2- Chloropyridine, nucleophilic displacement

Due to the electronegativity of the two nitrogen atoms, pyrimidine is a deactivated, rc-electron-deficient heterocycle. Its chemical behavior is comparable to that of 1,3-dinitrobenzene or 3-nitropyridine. One or more electron-donating substituents on the pyrimidine ring is required for electrophilic substitution to occur. In contrast, nucleophilic displacement takes place on pyrimidine more readily than pyridine. The trend also translates to palladium chemistry 4-chloropyrimidine oxidatively adds to Pd(0) more readily than does 2-chloropyridine. 

In contrast with the azoles, diazoles and their benzo derivatives tend to react with dichlorocarbene to yield the tris(diazolyl)methanes, presumably via the initial formation of the N-dichloromethyl derivative [6, 13]. Only in more activated polymethyl derivatives does reaction occur at a ring carbon atom. In a similar manner (7.7.1.B), 2-chloropyridine and 2-chloroquinoline react with dichlorocarbene at the ring nitrogen atom to yield, after nucleophilic displacement of the chloro group, the 1 -dichloromethyl-2-oxo derivatives (13-25%) [14] (Scheme 7.38). 2-Chlorobenzothiazole reacts in an analogous manner, but other pyridine and quinoline derivatives fail to react. It is also noteworthy that the dichloromethyl group is unusually stable and is not converted into the formyl group. 

Just as in benzene chemistry, all types of halogen atom are activated toward nucleophilic displacement by the presence of other electron-withdrawing substituents. This is illustrated by the conversion of 5-nitro-2 chloropyridine (916) to the 2-hydrazine derivative (N2H4, 20°C) and the 2-thione (917) under relatively mild conditions. 

All four isomeric selenolopyridines which can be derived from benzoselenophene (423— 426 Scheme 123) have been described. Ethyl 3-hydroxyselenolo[2,3-fe]pyridine-2-carboxy-late (429) has been prepared as shown in Scheme 124 (73BSF704). Treatment of ethyl 2-chloropyridine-3-carboxylate with methaneselenol yields (427). Nucleophilic displacement of bromine in bromoacetic acid with subsequent loss of methyl bromide yields (428), which after esterification is cyclized under Dieckmann conditions to give (429). The parent compound (423 colorless oil with b.p. 92 °C/1 mmHg) is prepared either by cyclization of compound (430) and subsequent decarboxylation of the intermediate acid (equation 57) or by reduction of 2-nitroselenophene and subsequent condensation of the amino compound with malonaldehyde bis(diethyl acetal) in the presence of zinc chloride (equation 58) (76BSF883). Selenolo[3,2-6]pyridine (426 b.p. 127-129°C/10 mmHg m.p. 35.5-37.0°C) has been obtained in an analogous manner. 

Methods based on the pyridine to thieno[3,2-c]pyridine transformation are less well developed. Most of the above-described procedures are based on the nucleophilic displacement of the substituent at position 4 of the pyridine ring with a sulfur-containing fragment followed by cyclization of the resulting product. For example, the reaction of 4-chloropyridines 286 with methyl thioglycolate produced 287 and 288 in one step as a result of the replacement of the chlorine atom and Thorpe or Thorpe Dieckmann cyclization (1987JHC85). 

Extending these studies to pyridine 1-oxides, Dinan and Tieckel-mann investigated the behavior of 2-allyloxypyridine-l-oxide.6 The ether was prepared by nucleophilic displacement of chlorine from 2-chloropyridine-1-oxide by sodium allyloxide. Rearrangement of this compound was complete within 3 hours at 100°. Essentially quantitative yields of l-allyloxy-2-pyridone were obtained [Eq. (4)]. 

In a contemporaneous investigation, Thyagarajan et al.l prepared the two ethers 4-allyloxypyridine-l-oxide and 4-cinnamyloxypyri-dine-1-oxide by nucleophilic displacement of either 4-nitro- or 4-chloropyridine-1-oxide at room temperature using the appropriate alkoxides. However, attempts to rearrange the ethers led to much tar formation and little tractable material. 

Pyridones can also be converted to 2-chloropyridines by exchanging the carbonyl functionality using phosphoroxychloride (POCI3) [72]. A combination of N-halosuccinimides and triphenylphosphine has also been applied to introduce halogens in this position [73]. The carbonyl functionality in 2-pyridones makes these systems reactive towards nucleophiles as well, which add in 1,4-reactions with displacement of halides [74]. The use of transition metal mediated couplings like Heck, and Suzuki have also been successfully applied on halogenated 2-pyridones (d. Scheme 10) [36,75]. 

Azaperone (128) is yet another of the tranquilizers related to haloperidol. Nucleophilic aromatic displacement of 2-chloropyridine by piperazine leads to amine 126 which is then alkylated in turn by 4-chloro-p-fluorobuterophenone (127) to give... 

Reactivity increases in the diazines as compared with pyridines. 3-Chloropyridazine (910) and 2-chloropyrazine, for example, undergo the usual nucleophilic replacements (cf. Section 3.2.3.10.6.ii) rather more readily than does 2-chloropyridine. 2-, 4- and 6-Halogen atoms in pyrimidines are easily displaced. The reactivity of halogens in pyridazine 1-oxides toward nucleophilic substitution is in the sequence 5 > 3 > 6 > 4. 

A convenient one-step conversion of moderately activated nitroarenes to phenols was achieved in DMSO via nucleophilic nitrite displacement by the anion of an aldoxime.153 TTie resulting O-arylaldox-ime is rapidly cleaved to the phenol derivative under the reaction conditions. The reaction is also applicable to activated fluorides and even to 2-chloropyridine which, at 110 °C, is converted to 2-pyridone in 72% yield.153 A somewhat related process concerns the synthesis, in 82-92% yield, of 4-alkoxybenzoni-triles (45 R = Me, CH2-oxirane, CHrfh, CHMeCTfcMe from O-alkyl-4-nitrobenzaldoximes (44) via hydride-induced elimination of the alkoxide followed by alkoxy denitration (Scheme 17).154... 

In some, apparently straightforward, displacements, more detailed mechanistic study reveals the operation of alternative mechanisms. For example the reaction of either 3- or 4-bromopyridine with secondary amines in the presence of sodamide/ sodium t-butoxide, produces the same mixture of 3- and 4-dialkylaminopyridines this proceeds via an elimination process (Sn(EA) - Substitution Nucleophilic Elimination Addition) and the intermediacy of 3,4-didehydropyridine (3,4-pyr-idyne)." That no 2-aminated pyridine is produced shows a greater difficulty in generating 2,3-pyridyne, it can however be formed by reaction of 3-bromo-2-chloropyridines with butyllithium" or via the reaction of 3-trimethylsilyl-2-trifluoromethanesulfonyloxypyridine with fluoride." ... 

The chloro substituent in 2-chloropyridines has been displaced using sulfur nucleophiles, 4-methoxybenzylthiol (94SST21), 4-chlorobenzylamine (94JHC(31)73>, and 2,2,2 trifluoroethanol (Scheme 35) <94JFC(67)57). 

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