Diazonium salts chlorination

The diazonium salts usually decompose when warmed with water to give a phenol and nitrogen. When treated with CuCl, CuBr, KI, the diazo group is replaced by chlorine, bromine or iodine respectively (Sandmeyer reaction). A diazonium sulphate and hydroxyl-amine give an azoimide. The diazonium salt of anthranilic acid (2-aminobenzoic acid) decomposes to give benzyne. ... 

Copper 1) chloride, bromide and cyanide were used by Sandmeyer to introduce a chlorine, a bromine atom and a cyanide group respectively into a benzene ring by addition to the phenyl diazonium salt. 

Replacement of chlorine on the pendant benzoyl group by azide is apparently consistent with antiinflammatory activity. Acylation of indomethacin intermediate with p-nitrobenzoyl chloride leads to the corresponding amide (7). Saponification ( ) followed by reduction of the nitro group gives the amine 9. The diazonium salt (10) obtained on treatment with nitrous acid is then reacted with sodium azide there is thus obtained zidomethacin (11). 

Bromination of 136 in methanol gave the 3-bromo derivative, identical with the product of Sandmeyer reaction of the 3-diazonium salt. When the reactive 3-position was blocked, electrophilic bromination would not take place (66JOC265). Chlorination appears to occur by addition [83AHC(34)79], and perhalides are known [84MI25 90AHC(47)1]. Activating substituents are able to induce some bromination in the pyridine ring. 

In the isomer (156) (and its 4-amino and 4-oxo derivatives) 3-bromination also occurred [82CHE753 87AHC(41)320]. The 4-bromo compound was made in 40% yield from the diazonium salt (82CHE753), whereas a 3-oxo function was replaced by chlorine in the usual way [92JCS(P1)239]. 

Butadienes are arylated in the 1-position and add the chlorine in the 4-position, thus yielding 2-butene derivatives. The double bond in 2-butene is much less reactive than those in 1,3-butadiene, and therefore the latter does not form diarylbutane derivatives when more than one equivalent of the diazonium salt is present. An extensive study of the effects of reaction conditions on Meerwein reactions with butadiene was made by Dombrovskii and Ganushchak (1961). 

Treatment of diazonium salts with cuprous chloride or bromide leads to aryl chlorides or bromides, respectively. In either case the reaction is called the Sandmeyer reaction The reaction can also be carried out with copper and HBr or HCl, in which case it is called the Gatterman reaction (not to be confused with 11-16). The Sandmeyer reaction is not useful for the preparation of fluorides or iodides, but for bromides and chlorides it is of wide scope and is probably the best way of introducing bromine or chlorine into an aromatic ring. The yields are usually high. 

The chlorine can be disconnected with the alternative polarity via the diazonium salt to amine (19) (guideline 4), The amino group is more powerfully electron-donating than OMe so we can disconnect the NO group. The amino group is itself derived from another nitro group. 

Entries 7 and 8 illustrate conversion of diazonium salts to phenols. Entries 9 and 10 use the traditional conditions for the Sandmeyer reaction. Entry 11 is a Sandmeyer reaction under in situ diazotization conditions, whereas Entry 12 involves halogen atom transfer from solvent. Entry 13 is an example of formation of an aryl iodide. Entries 14 and 15 are Schiemann reactions. The reaction in Entry 16 was used to introduce a chlorine substituent on vancomycin. Of several procedures investigated, the CuCl-CuCl2 catalysis of chlorine atom transfer form CC14 proved to be the best. The diazonium salt was isolated as the tetrafluoroborate after in situ diazotization. Entries 17 and 18 show procedures for introducing cyano and azido groups, respectively. 

Arylation of activated double bonds with diazonium salts in the presence of copper catalysts is known as the Meerwin reaction. The reaction is postulated to either proceed through an organocopper intermediate or through a chlorine atom transfer from chiral CuCl complex to the a-acyl radical intermediate. Brunner and Doyle carried out the addition of mesityldiazonium tetrafluoroborate with methyl acrylate using catalytic amounts of a Cu(I)-bisoxazoline ligand complex and were able to obtain 19.5% ee for the product (data not shown) [79]. Since the mechanism of the Meerwin reaction is unclear, it is difficult to rationalize the low ee s obtained and to plan for further modifications. 

Aiyl fluorides and iodides cannot be prepared by direct halogenatlon. The cyano group cannot be Introduced by nucleophilic substitution of of Aromatic chlorine in chlorobenzene but cyanobenzene can be easily obtained from diazonium salt. 

Chlorotoluene has been obtained by the action of chlorine on toluene in the presence of various catalysts 5 by the action of sulfuryl chloride on toluene in the presence of aluminum chloride 6 by the electrolytic reduction of -chlorobenzalde-hyde 7 by the diazotization of -toluidine followed by replacement of the diazonium salt group with chlorine.8... 

In pyrazolium salts chlorine can be displaced quite readily by iodide (77BSF171), and Sandmeyer reactions have found application in the preparation of iodopyrazoles from their diazonium salts [90AHC(48)65 90JAP(K)02/304064]. 

Nucleophilic processes that introduce chlorine include displacement of diazonium functions, but these are not well known in the imidazoles because of the instability of many simple aminoimidazoles. In one instance the lack of success may have been a function of the high stability of 5-ethoxycarbonyl-4-diazoimidazole. Other 1-substituted 4-diazonium salts showed expected reactivity, and 1-substituted 5-aminoimidazoles formed sufficiently reactive diazonium salts to give good yields of the 5-chloro compounds [80JCS(P1)2310]. Most of the thrust in this reaction strategy has focused on the preparation of fluoroimidazoles (see B,2,d). 

As diazonium tetrafluoroborates are more soluble in strongly acidic media, the precipitation of the diazonium tetrafluoroborate from an auxiliary diazonium salt and alkaline tetrafluoroborate is preferred when the diazonium tetrafluoroborate is thought to be too soluble an increase of the ionic strength tends to decrease its solubility.3-129 However, some alkaline chloride can co-precipitate with the diazonium tetrafluoroborate. Consequently, the diazonium tetrafluoroborate yields can be a little optimistic and some chlorinated aromatics can be produced together with fluorinated aromatics during the dediazoniation step.3,171 To prevent such contamination, the diazonium tetrafluoroborate is washed with the minimum amount of chilled water, then with another polar solvent, such as an alcohol, and finally with a water-insoluble solvent, such as diethyl ether. When their decomposition points are not too low, diazonium tetrafluoroborates can also be purified by rccrystallization (in water or acetic acid) or by dissolution in acetone then salting out with diethyl ether.3... 

Except for carbon tetrachloride, aliphatic chlorinated solvents cannot generally be employed since they react with the diazonium salt to generate chloroaromatics along with the expected fluoroaromatics (PhCl/PhF 46 54 in 1,2-dichloroethane5 and 66 34 in CHjClj11). 

The Meerwein arylation is at least formally related to the atom transfer method because a net introduction of an aromatic ring and a chlorine across a double bond is accomplished (Scheme 62). Facile elimination of HC1 provides an efficient route to the kinds of substituted styrenes that are frequently prepared by Heck arylations. Standard protocol calls for the generation of an arene diazonium chloride in situ, followed by addition of an alkene (often electron deficient because aryl radicals are nucleophilic) and a catalytic quantity of copper(II) chloride. It is usually suggested that the copper salt operates in a catalytic redox cycle, reducing the diazonium salt to the aryl radical as Cu1 and trapping the adduct radical as Cu11. 

It has been demonstrated that the presence of chlorine or bromine in the nucleus facilitates replacement of the diazo group by hydrogen little or no ether formation occurs.26 Apparently iodine also favors the redudng action of alcohols, but this point has not been investigated carefully.26 27 No attempts to deaminate fluorinated amines are recorded. Representative of the effitiency with which ethanol reduces diazonium salts derived from halogenated amines are the deaminations of m-chloroaniline 26 (87% yield), of 2-bromo-4-methylaniline 28 (67% yield), of 2,4,6-tribfomoaniline 29 (ca. 80% yield), and of 2-carboxy-4-iodoaniline30 (ca. 45% yield) in the biphenyl series the deamination of VIII in 53% yield 31 may be dted. 

As has already been noted in the section on ethanol deaminations, upon diazotizing some nitroamines in hydrochloric acid, a diazonium salt is obtained in which the nitro group has been replaced by chlorine (pp. 272-273). Consequently, hypophosphorous acid reduction gives a deaminated product Containing chlorine in place of the nitro group. For example, when 5-amino-8-nitroisoquinoline (XVIII) is diazotized with hydrochloric acid and then treated with hypophosphorous acid, 8-chloro-isoquinohne (XIX) is obtained in 60-70% yield instead of 8-nitro-isoquinoline.86... 

Microreactors provide a safe means by which reactions, including multistage schemes, can be undertaken where, otherwise, products involving unstable intermediates may be formed. This is exemplified by Fortt who showed that for a serial diazonium salt formation and chlorination reaction performed in a microreactor under hydrodynamic pumping, significant yield enhancements (15-20%) could be observed and attributed them to enhanced heat and mass transfer [77]. This demonstrates the advantage of microreactor-based synthesis where diazonium salts are sensitive to electromagnetic radiation and static electricity, which in turn can lead to rapid decomposition. Microreactors facilitate the ability to achieve continuous-flow synthesis, which is often not possible with conventional macroscale reactors and batch production. 

Frequently, by treatment with weak alkali, an ortho sulfo or nitro group, or a chlorine atom, in a diazonium salt is smoothly replaced by the hydroxyl group. 

SAFETY PROFILE Poison by intravenous route. Moderately toxic by ingestion and intraperitoneal routes. Human teratogenic effects by ingestion developmental abnormalities of the endocrine system. Experimental teratogenic and reproductive effects. Mutation data reported. Explosive reaction with charcoal + ozone, trifluoroacetyl hypofluorite, fluorine perchlorate. Violent reaction or ignition on contact with diazonium salts, diisopropyl peroxydicarbonate, bromine pentafluoride, chlorine trifluoride. Incompatible with oxidants, BrFs, FCIO, metallic salts, calomel. When heated to decomposition it emits very toxic fumes of K20 and I . See also IODIDES. 

A diazonium salt reacts with copper(I) chloride or copper(I) bromide to form an aryl chloride or aryl bromide, respectively. This is called the Sandmeyer reaction. It provides an alternative to direct chlorination and bromination of an aromatic ring using CI2 or Br2 and a Lewis acid catalyst. 

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