Preparation of halogen derivatives

The classical ambiguity between direct substitution on an aromatic system and substitution via an addition-elimination pathway [Eq. (16), Section III, A] persists for the halogenation of heterocycles under conditions of low polarity. Indeed, with suitable heterocyclic nuclei the three possibilities of substitution, addition, and addition-elimination have all been observed. From existing evidence one cannot assign as yet relative importance to these limiting cases in halogenation mechanisms. However, experimental conditions often can be regulated to favor one or other process for preparative success. These three processes will receive our attention in this review. 

Of lesser relevance to this discussion are halogenation methods involving the modification of the carbon skeleton (synthesis and degradation). The Hunsdiecker reaction, as applied to certain heterocyclic acids, has had limited application for the synthesis of halogen derivatives. The preparation of 3-bromo-4,6-dimethyl-2-pyridone from the silver salt of the respective 3-carboxylic acid by treatment with bromine in carbon tetrachloride is a rare example of success.13 The interaction of carbenes with heterocycles also has been employed infrequently, but recent advances in carbene generation may reactivate this approach.14 The Ciamician-Dennstedt ring expansion of pyrrole to / -halopyridines is a case in point18 [Eq. (4)]  

Divalent Carbon. Ronald Press, New York, 1964. 

These and other methods of introducing halogen into heterocycles, such as the transformation of a- and y-hydroxypyridinoid bases with inorganic acid halides, the treatment of pyridinoid A-oxides with sulfur or phosphorus halides, and the decomposition of diazonium compounds, are treated adequately in existing references. 

Clauson-Kaas, S.-O. Li, and N. Elming, Acta Chem. Scand. 4, 1233 (1950). 

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By preparation of halogenated derivatives, advantage may be taken of the enhanced sensitivity of the electron capture (EC) detection system in GC analysis. 

Chlorine and bromine react with the hydrocarbons to form substitution-products. As mixtures of compounds are obtained in this way the reactions are not often used in the preparation of halogen derivatives. 

Traugott Sandmeyer (Wettingen, 15 September 1854-Zurich, 9 April 1922) was Victor Meyer s lecture assistant and participated in the discovery of thiophen (see p. 810). He discovered the Sandmeyer reaction for the preparation of halogen derivatives of aromatic hydrocarbons by warming a solution of a diazonium compound with cuprous chloride and hydrochloric acid, or cuprous bromide and hydrobromic acid, or with hydriodic acid or potassium... 

Halogenated 2-propanol derivatives, eg, l,3-dichloro-2-propanol [96-23-1], are generally prepared from glycerol [56-81-5] (qv). These materials are used in the preparation of halogen-containing phosphates to plasticize and lower the flammability of plastics, eg, polyurethanes and ceUulosics. 

Halogenation. Halogens and halogen acids add readily to the unsaturated carbon linkages of the cyclopentadiene molecule. By such additions a series of halogenated derivatives range, in the case of the chloride, from 3-chlotocydopentene to tetrachlorocyclopentane. Of all the possible chloto derivatives of CPD, only hexachlorocyclopentadiene [77-47-4] ever reached commercial status. It was used as an insecticide, but this use has been discontinued because of its toxicity (see Chlorocarbons and chlorohydrocarbons, toxic aromatics). It can be prepared by a Hquid phase chlorination of CPD below 50°C (29). 

The reaction of methane tricarboxylate with indoline 342 gave the tricyclic derivative 361 which can be transformed to the amide derivatives 362 (97JHC969). Alkylation of the iV-benzyl indoline 360 with pentafluor-oacetone gave 363 which upon debenzylation and subsequent acylation with diketene followed by cyclization gave 364. Other haloacetones were used to prepare different halogenated derivatives (79BEP872311) (Scheme 63). 

The preparation of purine derivatives substituted at the C-2 position via amine displacement of a halogen is known as a difficult reaction step requiring several days of reaction time. However, Al-Obeidi and coworkers have recently prepared 2,6,9-trisubstituted purines on soUd-phase by employing a synthetic route in which the critical step was performed with microwave irradiation (Fig. 37) [62]. PS resin-bound 2-iodosubstituted purine was treated with diethanolamine or propanolamine in NMP with microwave irradiation at 200 °C for 30 min. Trifluoroacetic acid-mediated cleavage resulted in the 2-amino substituted purines in 45-59% yields and 77-89% purities. 

Another route to the preparation of Cgo derivatives involves the reaction of a halogen derivative of diethylmalonate in the presence of a strong base with fullerenes, which results in a... 

The preparation of quinoxaline derivatives carrying a substituent in the benzene ring requires suitably substituted o-phenylenediamines. These have been prepared by reductive cleavage (SnCl2) of appropriately substituted 2,1,3-benzoselenadiazoles (I9).21 Benzo-selenadiazoles, readily prepared from 1,2-diaminobenzenes and selenium dioxide, undergo halogenation at positions 4 and 7 and sulfonation at C-4. 5,6-Dichloro- 2,3-diphenylquinoxaline has been synthesized from benzil and l,2-diamino-3,4-dichlorobenzene, the diamine in turn was obtained from 4,5-dichloro-2,l,3-benzoselenadiazole.22... 

Little work has been carried out on halogenation of indolizines. Only the preparation of iodo derivatives appears to be straightforward (71MI30800). Thus iodination of the 3-position of l-acetyl-2-methylindolizine was achieved by treatment with iodine and sodium acetate (69YZ1020). 

Reductive 1,3-elimination reaction of alkyl dihalides constitutes one of the classical methods for the preparation of cyclopropyl derivatives and is particularly useful for the synthesis of highly strained polycyclic hydrocarbons. A new preparation method of [l.l.ljpropellane, more versatile than the original Wiberg s method, has been devised3,4. Thus, treatment of l,l-dibromo-2,2-bis(chloromethyl)cyclopropane with alkyllithium or lithium powder affords [1.1. ljpropellane by two successive 1,3-eliminations of halogens by way of 1 -bromo-2-(chloromethyl)bicyclo[l. 1. Ojbutane (equation 1). This method has been... 

Very little work has been carried out on halogenated compounds.4 The preparation of iodo derivatives, discussed in a recent review,178 appears to be very straightforward. Thus l-acetyl-2-methylindolizine is converted into the 3-iodo compound by iodine and sodium acetate.29... 

Nearly all the methods described in Chapter 2 have been applied for the preparation of uranium derivatives. The reaction of metallic uranium with alcohols in the presence of halogenes (method 1) doesn t lead, as it turned out, to homoleptic alkoxides, but is a facile route to alkoxide halides [79, 1669] ... 

The oxidation of halogenated toluenes and similar compounds and of compounds with side chains of the type — CH2C1 and — CH2OH proceeds comparatively smoothly with alkaline permanganate solution (for experimental details, see under Aromatic hydrocarbons, Section 9.6.3, p. 1239 and also Expt 6.149). The resulting acid may be identified by a m.p. determination and by the preparation of suitable derivatives (see Section 9.6.15, p. 1261). 

The saccharides represent a structurally diverse group of compounds, which are often derivatised with a variety of functional groups. The chemical modification of saccharides often involves the installation of a functional group that at an appropriate time can be converted into another functionality. In this chapter, synthetic methodologies for the preparation of halogenated, unsaturated and deoxygenated sugar derivatives will be discussed and furthermore methods for the introduction of amino, sulfate and phosphate moieties will be covered. 

Halogenated acyl derivatives of steroids have been applied in order to increase sensitivity of the analysis. It follows from a comparison of the ECD responses of haloacetates of steroids that the highest sensitivity can be obtained with the aid of monochloro-acetates [351]. Brownie et al. [352] applied them in the analysis of testosterone in blood. The method involves the extraction of blood plasma with diethyl ether, purification by TLC and derivatization. GC analysis is performed only after a preliminary separation on a thin layer. Preparation of the derivatives is carried out by treating a dried extract with... 

Oxidative Addition is also common for those central atoms that can increase their oxidation state (see Oxidation Number) (equations 27 and 28). Substitution of halogen by organic groups is usefiil for the preparation of organo derivatives, as mentioned in Section 3.1 (equations 12 and 13). 

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