Microwave assisted rapid synthesis of 4-amino-3, 4-dihydroquinolin-2-ones from azetidin-2-ones

An efficient one-pot synthesis of 4-amino-3, 4-dihydroquinolin-2-ones from 3-(2-nitrophenyl)-1, 4-disubstituted azetidin-2-ones is described. Microwave assisted transfer hydrogenation of a nitro group followed by in situ β -lactam ring opening by the newly formed amino group is the key step in this synthesis


Introduction
Apart from the substructure of widely used antibiotics [1][2][3] such as penicillin, cephalosporins, monobactams etc., the azetidin-2-one (β-lactam) skeleton has been recognized as a useful building block in stereoselective syntheses of biologically important compounds. 4This is mainly because there are many methods available to prepare them in large quantities.The strain energy associated with the four membered azetidin-2-one ring makes it susceptible for nucleophilic ring cleavage.This factor is also responsible for their application as synthon for various stereo selective syntheses of heterocyclic non β-lactam structures. 5Also, some of the synthetic βlactams display interesting biological activities such as inhibition of prostate specific antigens, 6 thrombin, 7 human cytomegalovirus protein, 8 cholesterol absorption, 9 human leukocyte elastase 10 and cysteine protease. 11As a consequence, the interest of organic chemists in the synthesis of new β-lactam derivatives remains high.] In continuation of our efforts towards the synthesis of substituted β-lactams via the Staudinger reaction 14 and their utility as synthons 15 for the synthesis of various biologically important compounds, we herein report a rapid and practical synthesis of 4-amino-3, 4-dihydroquinolin-2ones from 1,3-disubstituted-4-(2-nitrophenyl)azetidin-2-ones via reduction of the nitro group followed by the intramolecular nucleophilic opening of the azetidin-2-one ring.Although, a solid supported synthesis of 4-amino-3, 4-dihydroquinolin-2-ones is reported, 16 it is difficult to apply it for a gram-scale preparation.We have developed a practical synthesis of dihydroquinolinones, which can be adapted for a gram-scale preparation.Microwave assisted transfer hydrogenation of the nitro group followed by the nucleophilic opening of the β-lactam ring by the newly generated amino group is the key step in this synthesis.
Initially the reduction of 5a was carried out by transfer hydrogenation using ammonium formate and Pd/C (10%) in dry methanol at room temperature for 24 h.Formation of amino-βlactam 6 was observed in good yield along with trace amounts of cyclized 4-amino-3,4dihydroquinolin-2-one (7a).The cyclized product 7a was difficult to separate from amino βlactam 6.However, its formation was deduced from IR and 1 H NMR spectra of the crude reaction mixture.The IR spectrum of amino-β-lactam 6 showed a characteristic β-lactam carbonyl absorption at 1730 cm -1 and amino group absorptions at 3398, 3485 cm -1 , while the cyclized product 7a showed the δ-lactam carbonyl absorption at 1687 cm -1 and the NH absorption at 3373 cm -1 . 1 H NMR spectrum of the amino-β-lactam 6 showed two doublets at δ 5.46 and 5.61 for the C3 and C4 cis-β-lactam ring protons (J = 4.7 Hz for the cis-isomer).The amino β-lactam underwent smooth cyclization by refluxing in methanol for 2 h to give the dihydroquinolin-2-one 7a in quantitative yield.The 1 H NMR spectrum of 7a showed two doublets at δ 5.13 and 5.23 for C3 and C4 trans-δ-lactam ring protons (J = 8. 6 Hz).A direct transfer hydrogenation of 5a was also tried in refluxing methanol for 2 h, which gave mixtures of amino-β-lactam 6 and 4-amino-3,4-dihydroqunolin-2-one 7a along with several other unidentified products.

ARKAT
We envisaged that transfer hydrogenation of 5a under microwave irradiation (MW) would directly give us dihydroquinolin-2-one 7a.The use of microwave irradiation in enhancing chemical transformation has gained considerable attention in recent years due to several advantages such as a high reaction rate and pure product formation with higher yields. 17lthough the reason for the rate enhancement is not clear, selective absorption of microwave energy by polar molecules or transition states may be responsible for the acceleration of the reaction.
Microwave irradiation of 5a in the presence of ammonium formate and catalytic amounts of Pd/C (10%) in the presence of a small quantity of ethylene glycol was carried out in an open glass vessel using a domestic microwave.The reaction was over in just three minutes at 60% power of the microwave oven.The reaction mixture was diluted with water, methylene chloride and the catalyst was removed by filtration through a small bed of celite.The filtrate was extracted with methylene chloride and the removal of methylene chloride under reduced pressure gave almost pure product 7a in very good yield, which was further purified by crystallization from ethyl acetate-petroleum ether mixture.
This product was formed by the reduction of the nitro group followed by the nucleophilic β-lactam ring cleavage with the newly generated amino group.Several 4-amino-3,4dihydroquinolin-2-ones (7a-k) were prepared by transfer hydrogenation under microwave irradiation in very good yields (Table 2).In case of acetoxy compounds 7g, k (Table 2, entries 7 and 11) a small amount of the corresponding uncyclized amino-β-lactam was also observed along with the required dihydroquinolin-2-one, which was removed by crystallization from an ethyl acetate-pet-ether mixture.In conclusion, we have demonstrated a simple and efficient one-pot preparation of 4amino-3, 4-dihydroquinolin-2-ones from 3-(2-nitrophenyl)-1,4-disubstituted azetidin-2-ones.Microwave assisted transfer hydrogenation of the nitro group followed by the in situ β-lactam ring opening by the newly formed amino group is the key step in this synthesis.

Experimental Section
General Procedures. 1 H NMR and 13 C NMR Spectra were recorded in a CDCl 3 solution on a Bruker AC 200, Bruker MSL-300 and Bruker DRX-500 spectrometer and chemical shifts are reported in ppm downfield from TMS for 1 H NMR. Infrared spectra were recorded on Shimadzu FT IR-8400 using sodium chloride optics.Melting points were determined on a Thermonik Campbell melting point apparatus and were uncorrected.The microanalyses were performed on a Carlo-Erba, CHNS-O EA 1108 elemental analyzer.Microwave irradiation was carried out in an open glass vessel using a domestic microwave oven (800 Watt, BPL-make).

General procedure for the synthesis of azetidine-2-ones (5a-l).
To a solution of an imine 3 (5 mmol) and triethylamine (20 mmol) in dry methylene chloride (20 mL) was added dropwise a solution of an acid chloride 4 (7.5 mmol) in dry methylene chloride (10 mL) with stirring at 0 °C in about 20 min.The reaction mixture was then allowed to warm up to room temperature and stirred for 14 h.It was then washed with water (10 mL), saturated sodium bicarbonate (10 mL), brine (10 mL) and dried over anhyd.Na 2 SO 4 .The solvent was removed in vacuo to give crude azetidine-2-one, which was recrystallized from methanol to get pure azetidine-2-one.
General procedure for microwave assisted synthesis of 3,4-dihydro-1H-quinolin-2-one (7ak).To a solution of azetidin-2-one (5, 0.5 mmol), in ethylene glycol (3 mL) was added ammonium formate (2.5 mmol) followed by Pd/C (10%, 30 mg).The mixture was then subjected to microwave irradiation at low power setting (60%) for 3 min.in an open glass vessel.It was then allowed to come to room temperature, diluted with water (2 mL) and filtered through a small pad of celite.The residue was washed with methylene chloride (2 x 10 mL), the organic layer was separated, washed with brine (2 mL), dried over anhyd.Na 2 SO 4 and the solvent was removed in vacuo to get crude quinolinone, which was recrystallized from an ethyl acetate-petether mixture.

Entry No Compound R R 1 Yield a (%) Mp (˚C)
a Isolated yields.