1-Boc-3-methylideneazetid...

A mixture of potassium /e/t-butoxide (15.5 g, 137 mmol) and methyltriphenylphosphine bromide (49 g, 137 mmol) in diethyl ether (300 mL) was stirred at room temperature for 1 hour, followed by the addition of 1, 1-dimethylethyl 3-oxoazetidine- 1 -carboxylate (10 g, 58 mmol in 100 mL diethyl ether). The mixture was stirred at 35 °C for 2 hours and then allowed to cool to room temperature. The mixture was filtered through a pad of celite, washing with diethyl ether. The filtrate was partitioned with water and washed twice with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an orange oil which was purified by column chromatography. Eluting with 10percent ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 9.80 g, 58 mmol (100percent) of 1, 1-dimethylethyl 3 -methylideneazetidine- 1-carboxylate as a colorless oil. A mixture of potassium ter/-butoxide (15.5 g, 137 mmol) and methyltriphenylphosphine bromide (49 g, 137 mmol) in diethyl ether (300 mL) was stirred at room temperature for 1 hour, followed by the addition of 1, 1-dimethylethyl 3-oxoazetidine-l-carboxylate (10 g, 58 mmol in 100 mL diethyl ether). The mixture was stirred at 35 A mixture of potassium tert-butoxide (15.5 g, 137 mmol) and methyltriphenylphosphine bromide (49 g, 137 mmol) in diethyl ether (300 mL) was stirred at room temperature for 1 hour, followed by the addition of 1, 1 -dimethyl ethyl 3-oxoazetidine- 1-carboxylate (10 g, 58 mmol in 100 mL diethyl ether). The mixture was stirred at 35 °C for 2 hours and then allowed to cool to room temperature. The mixture was filtered through a pad of celite, washing with diethyl ether. The filtrate was partitioned with water and washed twice with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an orange oil which was purified by column chromatography. Eluting with 10percent ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 9.80 g, 58 mmol (100percent) of 1, 1-dimethylethyl 3-methylideneazetidine-l-carboxylate as a colorless oil. 3-(3-Chlorophenyl-ethynyl)-7-(6-methyl-3-nitro-2-pyridyl)-l-oxa-2.7-diazaspiro[4.31oct-2-ene l-(t.butoxycarbonyl)-3-methylene-azetidine (Compund 28a)To a suspension of methyltriphenylphosponium bromide (1.56 g, 4.37 mmol) in 30 ml of Et20 stirred at 0°C was added potassium tert-butylate (0.459 g, 4.09 mmol). After 0.5h the cold bath was removed and the mixture was stirred for lh at r.t. Afterrwards, it was cooled off in water- ice bath, and l-(t.butoxycarbonyl)-3-azetidinone (500 mg, 2.92 mmol) was added. The cold bath was removed. After overnight resting, the reaction mixture was quenched with a saturated solution of NHA mixture of methyltriphenylphosphonium bromide (49 g, 137 mmol), potassium 2-methylpropan- 2-olate (15.5 g, 138 mmol) in tetrahydrofuran (400 mL) was stirred for 1 h at room temperature. This was followed by the addition of a solution of fert-butyl 3-oxoazetidine-l-carboxylate (10 g, 58.4 mmol) in tetrahydrofuran (100 mL) drop wise with stirring. Then the reaction system was stirred for additional 2 h while the temperature was maintained at 35 °C. The solution was diluted with water, extracted with ethyl acetate, washed with brine and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (solvent gradient: 0-10percent ethyl acetate in petroleum ether) to afford the title compound (8.0 g, 81percent) as a yellow oil. LCMS (ESI): [M+H]Step 1: Preparation of tert-butyl 3-methyleneazetidine-l-carboxylate [0217] Potassium tert-butoxide (4.27 g, 37.96 mmol) was added to a suspension of methyltriphenylphosphonium bromide (13.56 g, 37.96 mmol) in tetrahydrofuran (80 mL) and the reaction mixture was heated at 70 °C for 4 h. Then the reaction mixture was cooled to 50 °C and added a solution of tert-butyl 3-oxoazetidine-l-carboxylate (5 g, 29.2 mmol) in tetrahydrofuran (20 mL) and heated at 70 °C for 15 h. The reaction mixture was cooled to room temperature and evaporated to dryness. The crude material was purified by combiflash purifier using 4percent ethyl acetate in hexane to afford the title compound tert-butyl 3- methyleneazetidine-l-carboxylate (4 g, 80percent yield) as a colorless liquid. To a 0[0379] After potassium tert-butoxide (13.3 g) was added to a mixture of methyl(triphenyl)phosphonium bromide (38.7 g) and THF (150 mL) at 0°C, the resultant was stirred for 1 hour. A solution of tert-butyl 3-oxoazetidine-l-carboxylate (16.9 g) in THF (50 mL) was added to the reaction mixture, and the resultant was stirred for 2 hours at 50°C. After water was added to the reaction rnixture, extraction thereof was performed using ethyl acetate. The obtained organic layer was sequentially washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was dissolved into a solution in which ethyl acetate and hexane is mixed at a ratio of 1:3, the resultant was filtered using celite, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by a silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the title compound (10.9g). NMR (300 MHz, DMSO-ds) δ 1.45 (9H, s), 4.46-4.51 (4H, m), 4.96-5.02 (2H, m).Was added t-BuOK in 300ml diethyl ether (15.5g, 0.14mol) and methyl triphenylphosphonium bromide (49g, 0.14mol) at room temperature the reaction mixture was stirred1hour, then intermediate 664603 (10g, 58mmol). The reaction mixture was after thereaction was stirred for 35 2h, cooled to room temperature. Filtered, the filter cakewashed with diethyl ether. The filtrate was washed with water and brine, dried over anhydrous Na 2SO 4Dried, filtered and concentrated to give an oil product groups, columnchromatography give Intermediate 664604 (9.80g, 99percent).In a thick-wall, sealable glass reaction vessel equipped with a Teflon screwcap and a magnetic stirrer was combined 5-bromoquinoline (0.30 g, 1.4 mmol, 1 eq), /cvV-butyl 3- methyleneazetidine-l-carboxylate (0.0.37 g, 2.2 mmol, 1.5 eq) and triethylamine (0.6 mL, 4.3 mmol, 3.0 eq) in acetonitrile (3 mL). The mixture was sparged with nitrogen. Pd(OAc)2 (0.032 g, 0.14 mmol, 0.1 eq) and (o-Tol)3P (0.088 g, 0.29 mmol, 0.2 eq) were added and the reaction vessel was sealed and heated to 100 C for 19 h. The reaction mixture was cooled to RT, diluted with water and EtOAc, and filtered though celite. The organic phase was separated, washed with brine, dried over MgS04, filtered and concentrated. The crude residue was purified on silica gel to give /er/-butyl 3-(quinolin-5-ylmethylene)azetidine-l-carboxylate (0.35 g, 82% yield), LCMS: m/z = 297 [M+H]+.General procedure: Chlorofluoroacetic acid (133 mL, 1.80 mmol, 6.0 equiv) was added to a suspension of phenyliodine(III) diacetate (290 mg, 0.90 mmol, 3.0 equiv) and alkene (0.30 mmol) in THF (4.5 mL). The mixture was stirred under blue LED irradiation (SynLED photoreactor) at rt for 5 h, after which a second portion of phenyliodine(III) diacetate (290 mg, 1.80 mmol, 3.0 equiv) was added. The suspension was stirred under blue LED irradiation for another 14 h. alpha, alpha, alpha-Trifluorotoluene (123 mL, 1.00 mmol, 3.33 equiv) was added and the mixture was analyzed by 19F NMR spectroscopy. The solvents were removed in vacuo and the residue was purified by column chromatography (silica, EtOAc in heptane 0/100 to 100/0) to yield the desired product.[00741] To a solution of tert-Butyl 3-methyleneazetidine-1-carboxylate (0.413 g, 2.442 minol) in dry THF (20 mL) was added 9-BBN (6.1 mL, 6.11 minol, 1M solution in THF) and the resulting mixture was stirred for 16 hours at 6000 in a sealed reaction vial. A second reaction vial was charged with Intermediate 11(0.5 g, 1.22 minol) in DMF (9 mL) and H20 (1 mL). Then K2003 (0.51 g, 3.67 minol) was added and the mixture was degassed with nitrogen for 10 min. The above prepared BBN-complex in THF was then added at ambient temperature and again degassed with nitrogen for 10 min followed by the addition of PdCI2(dppf)DCM (0.01 g, 0.122 minol). The mixture was then heated at 8000 for 16 hours in a sealed reaction vessel. The reaction was cooled and filtered. The filtrate was diluted with EtOAc and washed with water (3 x 30 mL) and brine solution (3 x 30 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by column chromatography (eluent: 50% ethyl acetate in heptane) to afford tert-Butyl 3-(4-((5-(3-carbamoyl-5-methyl-1 Hpyrazol-1-yl)-1H-indol-1-yl)methyl)benzyl)azetidine-1-carboxylate (0.5 g, 81 %). 1H NMR (400 MHz, DMSO-d6) O 7.73-7.57 (m, 3H), 7.46 (5, 1H), 7.31 -7.18 (m, 4H), 6.59 (d, J = 4.3 Hz, 2H), 5.45 (5, 2H), 3.51 (5, 4H), 2.80-2.67 (m, 3H), 2.27 (5, 3H), 1.35 (5, 12H).

Molecular Weight:169.22
XLogP3:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:169.110278721
Monoisotopic Mass:169.110278721
Topological Polar Surface Area:29.5
Heavy Atom Count:12
Complexity:207
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes