By Direct Halogenation

This route has occasionally been followed to make both nuclear and extranuclear halogeno-1,5-naphthyridines. Some examples follow. 

The Naphthyridines The Chemistry of Heterocyclic Compounds, Volume 63, by D.J. Brown Copyright 2008 John Wiley Sons, Inc. 

5-Naphthyridine (3, Q = R = H) gave a separable mixture of 3-bromo- (3, Q = Br, R = H) and 3,7-dibromo-l,5-naphthyridine (3, Q = R = Br) (substrate, Br2, CC14, reflux, 1 h then pyridine), reflux, 12 h 27% and 10%, respectively) 173 for other procedures affording different brominated products, see Section 2.1.3. 

4-Diethoxycarbonylmethyl-l,5-naphthyridine 1-oxide (4, R = H) gave 4-(a-bromo-a,a-diethoxycarbonylmethyl)-l,5-naphthyridine 1-oxide (4, R = Br) (Br2, CHC13, reflux, 4 h 80%).814 For another example, see Section 2.2.2 

Behun and Levine (694) have shown that a,a-dichloromethylpyrazine was obtained when acetonyl- and phenacylpyrazines were treated with potassium hypochlorite. 

The reactions of various methylpyrazine A -oxides with phosphoryl chloride to 

5- Dichloro-3,6-dimethylpyrazine 1,4-dioxide with phosphoryl chloride at 170° gave 2,5-dichloro-3,6-bis(chloromethyl)pyrazine and 2,5-dichloro-3-chloromethyl-6-methylpyrazine 1-oxide and 2,5-dichloro-3,6-dimethylpyrazine 1-oxide gave 2,5-dichloro-3-chloromethyl-6-methylpyrazine (756). 

6-dimethylpyrazine and 2-chloromethyl-3-ethoxy-5-methylpyrazine (872), and 3-chloro-2,5-dimethylpyrazine 1-oxide gave 2,5-dichloro-3,6-dimethylpyrazine and 3 chloro-2-chloromethyl-5-methylpyrazine (842). 

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The tnhahdes of phosphoms usually are obtained by direct halogenation under controlled conditions, eg, in carbon disulfide solution in the case of the triiodide. Phosphoms trifluoride [7647-19-0] is best made by transhalogenation of PCl using AsF or Cap2. AH of the phosphoms tnhahdes are both Lewis bases and acids. The phosphoms tnhahdes rapidly hydroly2e in water and are volatile. Examination by electron diffraction has confirmed pyramidal stmctures for the gaseous tnhahde molecules (36). Physical properties and heat of formation of some phosphoms hahdes are hsted in Table 7. 

The best known of the hahdes are the trialkyldihalo- and triaryldihaloantimony compounds. The dichloro, dibromo, and diiodo compounds are generally prepared by direct halogenation of the corresponding tertiary stibiaes. The difluoro compounds are obtained by metathasis from the dichloro or dibromo compounds and silver fluoride. The diiodo compounds are the least stable and are difficult to obtain ia a pure state. The tri alkyl- and triaryldichloro- and dibromoantimony compounds are all crystalline soHds which are stable at room temperature that but decompose on heating ... 

In contrast to the 3-substituted products above, 4-chloro-, 4-bromo- and 4-iodo-isoxazoles are readily prepared by direct halogenation of the corresponding isoxazoles, from 4-isoxazolediazonium salts by the Sandmeyer reaction, or by reaction of hydroxylamine with a-halo- 8-dicarbonyl compounds (62HC(l7)l, p. 66, 63AHC(2)365). 3,5-Bis(dimethyl-amino)-4-fluoroisoxazole has been synthesized by reaction of (Me2NCO)2CHF with hydroxylamine (78BSB391). 

BCI3 and BBr3 are prepared on an industrial scale by direct halogenation of the oxide in the presence of C, e.g. ... 

Nitrogen forms two series of oxohalides — the nitrosyl halides XNO and the nitryl halides XNO2. There are also two halogen nitrates FONO2 (bp -46°) and CIONO2 (bp 22.3°), but these do not contain N-X bonds and can be considered as highly reactive derivatives of nitric acid, from which they can be prepared by direct halogen ation ... 

The nitrosyl halides are reactive gases that feature bent molecules they can be made by direct halogenation of NO with X2, though fluorination of NO with Agp2 has also been used and CINO can be more conveniently made by passing N2O4 over moist KCl ... 

All 4 trihalides are volatile reactive compounds which feature pyramidal molecules. The fluoride is best made by the action of CaF2, Znp2 or Asp3 on PCI3, but the others are formed by direct halogenation of the element. PF3 is colourless, odourless and does not fume in air, but is very hazardous due to the formation of a complex with blood haemoglobin (cf. 

Most halogenoalkyl- and halogenoarylquinoxalines have been made by primary synthesis (see Chapter 1) or by direct halogenation of alkyl- or arylquinoxalunes (see Section 2.2.4). However, other minor procedures may be used, as illustrated in the following classified examples. 

Although pyrrolyl halides are well-known compounds, their instability to acid, alkali, and heat precludes their commercial availability. Since pyrrole is a very reactive, Jt-excessive heterocycle, it undergoes halogenation extremely readily [6, 7], For example, the labile 2-bromopyrrole, which decomposes above room temperature, is a well-known compound, as are A-aIkyl-2-halopyrroles, readily prepared by direct halogenation, usually with NBS for the synthesis of bromopyrroles [8, 9], The 2-halopyrrole is usually the kinetic product but the 3-halopyrrole is often the thermodynamic product, and this property of halopyrroles can be exploited in synthesis. For example, A-benzylpyrrole (1) can be dibrominated to give 2 as the kinetic product, which rearranges to 3 upon treatment with acid [10, 11]. Other A-alkyl-2,5-dibromopyrroles are available in this fashion. 

Another reliable method of halopyrimidine synthesis is dehydroxy-halogenation . Refluxing pyrimidinones 10 and 13 with phosphorus oxychloride was followed by treating the resulting chloropyrimidines with hydroiodic acid to afford iodopyrimidine 11 and 14, respectively [10, 11]. 4-Chloropyrimidinone 13, on the other hand, was prepared by direct halogenation of pyrimidone 12. 

Other renewable resources sorbitol (I), cellobiose (XXV), etc. can be used in similar ways as starting materials in the preparation of epoxy resins. We are now working on a direct two-step preparation of diepoxy sorbitol derivatives by direct halogenation of the two primary hydroxyl groups with the formation of 1,6-dichloro-1,6-dideoxy-sorbitol, (XXIII), followed by epoxy ring formation (1,2 5,6-dianhydrosorbitol (XXIV) ... 

There is also an apparent trend in manufacturing operations toward simplification by direct processing. Examples of this include the oxidation of ethylene for direct manufacture of ethylene oxide the direct hydration of ethylene to produce ethyl alcohol production of chlorinated derivatives by direct halogenation in place of round-about syntheses and the manufacture of acrolein by olefin oxidation. The evolution of alternate sources, varying process routes, and competing end products has given the United States aliphatic chemical industry much of its vitality and ability to adjust to varying market conditions. 

Chloroindole has been prepared from indole and sulfuryl chloride (66JOC2627) and 3-bromo- and 3-iodo-indole have been obtained by direct halogenation in DMF (82S1096). 2-Methylindole reacts with sodium hypochlorite in carbon tetrachloride to give a 2 1 mixture of 1,3- and 3,3- dichloro derivatives (81JOC2054). 3-Substituted indoles are halogenated to yield 3-haloindolenium ions which react in a variety of ways, as illustrated by the reaction of 3-methylindole with NBS in aqueous acetic acid (Scheme 12). 

The two most common methods of preparing aryl halides are by direct halogenation of benzene and via diazonium salt reactions. 

Haloanthraquinones with additional substituents commonly are prepared by direct halogenation of the corresponding anthraquinones in water, hydrochloric acid, sulfuric acid, or organic solvents. Electron-withdrawing substituents, such as sulfonic acid or nitro groups, direct the halogenation to the other nucleus. 

With the exception of those halogenopyrazines made by primary synthesis (see Chapters 1 and 2), most chloropyrazines have been made recently by the reaction of tautomeric pyrazinones with a phosphorus chloride or by the reaction of pyrazine iV-oxides with phosphoryl chloride in contrast, most other halogenopyrazines have been made by direct halogenation or by transhalogenation of chloropyrazines. A single interesting example of the conversion of a methoxy- into a chloropyrazine is included at the end of Section 4.1.1. 

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