4- Amino-2-bromo-1,5-naphthyridine

Amino-2-bromo-1,5-naphthyridine (84) may be an intermediate (see Section III,B,l,a for its formation) that undergoes a covalent amination at C-4, yielding the gem 4,4-diamino-2-bromodihydro-l,5-naphthyridinide (153) and an amino debromination at C-2, yielding 85. Ring opening of 153... 

Naphth[2,l-d]oxazolium iodide, 2,3-dimethyl-reactions, 6, 215 Naphthyridine, amino-reactions, 2, 598 Naphthyridine, N-amino-reactions, 2, 596 Naphthyridine, 3-bromo-reactions... 

The amination of 2-bromo-l,5-naphthyridine also proceeds without rearrangement to yield 2-amino-1,5-naphthyridine (up to 80%) together with 1,5-naphthyridine (10%) and a substance (CgH8N4,10% yield) of unknown structure as by-products. Thus, here also it remains uncertain whether a 2,3-aryne is an intermediate. 

Heating 6-bromo- and 6-chloro-2-halomethyl- (99JHC1065) and 6-bromo-, 6-chloro- and 6-fluoro-2-phenyl-4/f-pyrido[l, 2-u]pyrimidin-4-ones (00JMC2814) in phenyl ether at 220 °C for 10 min yielded the appropriate 7-halo-1,8-naphthyridin-4-ols. 6-Amino-2-trifluoromethyl-4//-pyrido[l, 2-a]-pyrimidin-4-one was transformed into 7-amino-2-trifluoromethyl-l,4-dihy-dro-l,8-naphthyridin-4-one in 90% yield (98EJM383). 

Amide-induced pyridine-pyrimidine transformation is also reported with 2-bromo-l, 5-naphthyridine. 2-Methyl-4-amino-l, 3,5-triazanaphtha-lene is obtained, together with its 4-amino derivative The presence of the amino group at position 4 is certainly due to a SnH amino-dehydrogenation in preformed 2-methyl-l,3,5-triazanaphthalene (63RTC997, 73RC459, 94MI1). 

However, in view of the results mentioned earlier, direct attack of the amide ion on position 2 seems highly unlikely. An Sn(ANRORC) mechanism, starting with an attack of the amide ion at position 6 containing the amino group, seems to be involved. Adduct formation at a position already occupied by an amino group is not unprecedented. The conversion of 4-amino-2-bromoquinoline into 4-amino-2-methylquinazoline (72RTC841) and of 4-amino-2-bromo-l,5-naphthyridine into 4-amino-2-methyl-l,3,5-... 

The amination products from 5-halogeno-1,7-naphthyridines include the 8-amino and the 5-halogeno-8-amino derivatives. The 2-aminodiazine is also obtained from the bromo compound. 

Czuba07 prepared 2-, 3-, and 4-bromo-1,5-naphthyridine and treated them with potassium amide in liquid ammonia. The results of this study were explained by the intermediacy of 1,5-naphthyridyne-3,4 (133)149 in the reaction of the 3- and 4-bromo derivatives. A competing addition-elimination mechanism was also suggested since the ratios of the amino products from the 3- and 4-bromo compounds were not the same.147... 

Bromo-l,5-naphthyridine (17) forms with potassium amide in liquid ammonia 6-amino-2-bromodihydro-1,5-naphthyridinide (18) as evidenced by... 

These results combined with those obtained in the aminations of the 3-halogenoquinolines (Section III,B,1) show that 3,4-didehydro-1,5-naphthyri-dine (68) is an intermediate and that 2,3-didehydro-l,5-naphthyridine does not occur, because if it had, then 2-amino- 1,5-naphthyridine should have been formed. 4-Bromo-1,5-naphthyridine (70) also gives a mixture of 69 and 49. The ratio is 77 23, which indicates that the 4-bromo compound (70) undergoes SN(AE),pso aminodebromination to 4922 in addition to an SN(EA) process via 68, yielding 49 as well as 69. 

It has been reported that 3-bromo-2-ethoxy-l,5-naphthyridine (71) with potassium amide gives as sole product the unrearranged 3-amino-2-ethoxy-... 

Convincing evidence has also been presented for the formation of the intermediate 3,4-didehydro-1-ethyl-l,5-naphthyridin-2[l//]-one (75),53 of the anion of 2-amino-3,4-didehydro-1,5-naphthyridine (76)52 and of 2-bromo-3,4-didehydro-l,5-naphthyridine (77).52... 

Bromo-l-ethyl-l,5-naphthyridin-2[l//]-one (78) with potassium amide gives a mixture of 3- and 4-amino-l-ethyl-l,5-naphthyridin-2[lH]-one (79 13% and 80 58%).53 As intermediate species 75 is proposed in which the... 

Reaction of 2-amino-3-bromo-1,5-naphthyridine (81) with potassium amide gives 2,3-diamino-1,5-naphthyridine (82), the formation of which can be explained by a site-specific addition of the amide ion to C-3 in the anionic intermediate (76).52 This addition pattern is very similar to the one observed... 

Amination of 5-bromo-l,6-naphthyridine (113) gives as tele product 2-amino-l,6-naphthyridine (51 ),24 but in addition to the intermediacy of anionic cr-adduct (114) (as proved by H-NMR spectroscopy), its formation involves anionic cr-adduct 115, which is formed by a proton shift from 114. The number of atoms between positions 2 and 5 is five, thus this reaction is referred to as an odd tele substitution. Both types of tele substitution involve Addition of the nucleophile as the initial step and Elimination of the leaving group as the last step. However, in the even tele substitution the elimination can be described to take place from a neutral dihydro species, while in the odd tele substitution the elimination must occur from an anionic intermediate. In the naphthyridines several examples of even and odd tele substitutions are found, and in the following sections the results of studies concerned with tele amination are presented. 

From the mass spectrometric data it was calculated that the 5-deutero-l-chloro compound reacted about 5 times faster in the SN(AE)lele process than in the SN(AE) pso process. The SN(AE)lcle reaction was found to have a kinetic isotope effect of 2.5. This leads to the conclusion that for the undeuterated l-chloro-2,6-naphthyridine (121 X = Cl, R = H), the S AE)16 6 substitution proceeds about 13 times faster than does the SN(AE) ps0 process, i.e., 93% of the 1-amino-2,6-naphthyridine is formed in an SN(AE) ele process. Similar results were obtained with the l-bromo-2,6-naphthyridine, although the contribution of the SN(AE)lele process in that substitution reaction was somewhat less important. 

---