3- Bromopyridines 3-amination

Amines or ammonia replace activated halogens on the ting, but competing pyridyne [7129-66-0] (46) formation is observed for attack at 3- and 4-halo substituents, eg, in 3-bromopyridine [626-55-1] (39). The most acidic hydrogen in 3-halopyridines (except 3-fluoropyridine) has been shown to be the one in the 4-position. Hence, the 3,4-pyridyne is usually postulated to be an intermediate instead of a 2,3-pyridyne. Product distribution (40% (33) and 20% (34)) tends to support the 3,4-pyridyne also. 

The first amination of a halogenopyridine involving a rearrangement was carried out by Levine and Leake in 1955 in an attempt to prepare 3-phenacylpyridine. When 3-bromopyridine (27, X = Br) was allowed to react with sodium amide in liquid ammonia in the presence of sodio-acetophenone, the reaction mixture obtained consisted chiefly of amorphous nitrogenous material from which only 10% of 4-aminopyridine (34, Y = NH2) and 13.5% of 4-phenacylpyridine were isolated. 

Ethoxy-3,4-pyridyne (46) is involved in the amination of 3- and 4-bromo-2-ethoxypyridine, and mixtures of aminoethoxypyridines of the same composition are formed in both reactions. Thus, from 4-bromo-2-ethoxypyridine only the 3-hydrogen atom, situated between the bromine and ethoxyl groups (and not the 5-hydrogen atom) is abstracted. Pyridyne 47 is an intermediate in the amination of 4- and 5-bromo-3-ethoxypyridine. In the last-mentioned substance, just as in 5- (or 3-)bromopyridine, only the 4-hydrogen atom, and not the 2-hydrogen atom, is abstracted. The amination of 3-bromo-6-ethoxypyridine proceeds via 6-ethoxy-3,4-pyridyne (48). again the 2,3-pyridyne derivative is not formed. 

Amination of derivatives of 2-bromopyridine gave, just as did the same reaction of 2-bromopyridine itself, no decisive answer concerning the mechanism of these processes, except that 2-bromo-3-ethoxy-... 

A disubstituted butyramide, disopyramide, distantly related to some acyclic narcotics interestingly shows good antiarrhythmic activity. Alkylation of the anion from phenylacetonitrile with 2-bromopyridine yields 99. Alkylation of the anion from the latter with N,N-diisopropyl-2-chloroethyl-amine leads to the amine 100. Hydration of the... 

In one case, the intermolecular Heck reaction of 3-pyridyltriflate with ethyl acrylate was accelerated by LiCl to give 159 [127,128], Here, both electronic and steric effects all favored p-substitution. In another case, however, electronic effects prevailed and complete a-substitution was observed. In the presence of an electron-donating substituent (i.e., a protected amine), 3-bromopyridine 160 was coupled with f-butoxyethylene to give 3-pyridyl methyl ketone 162 [126]. The regiochemistry of the Heck reaction was governed by inductive effects, leading to intermediate 161. 

The results obtained in the photostimulated Sj l reaction between carbanions from 2,4,4-trimethyl-2-oxazoline or 2,4-dimethylthiazole and 2-bromopyridine are also consistent with the incomplete formation of the carbanions in KNH2-NH3(ii ) system. In these cases, 2-aminopyri-dine is formed alongside the corresponding pyridyl-2-methylene oxazolinyl or thiazolyl substitution products (Wong et al. 1997). When the Sr I pathway is impeded by conducting the reaction in the dark or in the presence of di(tert-butyl) nitroxide, the ionic amination reaction dominates. 

Amination of 3-bromoisoquinoline with potassium amide/liquid ammonia involves (in contrast to the amination of 2-bromopyridine, see Section an ANRORC process. When 3-bromo[ N]isoquinoline was used as substrate, the 3-aminoisoquinoline being obtained contains 55% of its enrichment on the exocyclic nitrogen, i.e., the formation of 3-[ N-aminoJisoquinoUne (14), and 45% inside the heterocyclic ring, i.e., formation of 3-amino[ N]isoquinoline (13) (74RTC198). 

In 2006 Maes and co-workers described the intramolecular Pd-catalyzed amination of A-(2-chloropyridin-3-yl)pyr-idazin-3-amine and A-(3-bromopyridin-2-yl)pyridazin-3-amine which involves intramolecular coordination of Pd(ll) to the N-2 nitrogen of the A-arylpyridazin-3-amine entity (Equation 8). A-(2-Chloropyridin-3-yl)pyridazin-3-amine and A-(3-bromopyridin-2-yl)pyridazin-3-amine are intermediates in the auto tandem amination of 2-chloro-3-iodo-pyridine and 2,3-dibromopyridine with pyridazin-3-amine, respectively <2004CC2466, 2006JOC260>. In the former case the ring closure proceeds partly via an SNAr process. 

On the other hand, LDA metalation of 3-bromopyridine (42) at -70°C yields, after hydrolysis, a mixture of 3- and 4-substituted products (43 and 44) in addition to starting material 42 (Scheme 14) (82T3035). A potential explanation for these results involves the formation of 3,4-pyridyne, which undergoes nonregioselective attack by amine or lithio amide to give 43 and 44. An alternative rationalization is the isomerization of 42 into the 4-isomer 45 under the metalation conditions (see Section II,B,4), followed by the conversion of either isomer into the radical anions 46 which, via the caged radical pairs 47, is converted into 43 and 44 (Radical Anion-Radical Pair = RARP pathway). 

Chloroindolizine is formed in a reaction of 2-vinylpyridine with dichlorocarbene (77ACS(B)224). Af,(V-Disubstituted 3-aminoindolizines have been obtained from a reaction of 2-bromopyridine, propanol and secondary amines (79CL24 l). Irradiation of N- phenylpyr-role and N-methyldibromosuccinimide in benzene gave 18% of the indolizine (187) (80CB2884). 

The initiation by aromatic tertiary amines is affected by the type of substituent and its position in the ring. A series of meta-substituted pyridines show a higher activity than ortho- or para-substituted derivatives with electron-releasing substituents. 3-Aminopyridine is much more reactive than 2-aminopyridine and 3-methylpyridine is more effective than 2- or 4-methylpyridine 19). The strong electron-withdrawing substituent of 2-bromopyridine and its steric hindrance eliminate the effect of this amine. A 2,6-Dimethylpyridine was also found to display a steric effect. Thus, in the presence of this amine, the rate of copolymerization decreases by a factor of 4 compared with 3-methylpyridine 69). 

When 3-chloro- or 3-bromopyridine is heated with lithium piperidide and piperidine in boiling ether, 156 is formed, which reacts further with piperidine to give a mixture of 3- and 4-piperidinopyridine in the ratio of 48 52. No 2,3-pyridyne intermediate is apparently produced under these conditions.388 Such an intermediate is probably involved in the reaction of potassium amide in liquid ammonia with 3-bromo-4-ethoxypyridine, which gives 2-amino-4-ethoxypyridine (55-60%). The reaction is, however, complicated by the fact that 2-amino-5-bromo-4-ethoxypyridine (15-20%) and 4-ethoxypyridine (25%) are also obtained.387 The formation of these two by-products may proceed by the preliminary disproportionation of some 3-bromo-4-ethoxy-pyridine to 3,5-dibromo-4-ethoxypyridine and 4-ethoxypyridine.388 The remarkable observation that both 2-amino-6-ethoxypyridine (157) (85%) and 4-amino-2-ethoxypyridine (158) (15%) are formed during the amination of 2-bromo-6-ethoxypyridine367 still requires explanation. No such rearrangement is observed with lithium piperidide.3880... 

---