Lithium 2-aminopyridinate, reaction

A mixture containing 186 g (0.20 mol) of 2-aminopyridine, 0.55 g of lithium amide and 75 cc of anhydrous toluene was refluxed for 1.5 hours. Styrene oxide (12.0 g = 0.10 mol) was then added to the reaction mixture with stirring over a period of ten minutes. The reaction mixture was stirred and refluxed for an additional 3.5 hours. A crystalline precipitate was formed during the reaction which was removed by filtration, MP 170°C to 171°C, 1.5 g. The filtrate was concentrated to dryness and a dark residue remained which was crystallized from anhydrous ether yield 6.0 g. Upon recrystallization of the crude solid from 30 cc of isopropyl alcohol, 2.0 g of a light yellow solid was isolated MP 170°C to 171°C. 

Conversion of aromatic amines to azides was studied by Scechter et al. <2002TL8421> and these studies lead to the recognition of a new approach to tetrazolo[l,5- ]pyridine. Thus, reaction of 2-aminopyridine 142 with butyl-lithium followed by treatment with azidotris(diethylamino)phosphonium bromide gave rise to tetrazolo[l,5- ]pyr-idine 1 in 80% yield. The first intermediate is obviously the azide 7. 

The benzotriazole derivatives 101 (R1 = alkyl) formed from aliphatic aldehydes, ben-zotriazole and primary aromatic amines are reduced by lithium aluminium hydride or sodium borohydride to secondary amines 102, while Grignard reagents yield compounds of type 103116. The reaction has been used for the side-chain alkylation of 2-aminopyridine (equation 42) (direct alkylation occurs predominantly at the ring nitrogen atom). 

An alternate approach, which utilizes lithium amides such as lithium hexamethyldisilazide or lithium amide, was also efficient in converting 2-chloropyridine into 2-aminopyridine (7.73.), In these reactions 2-(dicyclohexylphosphino)biphenyl was used as catalyst and the silyl protecting group was removed by TBAF.94... 

We have prepared aminoborane derivatives by reaction of 2-aminopyridine with B[N(CH3)2]3 in CeHe. The nB NMR spectrum shows a broad signal (8 = 23.6) characteristic of a trisaminoborane, l3C and are also in agreement with the structure depicted in Figure 14. The same product can be obtained through the reaction of the lithium amide of 2-aminopyridine and BF3-OEt2. A model of the trisaminoborane shows that intramolecular hydrogen bonds are possible. 

New uses for pyrylium salts include their reaction with azo-methines and ammonia to give 4-aminopyridines [e.g., (22)],37 with dimethylsulphonium methylide to yield the phenol (23) and with the anion of nitromethane to form the nitrophenol (24).38 The addition of lithium phenylacetylene to 2,6-diphenylpyrylium perchlorate in boiling ether has now been shown to form the pyran (25) but in THF at room temperature a dimeric product (26) is obtained.39 Its... 

The synthesis of aminopyridine 22 is shown in Scheme 12. The synthesis starts from Boc-protected piperazine 42 and nitropyridine 43, which undergo an SnAt reaction to produce 44. The addition of lithium chloride accelerates the reaction and suppresses the formation of impurities, which can result from SnAt displacement of nitrite instead of bromide. The displacement reaction is followed by a relatively straightforward hydrogenation of the nitro group to provide aminopyridine 22. 

Early process development studies had shown that the SnAt reaction between 21 and 22 worked best when a strong base was used. Based on these early studies, a process using lithium hexamethyldisilazide (LHMDS) was developed, and was effective for the production of early clinical supplies (Scheme 14). There were, however, two major issues with this reaction. First, it required 2 equiv of base and 2 equiv of aminopyridine 22. Second, the aminopyridine 22 needed to be treated with LHMDS, followed by portion-wise addition of chloropyrimidine 21. The requirement for 2 equiv of base was due to the increased acidity of the product 20 relative to the starting material 22. The requirement for 2 equiv of 22 was less obvious, but additional studies eventually revealed that this second equivalent of deprotonated 22 was acting as a weaker second equivalent of base (relative to LHMDS). This was important because both the chloropyrimidine 21 and the product 20 are unstable to LHMDS. 

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