Monoalkylated derivatives

The imide proton N-3—H is more acidic than N-1—H and hence this position is more reactive toward electrophiles in a basic medium. Thus hydantoins can be selectively monoalkylated at N-3 by treatment with alkyl haUdes in the presence of alkoxides (2,4). The mono-A/-substituted derivatives (5) can be alkylated at N-1 under harsher conditions, involving the use of sodium hydride in dimethylform amide (35) to yield derivatives (6). Preparation of N-1 monoalkylated derivatives requires previous protection of the imide nitrogen as an aminomethyl derivative (36). Hydantoins with an increased acidity at N-1—H, such as 5-arylmethylene derivatives, can be easily monoalkylated at N-3, but dialkylation is also possible under mild conditions. 

The monoalkyl derivatives in salt form appear to have low toxicity. The monomethyl sulfate sodium salt has an approximate oral lethal dose greater than 5000 mg/kg of body weight for rats (129). Monododecyl sulfate sodium salt is widely marketed as a detergent and shampoo ingredient (oral LD q 1268 mg/kg for rats) (126). Both dimethyl sulfate and monomethyl sulfate occur in the environment in coal fly-ash and in airborne particulate matter (130). 

I. Tile monoalkyl derivatives yield with nitrous acid the isoniiroso-dcriv.itiv0, from which the oitho-diketone may he obi.lined (v J crhmanu),... 

One of the advantages of the enamine alkylation reaction over direct alkylation of the ketone under the influenee of strong base is that the major product is the monoalkylated derivative 29,32). When dialkylation is observed, it occurs at the least substituted carbon in contrast to alkylation with base, where the a-disubstituted product is formed. Dialkylation becomes the predominant reaction when a strong organic base is added and an excess of alkyl halide is used (29). Thus 1-N-pyrrolidino-l-cyclo-hexene (28) on treatment with two moles of allyl bromide in the presence of ethyl dicyclohexylamine (a strong organic base which is not alkylated under the reaction conditions) gave a 95 % yield of 2,6-diallylcyclohexanone (29). 

The course of alkylations of 6-azauracil is in good agreement with the results of determination of the dissociation constants of 6-azauracil and of its two monomethyl derivatives. On the assumption that a methyl group does not much affect the dissociation constant, and on the basis of the lactam structure, it may be concluded from the values of the dissociation constants iKa of 6-azauracil = 7.00, of l-methyl-6-azauracil = 6.99, and of 3-methyl-6-azauracil = 9.52) that dissociation takes first place at the NH group in position 3. The same results are obtained independently by comparing the pH dependence of the XJV spectra of these compounds. These results represent an exact confirmation of the older observation by Cattelain that the monoalkyl derivatives of 6-substituted dioxotriazines possess different acidity. 

It should be mentioned that a similar comparison of the dissociation constant values of uracil monoalkyl derivatives does not permit the determination of the sequence of dissociation on account of the small differences between the pEo values. However, the pH dependence of the XJV spectra showed that the first dissociation of uracil occurs at the NH group in position 1 and thus differently than in 6-azauracil. This, together with different acidity, represents the main differences between the properties of uracil and its 6-aza analogs. 

The ESR spectrum of the thioxanthene S, S-dioxide radical anion itself shows that the two possible conformers coexist, since the two methylene protons are not equivalent. In the case of the 9-monoalkyl derivatives, the large coupling constant observed for the 9-proton leads to the conclusion that the 9-substituent is in the boat equatorial position as in II1 F Thus the radical anions and the neutral molecule display different conformations. The protons in the 9-position of the radical anions of cis-9-methylthioxanthene S-oxides (2, n — 1, R1 = H, R2 = CH3) have an appreciable coupling constant10 which suggests that these radical anions have the substituent in the pseudo-axial position. Furthermore, in the radical anions the S—O bond is pseudo-axial. These situations are exactly the opposite of that observed for the neutral compound. 

In summary, primary amine and monoalkyl derivatives of tryptamine have not yet been demonstrated to produce hallucinogenic effects in man or to consistently produce profound behavioral effects in animals. Admittedly, relatively few compounds have been examined, and few studies have been conducted. Nevertheless, present evidence suggests that these derivatives, by virtue of their inability to penetrate the blood-brain barrier and/or their rapid metabolism, may not be able to achieve adequate brain levels to elicit effects. In some cases, these factors may lead to masking of potential central effects by peripheral actions of the compounds or their metabolites. 

Whereas alkylation of activated methylene systems by classical methods produces a mixture of mono- and dialkylated products, with the latter frequently predominating, phase-transfer catalytic procedures permit better control and it is possible to obtain only the monoalkylated derivatives. Extended reaction times or more vigorous conditions with an excess of the alkylating agent lead to dialkylated products or, with dihaloalkanes, carbocyclic compounds as the technique mimics dilute concentration conditions, e.g. the resonance stabilized cyclopentadienyl anion, generated under solidiliquid two-phase conditions, or under liquiddiquid conditions, reacts with 1,2-dihaloethanes to form spiro[2,4]hepta-4,6-diene (70-85%) [1-3]. Reaction with dichloromethane produces bis(cyclopenta-2,4-dien-l-yl)methane (60%) [4],... 

Method D The phosphoric diamide (30 mmol), alkylating agent (37 mmol) and TEA-C1 (75 mg, 3 mmol) in aqueous NaOH (50%, 75 ml) are stirred at room temperature for 3 h. The mixture is then diluted with H20 (8 ml) and extracted with CHC1, (3 x 25 ml). The dried (MgS04) extracts are evaporated to yield the monoalkylated derivative. 

The greater CH acidity of Meldrum s acid (ptfa 4.97), compared with the malonic esters, results in a more rapid mono- and dialkylation. Concomitant hydrolytic ring opening may occur under liquidtliquid two-phase conditions and yields of the monoalkyl-ated product tend to be low (30-40%) [ 111 ], but the ring is retained under non-aqueous solidtliquid two-phase conditions [112, 113]. Further alkylation of the monoalkylated derivatives with a second (different) alkylating agent is possible [112, 113]. 

Methylene groups can be dialkylated if sufficient base and alkylating agent are used. Dialkylation can be an undesirable side reaction if the monoalkyl derivative is the desired product. Use of dihaloalkanes as the alkylating reagent leads to ring formation, as illustrated by the diethyl cyclobutanedicarboxylate synthesis (entry 7) shown in Scheme... 

Reflecting its electronegative character, C q readily undergoes nucleophilic additions with various nucleophiles [7]. Apparently the most fundamental C-C bond forming reaction is the reaction with alkyllithium or Grignard reagents, giving the monoalkylated derivative of l,2-dihydro-C6o after protonation of the initially formed alkyl-Cso carbanion [48]. 

Nitration of triazole and its C-monoalkyl derivatives fails. Aryltriazoles are nitrated on the aryl ring in preference to the triazole, but 3-p-nitrophenyltriazole in which each ring is deactivated gives l-nitro-3-j7-nitrophenyltriazole which rearranges at 120°C to 3-nitro-5-p-nitrophenyltriazole <72CC37>. 

The synthesis of selectively protected monoalkyl lanthionines, or otherwise alkylated and/or nonsymmetrically substituted lanthionines is made all the more difficult due to the introduction of additional stereocenters. For example, for the monoalkylated derivative 3-methyllanthionine, eight different stereoisomers are possible obviously, similar problems arise for the stereochemistry of other alkylated lanthionines. 

Similar methodology to that employed above gave dialkylated dihydropyrido[3,2- ]thiadiazines 207a-c (Scheme 29), while alkylation of the oxidized form 208 gave the A -monoalkyl derivatives 209a-c <1998JME2946>. 

Alkylation of 3-methyl-1,2,4,5-tetrahydro-3//-3-benzazepin-2-one in THF-DMF solution containing sodium hydride, with primary and secondary alkyl halides and with a-bromoesters, results predominantly in 1-monoalkyl derivatives, whereas with w,w-dibromoalkanes, 1,1-spiro derivatives are formed (80T1017). Apparently, 6,7-dihydro-5//-dibenz[6,rf]azepin-6-one does not condense with benzaldehyde or with nitrosobenzene at the active methylene group (55JA3393). 

A result that is of interest in the planning of synthetic strategy W as obtained by Gajewski and co-workcrs in the rate comparison of isopropenyl ethers 58-61.6 At 80 C the 4,4-dialkyl derivative 61 reacts roughly twice as fast as the 4-alkyl-4-(trifluoromethyl) compound 60, 20 times faster than the monoalkyl derivative 59, and 550 times faster than the parent compound 58. 

Attempts to correlate structure and spectra in the case of di- and polysubstituted compounds have again been largely unsuccessful. The spectra of various dialkylbenzo[6]thiophenes are very similar to those of monoalkyl derivatives, except that the bathochromic shift relative to benzo[6]thiophene is more pronounced.104 134-187 It is claimed that the sharp peaks in the 290-305 nip. region of the spectra of 5-substituted 2,3-dialkylbenzo[6]thiophenes are replaced by points of inflection in similar 6-substituted compounds, allowing such isomers to be distinguished.81104 136 Several 2-acetyl- and 3-acetyl-... 

As a consequence, in most cases, the preparation of dialkyl isohexides is described in the literature. Some mono ethers have also been prepared, bearing different acyl groups on the second hydroxyl group of the ring system. Only very few examples of monoalkyl derivatives lacking further substituents are known. 

Roberts, W. P. Ebner, C. L. Synthesis of monoalkyl derivatives of 7,7,8,8-tetracyano-p-quino-dimefhane from 2,5-dimefhoxybenzoic add. 

Anthranilic acid derivatives are also rather poor nucleophiles. Unsubstituted anthranilic acid can be N-alkylated selectively with some electrophiles under basic reaction conditions without the formation of esters by O-alkylation (Scheme 6.9) [40], Even use of excess alkylating agent still gives reasonable yields of monoalkylated derivatives this indicates that the second N-alkylation is significantly slower than... 

Although the monoalkyl derivatives (V) are formed in reasonable yields (1 0-60%) they cannot be subjected to further alkylation by the same general procedure involving the use of secondary or primary alkyl bromides. This markedly reduced reactivity is possibly due to steric reasons. 

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