Ring side reactions

Upon nitration of phthalazines a nitro group is introduced only into the carbocyclic ring. Side reactions occur frequently. For example, nitration of phthalazine or its 1-methyl analog with potassium nitrate in concentrated sulfuric acid gives the 5-nitro derivative (100) as the main product together with 5-nitrophthalazin-l(2H)-one (101) as a by-producf (Scheme 27). 

Manufacture and Processing. Mononitrotoluenes are produced by the nitration of toluene in a manner similar to that described for nitrobenzene. The presence of the methyl group on the aromatic ring faciUtates the nitration of toluene, as compared to that of benzene, and increases the ease of oxidation which results in undesirable by-products. Thus the nitration of toluene generally is carried out at lower temperatures than the nitration of benzene to minimize oxidative side reactions. Because toluene nitrates at a faster rate than benzene, the milder conditions also reduce the formation of dinitrotoluenes. Toluene is less soluble than benzene in the acid phase, thus vigorous agitation of the reaction mixture is necessary to maximize the interfacial area of the two phases and the mass transfer of the reactants. The rate of a typical industrial nitration can be modeled in terms of a fast reaction taking place in a zone in the aqueous phase adjacent to the interface where the reaction is diffusion controlled. 

The third and newest modified natural mbber available is epoxidized natural mbber (ENR). This modification was actually discovered as early as 1922 (50), although the elimination of ring opening and side reactions to give a purely epoxidized material took another 50 years or so to achieve (51). The resulting polymer is a new material, with properties totally different from natural mbber, as iadicated ia Table 5. 

Nitro groups in the pyridine ring are reduced to amines catalytically, but side reactions can occur with dithionite, leading to, e.g. (92) (75JOC3608). 

The only synthesis which corresponds with this description formally, though not mechanistically, resulted in formation of (385) from a side reaction in the attempted esterification of the pyridinone acid (383) with diazoethane, via ring expansion of the putative intermediate (384) (76CPB1870). 

Treatment of thiiranes with lithium aluminum hydride gives a thiolate ion formed by attack of hydride ion on the least hindered carbon atoms (76RCR25), The mechanism is 5n2, inversion occurring at the site of attack. Polymerization initiated by the thiolate ion is a side reaction and may even be the predominant reaction, e.g. with 2-phenoxymethylthiirane. Use of THF instead of ether as solvent is said to favor polymerization. Tetrahydroborates do not reduce the thiirane ring under mild conditions and can be used to reduce other functional groups in the presence of the episulfide. Sodium in ammonia reduces norbornene episulfide to the exo thiol. 

Because of side reactions which break the ring the ultimate polymers are more likely to be linear. 

Whilst reaction can take place in the absence of catalysts it is more common to use such materials as tetra-alkylammonium halides and tertiary amines such as triethylenediamine. A major side reaction leads to the production of isocyanurate rings, particularly in the presence of tertiary amines. 

The most frequently encountered examples of cyclopropyl ring opening reactions in the steroid field are usually associated with angular or side chain methylation sequences. In fact, isotope labeling of the C-19 angular methyl group is the only reported application of this reaction for deuteration or tritiation pui poses. 

Alcoholic potassium hydroxide or sodium hydroxide are normally used to convert the halohydrins to oxiranes. Other bases have also been employed to effect ring closure in the presence of labile functional groups such as a-ketols, e.g., potassium acetate in ethanol, potassium acetate in acetone or potassium carbonate in methanol.However, weaker bases can lead to solvolytic side reactions. Ring closure under neutral conditions employing potassiunT fluoride in dimethyl sulfoxide, dimethylformamide or A-methyl-pyrrolidone has been reported in the patent literature. 

The common side reaction in most thermal studies of fluorine-substituted cyclopropanes is difluorocarbene extrusion Increasing the number of fluonne substituents on the cyclopropane ring significantly increases the rate of difluorocarbene extrusion [135, 136, 137]... 

The Cornforth rearrangement involves the thermal interconversion of 4-carbonyl substituted oxazoles, with exchange between the C-C-O side-chain and the C-C-O fragment of the oxazole ring. These reactions generally involve compounds where a heteroatom (-OR, -SR, -Cl) is attached to the 5-position (R2) of the starting oxazole. 

It has been shown that acetamidothiophenes 22 can be converted to either chlorothieno[2,3-h]pyridines 23 or chlorothieno[2,3-h]pyridinecarboxaldehydes 24 using POCI3 and DMF by appropriate choice of reaction conditions. However, unlike the acetanilides, initial ring formylation rather than side-chain formylation is believed to lead to the formation of the pyridine ring. These reactions have been extended to the synthesis of the isomeric thieno[3,2-I>]- and thieno[3,4-I>]pyridines, 25 and 26, from 3-acetamidothiophene and 3-acetamido-2,5-dimethylthiophene, respectively. 

There are very few homolytic reactions on triazolopyridines. A suggestion that the ring opening reactions of compound 1 involved free radical intermediates is not substantiated (98T9785). The involvement of radical intermediates in additions to ylides is discussed in Section IV.I. The reaction of radicals with compound 5 and its 1-substituted derivatives gives 4-substituted compounds such as 234 (96ZOK1085). A more detailed study of the reaction of the 1-methyl and 1-phenyl derivatives with r-butanol and ammonium persulfate produced 4-methyl substitution with a silver nitrate catalyst, and the side chain alcohol 235 without the catalyst (96ZOK1412). 

As a result of various side reactions, the yields are relatively low. However, in no case was ring fission found during the oxidations. Specially noteworthy is the ease with which the two methine groups in the 5-position of the 2-hydrazino-selenazoles are coupled together. Reference to models indicates that the quinonoid dyes exist in the trans form. 

The Diels-Alder reaction is the most important method for the construction of six-membered rings. For example it can be used as a step in a benzo-anellation procedure. The experimental procedure is simple, and yields are generally good side reactions play only a minor role. 

Various side-reactions may be observed with the Demjanov reaction the Tiffeneau-Demjanov reaction usually gives better yields of the ring-enlarged product. 

A special technique was necessary to obtain good yields of ethyl pyrrole-3-acetate from ethyl pyrrole-3-glyoxalate. Reduction over W-7 Raney Ni in 50% aq ethanol was accompanied by major ring reduction and tarring. By use of a two-phase system, toluene and 50% aq ethanol, these side reactions could be curtailed. Apparently the desired product was removed effectively from the aqueous layer into the toluene as soon as it was formed (26). 

Platinum, especially as platinum oxide, has been used by many investigators. If this catalyst contains residual alkali, it is apt to be ineffective for aromatic ring reduction unless an acidic solvent is used (1,3,19) or unless the compound also contains a carbonyl group, as in acetophenone, where 1,4-and 1,6-addition are possible (46). Nickel, unless especially active, requires vigorous conditions—conditions that may promote side reactions. 

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