Reaction at the 4-Position

Aminotriazole is carboxylated at the 5-position by heating with aqueous sodium bicarbonate in a Kolbe-type reaction (7lJCS(C)l50l). 2-Thiazolinones undergo the Gatter-mann and Reimer-Tiemann reactions at the 4-position, and 3- and 4-pyrazolinone anions on alkylation give 4-alkyl as well as O- and N-alkyl derivatives. 

Kinetic studies on 2-, 3-, and 4-chloro-l-methylpyridinium salts showed a 30 10 ratio of the reaction rates at 50° with 4-nitro-phenoxide ion in methanol. The activation energy for reaction at the 4-position is one kilocalorie lower ( 8-fold higher rate) than for reaction at the 2-position. The reversal in rates relative to the corresponding halopyridines is the result of a much higher entropy of activation for the 2-chloro compound. The 3-chloro compound has a favorable entropy of activation also, but the energy of activation is about 13 kcal higher than that of the isomers (cf. Table II and Section III, A, 2). 

The reaction of 2,4,6-tribromopyridine with phenoxide ion illustrates, in our opinion, the effect of hydrogen bonding as discussed in Section II, B, 3. Reaction (150°, 24 hr) in water gave approximately equal amounts (18% yields) of 2- and 4-monosubstitution, but in phenol under the same conditions only the 2-phenoxy derivative (in high yield plus a small amount of the 2,6-diphenoxy compound) was formed. In water, reaction at the adjacent 2- and 6-position is hindered by the hydrogen bonding (cf. 61) of the solvent to the azine-nitrogen, compared to reaction at the 4-position. On the other hand, in... 

New synthetic methods are the lifeblood of organic chemistry. Synthetic efforts toward natural products often provide the impetus for the development of novel methodology. Reactive synthons derived from 1,3-dioxanes have proven to be valuable intermediates for both syn- and anfz-1,3-diols found in many complex natural products. Coupling reactions at the 4-position of 1,3-dioxanes exploit anomeric effects to generate syu-1,3-diols (cyanohydrin acetonides), autz-1,3-diols (4-acetoxy-1,3-dioxanes), and either syn- or azztz-1,3-diols (4-lithio-1,3-dioxanes). In the future, as biologically active polyol-containing natural products continue to be discovered, the methods described above should see much use. 

The extraordinary regioselectivity shown with the 2-methylthio group was not displayed by the analogous sulfone 238, which underwent exclusive reaction at the 4-position <2000SL905>. 

Palladium-catalyzed alkenylation reactions involving pyrimidines can be achieved with hydrozirconated terminal alkynes, although the reaction is carried out in the presence of zinc chloride, so transmetallation to the zinc species is presumed to occur prior to the palladium-mediated coupling <1996ACS914, B-2002MI409>. Selective reaction at the 4-position of both 2,4-dichloropyrimidine and 2,4-dichloroquinazoline can be achieved. 

The oxazolinyl group directs metallation to the adjacent position. Thus, whereas a 2-furyloxazoline undergoes Friedel-Crafts reactions at the 4-position, metallation allows the introduction of the same functional groups at the 3-position (92T149). 

The reaction of 4,5-dihydro-4//-l,2,4-thiadiazine 1,1-dioxides 142, which have a leavable group in the 3-position (Y = OR1, SR1, NH2), with two molecules of an alkyl isocyanate (RNCO) produces the condensed system 143, while the alkyl isothiocyanate yields the different condensed system 145. The former reaction apparently proceeds through intermediate 144, i.e., by reaction at the 4-position. On the other hand, the first molecule of the isothiocyanate may, by analogy, react at the 2-position via a corresponding intermediate (74BSF1917). 

Kishimoto and coworkers showed in the 70 s that for 1-naphtholate ion the reaction at the 4-position is catalyzed by a variety of bases (HjPO, HPO, AcO , pyridine and water), whereas the rate of reaction at the 2-position is almost independent of tire concentration of these bases, except water. Their results therefore coincide well with previous work. 

S Ar reactions have been studied mostly with dinitro and trinitro activated benzenes. Recently, the aniline reactions with the highly activated super-electrophile, 4,6-dinitrobenzofuroxan (DNBF), have attracted considerable attention due to its ambident reactivity114. In acidic solvent, where aniline is almost completely protonated, the reaction by nitrogen attack is inhibited. However, a carbon-carbon bonded adduct is slowly formed by reaction at the 4-position of the aniline. Kinetic studies in H2O-DMSO have shown that this adduct formation involves two steps a carbon-carbon bond formation ( a), followed by elimination of a proton, Kiep (vide infra). The reactions of anilines with DNBF in DMSO have shown that the N-bonded adduct (a-N) is kinetically preferred, but the C-bonded adduct (a-C), formed in equilibrium with its deprotonated form, is the thermodynamically favored product (Scheme 14). 

Proton acidity in oxazole follows the order C-2 > C-5 > C-4. The use of 2-lithiooxazoles in synthesis is problematic, however, because they are in tautomeric equilibrium with their open chain form. When 2-lithiooxazole was reacted with DMF at — 75°C and the mixture was warmed to RT, oxazole-2-carbaldehyde (53) was formed quantitatively. Reaction of this product with a second equivalent of lithiooxazole did not give the expected product, but rather an unsymmetrical bis(oxa-zolyl)methanol (54) <9iJOC449> (Scheme 12). Reaction at the 4 position of lithiooxazole was found to be general for aldehydes. Less reactive electrophiles, such as, DMF, benzophenone, and ethyl formate, gave 2-substituted products, and iodobutane, benzyl bromide and ethyl carbonate did not react at all after an extended age at RT. Acylation of 2-lithio-5-phenyloxazole may be accomplished using A-methyl-7V-(2-pyridinyl)-carboxamides <84S1048>. 

Part III - Surprisingly Successful Direct Electrophilic Substitutions Sulfonation and halogenation at the 3-position in strong sulfuric acid The reaction with SOCl2 reaction at the 4-position, synthesis ofDMAP Part IV - Successful Nitration of Pyridine... 

In this case an S- i reaction at the 4-position is unlikely for steric reasons. 

Reaction at the 4-position of a guaiacyl system through electrophilic substitution followed by a ring closure involving an enamine was achieved in the synthesis of 8-hydroxy-9-methoxy-4,6,11,11 a-tetrahydro-1 H-benzo[bJquinoizin-2(3H)-6-one in 68% yield from the acetal shown with methyl vinyl ketone in ether solution by interaction at ambient temperature during 24 hours (under nitrogen) followed by solvent removal and treatment with concentrated hydrochloric acid at 100 C for 30 mins (ref.72). 

Reaction at the 4-position of a veratryl ring followed by cyclisation has been observed. To 2-(3,4-dimethoxyphenyl)-N,N-dimethylacetamide in acetonitrile, phosphorus oxychloride was added and after refluxing for 6 hours more reagent was introduced and refluxing extended for 2 hours producing a 56% yield of... 

Recently, the reactivity profile of pentafluoropyridine, where reaction at the 4-position is followed by substitution at the 2- and 6-positions selectively, has been used by medicinal chemists for the synthesis of small arrays of biologically active... 

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