2-Bromo-4-methylpyridine-3-carbonitrile

Both columns and the coil were preheated or precooled to the appropriate temperature prior to use. The flow rates for pumps A, B, and C were set to 2.00, 0.250, and 0.250 mL/min respectively for a 4 min residence time in the heated coil. After the equilibration period, determined using the FlowCommander software, 6 × 18 mL samples were collected. Immediately after collection, 2 × 15 mL of the reaction mixture from 2 vials were charged to a mixture of AcOH (7.2 mL) and a 33 wt% HBr in AcOH solution (13.2 mL) in a round-bottom flask via syringe while stirring vigorously (three reactions from one reactor run were performed in total). A condenser was attached to the flask and the reaction was heated to 55 C for 45 min. Upon cooling the reaction to room temperature, DCM was removed in vacuo. 200 mL of water was added to the remaining solution to cause the product to precipitate out. The solution was cooled before the product was collected by vacuum filtration and dried under high vacuum over P2O5 to yield 6b as an orange solid (first two fractions: 1.61 g, 68%, second two fractions: 1.65 g, 70%, third two fractions fraction: 1.62 g, 69%). To remove the orange color, the product was passed through a silica plug using DCM as the eluent. Upon removal of the solvent in vacuo, 95% of 6b was recovered as an off-white solid.This examples shows that Scheme 2 may be used to synthesize many different 2-halonicotinonitriles . [0049] In one set of experiments, brominated versions compounds 3b-3g were synthesized beginning from compounds lb-lg using 0.1 M dichloromethane as the organic solvent and HBr as the halogen halide. The HBr was present as 33% HBr in acetic acid. To produce the enamine intermediate from the alkylidene malononitrile, 20 mol% acetic anhydride and 1.2 equivalents DMF- DMA were used. The reactions took place over about 16 to about 24 hours and were performed at 5 mmol scale. The results of this set of experiments are summarized in Table 4. [0050] In another set of experiments, brominated versions compounds 3b and 3h-3n were synthesized beginning from compounds lb and lh-ln using 1 M toluene as the organic solvent and HBr as the halide donor. The HBr was present as 33% HBr in acetic acid. To produce the enamine intermediate from the alkylidene malononitrile, 20 mol% acetic anhydride and 1.2 equivalents DMF-DMA was used. The reactions took place over about 1 to about 18 hours and were performed at 5 mmol scale. The results of this set of experiments are summarized in Table 5. [ 0051 ] Run 8 in Table 5 was an anomaly. The reaction may not have worked well in run 8 because compound In was derived from an aldehyde, whereas the other alkylidene malononitriles tested were derived from ketones. [ 0052 ] Both sets of experiments show that Scheme 2 may be used to make many different 2-halonicotinonitriles with a yield of at least about 50%. [ 0053 ] In yet another set of experiments, the 2-chloro and 2- iodo nicotinonitrile versions of compound 3b were synthesized the from the enamine compound 5. To synthesize the 2-chloro-4- methylnicotinonitrile, HC1 gas was used in place of HBr . To synthesize 2-iodo-4methylnicotinonitrile, trimethylsilyl iodide (TMSI) was blended with compound 5 in acetic acid and water to produce HI in situ. Having an iodo functional group present on the nicotinonitrile is useful for coupling transition metals to the 2-halonicotinonitrile .

Molecular Weight:197.03
XLogP3:2
Hydrogen Bond Acceptor Count:2
Exact Mass:195.96361
Monoisotopic Mass:195.96361
Topological Polar Surface Area:36.7
Heavy Atom Count:10
Complexity:160
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes