Highly chemo-and diastereo-selective synthesis of 2,6-diazabicyclo[3.2.0]heptan-7-ones, pyrrolidines and perhydroazirino[2,3-c ]pyrroles

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Results and Discussion
The starting materials 3-aminoazetidin-2-ones 1, used in halocyclization reactions were prepared by reported methods. 33These variably substituted 3-aminoazetidin-2-ones 1 were initially investigated for intramolecular ring closure haloamination reactions using different combinations of halogenating reagents and bases in different solvents.The reaction led to the formation of pure 4-halo-3-aryl/alkyl-6-aryl-2,6-diazabicyclo[3.2.0]heptan-7-ones 2a-m (Scheme 1, Table 1).However, the yield of halocyclized products varied with the type of solvent, base and halogen used in the reactions.The reactions were, initially optimized with different halogenation reagents viz.I2, Br2, NIS, NBS and NCS.The best yield (90%) was achieved using iodine and potassium carbonate as base (Table 1; Entry 2).The halocyclization using NIS and NBS resulted in the formation of 4-halo-3-aryl/alkyl-6-aryl-2,6-diazabicyclo[3.2.0]heptan-7-ones in considerably lower yields.The use of sodium carbonate as base in halocyclization reactions of 1 using iodine and bromine resulted in slightly lower yields of the products (Table 1, entries 6-7).When NCS was used as a haloaminating reagent the reactions did not result in the desired product; the starting material remaining intact.The halocyclization was also tested using strong bases i.e. sodium hydride and potassium-t-butoxide.However, this resulted in deterioration of the products.We also studied the effect of a substituent at the alpha position of styryl of 3-aminoazetidin-2-ones in these haloamination reactions.The reactions did not give any haloaminations even at high temperature or using harsh reaction conditions, probably due to the steric hindrance at the alpha position of styryl of 3-aminoazetidin-2-ones.
We next studied the effect of substituents of the participating nitrogen of 3-aminoazetidin-2ones in these haloamination reactions (Scheme 3).Two substituents (i) electron withdrawing (tosyl), (ii) electron donating (methyl) were studied in these haloamination reactions.We have also explored the effect of N,N-dimethyl substitution for these haloamination reactions.The reaction of N-mono methylated 3-aminoazetidin-2-ones underwent halocyclization in good to fair yield (Table 3; Entries 1-2).However, the reaction of N-tosylated 3-aminoazetidin-2-ones did not give any useful product even at high temperature or using harsh reaction conditions.The reaction of N,N-disubstituted as well as mono N 5 -tosylatedazetidin-2-one did not provide any desired product and only led to the recovery of the starting material, even after several hours of stirring at different temperatures using even higher amounts of iodine/bromine or using different bases, such as potassium carbonate, sodium carbonate, sodium hydride and potassium-t-butoxide. From these experimental observations, it may be concluded that the endo-trig haloamination reaction was not observed in the presence of an electron withdrawing group at the N-position and that the reaction is facilitated by the presence of an electron donating group.However, the reaction of 5b and 5c was not observed due to the more steric crowding for endo-trig haloamination reaction.The diastereomerically pure, functionalized novel 4-halo-3-aryl/alkyl-6-aryl-2,6-diazabicyclo[3.2.0]heptan-7-ones 2, thus obtained were characterized on the basis of analytical and spectral evidence.The compound, 4-iodo-3,6-diphenyl-2,6-diazabicyclo[3.2.0]heptan-7-one 2a for example, analyzed for C18H17IN2O showed a molecular ion peak at m/z 391 (M+1) in its mass spectrum.Its IR spectrum showed strong absorption peaks at 1755 cm -1 corresponding to the carbonyl group of a azetidin-2-one.The 1 H NMR (300 MHz) spectrum showed a characteristic doublet at δ 4.91 having J 3.6 Hz corresponding to H1 proton of the ring, an unresolved doublet of doublet at δ 4.94 having J 3.6Hz corresponding to H5 of the lactam ring, a multiplet at δ 5.02 corresponding to H3 & H4 protons.The 13 C NMR have shown the presence of one carbonyl carbon at δ 164.2 and four aliphatic carbons at δ 30.7, 67.2, 71.80, and δ 74.7 corresponding to C-4, C-5, C-1 and C-3 respectively.The relative stereochemistry of the different ring protons has been established with the help of earlier report. 29The 4-iodo-3,6-diphenyl-2,6diazabicyclo[3.2.0]heptan-7-one (2a) has shown the anti stereochemistry between H 5 of azetidin-2-one and H 4 of the pyrrole ring (Figure 1).The 4-halo-3-aryl/alkyl-6-aryl-2,6-diazabicyclo[3.2.0]heptan-7-ones 2 were explored for the synthesis of pyrrolidine esters by amidolytic ring hydrolysis of N 6 -C 7 bond using different bases viz.sodium alkoxide.The reaction resulted in the formation of 4-halo-5-phenyl-3-arylaminopyrrolidine-2-carboxylic acid methyl esters 7 in excellent yields (90%; Scheme-5, Table 4).The diastereomerically pure, functionalized alkyl 4-iodo-5-aryl-3-(arylamino)pyrrolidine-2carboxylates (7) thus obtained were characterized on the basis of analytical and spectral evidence.The compound, methyl 4-iodo-5-phenyl-3-(phenylamino)pyrrolidine-2-carboxylate 7a for example, analyzed for C18H19IN2O2 showed a (M+1) molecular ion peak at m/z 423 in its mass spectrum (Figure 2).The 1 H NMR (300 MHz) spectrum showed a characteristic doublet (J 7.

Experimental Section
General.Oxygen-and moisture-sensitive reactions were carried out under nitrogen atmosphere.Solvents were purified and dried by standard methods prior to use.All commercially available reagents and solvents (purchased from Aldrich, Merck, Spectrochem, Acros) were used without further purification unless otherwise noted.Analytical thin layer chromatography (TLC) was conducted on Merck Kieselgel 60 F254.Compounds were visualized with both short-and longwavelength UV light.Column chromatography was performed on silica gel (100-200 mesh).Melting points were determined in capillary tubes using a Mel-Temp apparatus and are not corrected.Infrared spectra were obtained as films on KBr salt plates except where otherwise specified, using a Perkin Elmer FT-IR spectrometer. 1 H NMR spectra were obtained with CDCl3 at 300 & 500 MHz, using Bruker spectrometers (residual chloroform referenced to 7.26 ppm) or DMSO-d6 (residual DMSO referenced to 2.50 ppm and residual water in DMSO-d6 appearing at 3.33 ppm).Chemical shift values are expressed as parts per million downfield from TMS and J values are in hertz.Splitting patterns are indicated as s: singlet, d: doublet, t: triplet, m: multiplet, dd: double doublet, ddd: doublet of a doublet of a doublet, and br: broad peak. 13C NMR spectra were recorded with CDCl3 at 75 MHz, using Bruker spectrometers (residual chloroform referenced to 77.0 ppm) or DMSO-d6 (residual DMSO referenced to 39.5 ppm).Infrared spectra were recorded on a Perkin Elmer FT-IR spectrometer.HRMS were recorded on Bruker high resolution spectrometer (Bruker microTOF QII).

General
procedure for synthesis of compound 4-halo-3,6-diaryl-2,6-diazabicyclo[3.2.0]heptan-7-one 2. To a solution of compounds 1 (0.1 g, 1 equiv) in DCM (10 mL) was added bromine/iodine (1.2 equiv).The reaction was stirred for 10 minutes.This was followed by addition of K2CO3 at 0 o C. The solution was stirred at 0 o C for 1-2 h.The progress of the reaction was monitored with the help of tlc.After completion of the reaction, reaction mixture was diluted with DCM and washed with Na2S2O3/water solution followed by brine solution.The dichloromethane solution was dried over anhydrous Na 2SO4 and solvent was evaporated.Crude residue was purified by flash column chromatography using silica gel (100:200 mesh) in EtOAc/cyclohexane (2:8) as an elutent system to get compounds 2.   was monitored with the help of tlc.After completion of the reaction, reaction mixture was diluted with DCM and washed with Na2S2O3/water solution followed by brine solution.

4-Iodo-3,6-diphenyl-2,6-diazabicyclo[3.2.0]heptan-7-one (2a
The dichloromethane solution was dried over anhydrous Na2SO4 and solvent was evaporated.Crude residue was purified by flash column chromatography using silica gel (100:200 mesh) in EtOAc/cyclohexane (2:8) as an elutent system to get compounds 6.  (7).To a solution of compounds 2 (30mg, 1 eq) in methanol/ethanol (5 mL), NaOMe/NaOEt (3 eq) was added and the reaction mixture was stirred at 0 o C for 1.5 h.The progress of the reaction was monitored with the help of TLC.After completion of the reaction, the mixture was quenched with ice and pH adjust to 6 -7 extracted with ethyl acetate (3 times).The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and the solvent was evaporated to get compound (7)   To a solution of compound 2 (30mg, 1 eq) in methanol/ethanol (5 mL), NaOMe/NaOEt (6.5 eq) was added and the reaction mixture was stirred at room temperature for 1 hr.Then the reaction mixture was heated up to 50 o C for 30 minutes.The progress of the reaction was monitored with the help of TLC.After completion of the reaction, the mixture was quenched with ice and pH adjust to 6-7.Now, the reaction mixture was concentrated under reduced pressure and purified via flash column chromatography using silica gel (100:200 mesh) in MeOH/DCM (1:9) as an elutent system to get compound 6 as a pure product.
5 Hz) at δ 4.70 corresponding to H2 of the ring, a broad singlet at δ 4.46 corresponding to H3 and H4 of the ring, a doublet at δ 4.11 having J 7.2 Hz assigned to H5.The 13 C NMR have shown the presence of one carbonyl carbon at δ 172.1 and four aliphatic carbons at δ 71.0, 66.0, 61.7 & 29.3 corresponding to C-5, C-2, C-4 and C-3 respectively.

Table 1 .
Reaction of 1a under different reaction conditions a Reaction time in minutes.b Isolated yield after purification.DCM = dichloromethane

Table 2 .
Synthesis a Reaction time in minutes.b Isolated yield after purification.c 1.2 equivalent.

Table 3 .
b Isolated yield after purification.