1-BOC-ISONIPECOTIC ACID HYDRAZIDE

Atert-Butyl 4-(hydrazinylcarbonyl)piperidine-1-carboxylate; 10.0 g (38.9 mmol) of 1-tert-butyl 4-ethyl piperidine-1, 4-dicarboxylate were initially charged in 35 ml of ethanol, and 3.8 ml (3.90 g, 78 mmol) of hydrazine hydrate were added with stirring. The mixture was stirred at reflux for 9 h. The reaction mixture was cooled to RT, 1.9 ml (39 mmol) of hydrazine hydrate were added and the reaction solution was stirred at reflux for another 24 h. The solvent was concentrated, ethanol (50 ml) was added and the mixture was concentrated again. Diethyl ether (150 ml) was added, and the mixture was stirred in an ultrasonic bath for 5 min. The product was filtered off and dried. This gave 9.20 g (97percent of theory) of the product.LCMS (Method 6): RTo 1-tert-butyl 4-ethyl piperidine-1, 4-dicarboxylate (4.96 g, 19.3 πtmol) in methanol (20 mL) was added hydrazine hydrate (5 mL) and the mixture was heated to reflux for 3 days . The mixture was concentrated to dryness to give tert- butyl 4- (hydrazinocarbonyl)piperidine-l-carboxylate as a white crystalline solid (4.2 g, 90percent) : To a solution of 1-(tert-butyl) 4-ethyl piperidine-1, 4-dicarboxylate (5g, 19.4mmol) in EtOH (5OmL) was added hydrazine hydrate (9.7g, 19.4mmol) dropwise. The mixture was refluxed for 16 h. The TLC showed reaction to be complete. The solvent was removed under reduced pressure. The residue was triturated with Et20 (lOOmI) to afford tert-butyl 4-(hydrazinecarbonyl) piperidine- 1 -carboxylate as off white solid. Yield: 4.lg (87percent); 1H NMR (400 MHz, DMSO-d6): 8.99 (5, 1H), 3.91 (bs, 6H), 2.67 (bs, 2H), 2.17-2.25 (m, 1H), 1.56-1.61 (m, 2H), 1.44 (5, 9H); MS (ESl+) for CHNOS m/z 244.31 [M+H].To a solution of 1-tert-butyl 4-ethyl piperidine-1, 4-dicarboxylate (2.00 g, 7.77 mmol) in EtOH (26 mL) was added hydrazine hydrate (5.84 g, 117 mmol) at room temperature. Intermediate 63: 4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl esterTo a stirred solution of 1-ferf-butyl 4-ethylpiperidine-1 , 4-dicarboxylate (10 g, 38.9 mmol, 1.0 eq) in EtOH (100 mL) was added hydrazine hydrate (18.67g, 389 mmol, 10 eq.) and the mixture was refluxed for 8 h. The reaction was cooled to room temperature and evaporation of the solvent gave a viscous liquid which was dissolved in CHN- t-butoxycarbonyl-4-piperidine carboxylic acid methyl ester 2g (7.77mmol) was dissolved in ethanol and hydrazine hydrate (1: 1) mixed solvent (30 mL), and stirred at room temperature overnight. Ethanol was concentrated to dryness, added water (50mL) in dichloromethane (50mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid 1.8g, 95percent yield.To a stirred solution of 1-(tert-butyl) 4-methyl piperidine-1, 4-dicarboxylate (1.2 g, 0.49 mmol) in methanol (20 mL) was added hydrazine (2 mL) at room temperature. The reaction was stirred for 16 h at same temperature. The reaction was worked up via standard methods to afford tert-butyl 4- (hydrazinecarbonyl)piperidine-1-carboxylate (1.0 g, 83percent) as an off white gummy solid.6.0.1.23.01 4-Hydrazinocarbonyl-piperidine- 1-carboxylic acid tert-butyl ester 100 g piperidine-1, 4-dicarboxylic acid 1 -tert-butyl ester was dissolved in 100 mL methanol and 100 mL hydrazine mono hydrate was added. The mixture was reflux overnight. The reaction was cooled to RT and then the solvent was removed under vacuum to give 95 g of the desired product. RTo a mixture of General procedure: To a solution of 1 (1.0 mmol) in DMF (1.0 mL), TBSOTf (1.0 mmol) was added at room temperature. After stirring for 20 h, the volatiles were evacuated, and the residue was directly chromatographed (eluent: dichloromethane:methanol, 20:1, v/v) to obtain 2 as a white solid.General procedure: After analysis of the reaction mixture screening, several acylhydrazoneswere selected for larger-scale synthesis and purification.The required hydrazides (14.7-35.0 mg, 0.0932-0.138mmol)were weighed into 0.5mL Eppendorf tubes. To indole aldehyde 1(285mg, 1.13mmol), was added DMSO-d6 (1.885 mL, 600mM).Then, the aldehyde stock solution was added to each hydrazide, resulting in 1.05 equivalents of hydrazidewith respect to aldehyde.The Eppendorf tubes were mixed, shortly centrifuged and thenplaced in a pre-heated 90 C aluminum heating block overnight.The yellow solutions were allowed to cool down to room temperature, mixed, shortly centrifuged and then added dropwise toice-cold demi water (1500 mL). After mixing, the suspensions werecentrifuged at 12.5 103 g at 5 C for 10 min. The pale yellowaqueous DMSO layer was removed and in order to remove theremaining DMSO, the solids were washed with ice-cold demiwater (2 1200 mL; including mixing, sonication and centrifugation).Then, the remaining hydrazide was removed by washing thesolids with ice-cold absolute EtOH (3 1.2mL, same procedure aswith water). The solids were dried under high-vacuum until nomore weight loss was observed, resulting in product (yield62-92%) with purity 95% as confirmed by qHNMR (see supportinginformation) [14].

Molecular Weight:243.30
XLogP3:0.1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:243.15829154
Monoisotopic Mass:243.15829154
Topological Polar Surface Area:84.7
Heavy Atom Count:17
Complexity:291
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes