a-agonists such as phenylephrine (1 l)and metaraminol (8).Further indication that a-sites have a wider range of substituent tolerance for agonist activity is shown by the 2, 5 -dimethoxy substitution of methoxamine (9), which is a selective a-agonist that also has jS-blocking activity at high concentrations. 

Conditions have been developed which favour certain preferential O-demethyl-ation of aromatic ring dimethoxy-substituted 3,4-dihydroisoquinolines37 and... 

Coincidentally, all alkaloids belonging to this class occurring in Sri Lankan plants bear a common l-hydroxy-2,3-dimethoxy substitution. Arborinine [l-hydroxy-2,3-dimethoxy-10-methyl-9-acridone (10)], an... 

Aza-annulation of a number of dimethoxy-substituted P-tetralone derivatives, such as those represented by 136, with acrylamide was used to produce 137. In turn, 137 was an important intermediate in the synthesis of conformationally restricted congeners of dopamine (eq. 30).53... 

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