Reaction Intermediates for Microwave Irradiation Assisted Synthesis of N-Aryl Enaminoketones and their subsequent conversion to Quinolines: An experimental and DFT Study

 

Avijit Banerji1, Rina Saha2, Nivedita Acharjee*3

1Central Ayurveda Research Institute for Drug Development, CN Block, Sector V, Kolkata 700091, west Bengal, India.

2Centre of Advanced Studies on Natural Products including Organic Synthesis, Department of Chemistry, University of Calcutta, 92, Acharya Prafulla Chandra Road, Kolkata- 700009, west Bengal, India.

3Department of Chemistry, Durgapur Government College, Durgapur-713214 west Bengal, India.

*Corresponding Author E-mail: nivchem@gmail.com

 

ABSTRACT:

Reactions of acetyl acetone to aromatic amines have been carried out in presence of p-toluenesulphonic acid and molecular sieves by a new microwave irradiation assisted procedure to generate N-aryl enaminoketones. Two stereoisomeric enaminoketones, viz. cis and trans enaminoketones, are formed as intermediates which are characterized by NMR studies.Computations are performed at the DFT/B3LYP/6-311++G(2d,p) level to analyze the course of these reactions. The computed GIAO nuclear magnetic shielding tensors and experimental data are found to be in good agreement to each other in case of both cis and trans enaminoketones. Transition states and intermediates for the generation of cis and trans enaminoketones are successfully located at DFT/B3LYP/6-311++G(2d,p) level of theory and the relative energies are calculated to rationalize the selectivity of the process. Two transition states and one intermediate are located for both cis and trans pathways. The enaminoketones are subsequently converted to quinolines under acid catalysis with 80% sulphuric acid under microwave irradiation in high yields. This method is a significant improvement on the conventional methods for preparation of substituted quinolines from 1,3-diketones, particularly in view of very short times taken, the cleanness of the reactions and high yields. The present theoretical study of the reaction course at DFT/B3LYP/6-311++G(2d,p) level is the first contribution to computational calculations of such reactions.

 

KEYWORDS: Enaminoketones, Quinolines, Microwave Irradiation, DFT, Transition state.

 

 


INTRODUCTION:

Enaminoketones represent an important class of functionalized building blocks for the synthesis of bio-active heterocycles which are well known anti inflammatory, antitumor, antibacterial and anti-convulsant agents1. They perform as versatile intermediates due to their promptness for both electrophilic and nucleophilic attacks.

 

The most simple and straightforward conventional synthesis of enaminoketones involves the direct condensation of β-carbonyl compounds with amines at reflux with azeotropic removal of water in an aromatic solvent2,3. This conventional reaction has been subsequently improved by a variety of activators such as Zn(ClO4)2.6H2O4, ionic liquid5, ceric ammonium nitrate6, ferric (III) ammonium nitrate7, Amberlyst-158, AlPO49 etc. However, these major developments have not replaced the use of conventional heating.In the last two decades there has been a phenomenal growth of MORE (Micro-wave Irradiation Organic Reaction Enhancement) Chemistry in which microwave irradiation is used to assist reactions. The microwave assisted synthesis has offered a new energy source to complete reactions in minutes instead of hours or even days. Andrade etal.10 reported the preparation of enaminoketones under solvent free conditions with >90% yields using microwave irradiation. Lee et al.11 and Braibanteet al.12 have also employed the microwave irradiation methodology to prepare enaminoketones from alkyl amines and 1,3-dicarbonyl compounds. However, the transition states and reaction intermediates involved in such reactions have not been addressed by DFT calculations with higher basis sets in these communications.

 

In the present study, microwave irradiation assisted synthesis of N-aryl enaminoketones from acetyl acetone and aromatic amines and their subsequent acid catalyzed microwave induced conversion to quinolines has been carried out (Fig. 1). The aim of our work was not only to enhance the reaction rate but also to locate the transition states and reaction intermediates for the reaction and hence to study the selectivity of the process both from experimental and theoretical approaches. The major enaminoketone product was identified as the cis isomer. We then successfully located the transition states for the generation of cis and trans enaminoketones at DFT/B3LYP/6-311++G(2d,p) level of theoryand determined the relative energies and enthalpies. The computed GIAO nuclear magnetic shielding tensors at DFT/B3LYP/6-311++G(2d,p) level of theory were compared with the experimentally recorded chemical shifts of cis and trans enaminoketones.

 

Materials and methods:

All chemicals for reactions and CDCl3 (for NMR analysis) were obtained from Merck, India. A BPL-Sanyo model domestic microwave oven BMO-700T was used at a power setting of about 1000 watts. The microwave oven was modified by drilling a hole in the top of the casing to make provision for the fitting of a reflux condenser. The reactions were carried out in round bottomed flasks of the capacity of 100 ml kept on alumina base inside the microwave oven. IR spectra were recorded in KBr pellets using a Perkin Elmer RX-9 FT-IR spectrophotometer. 1H NMR and 13C NMR spectra of crude reaction mixtures and individual products were recorded in CDCl3 solution using a Bruker AV-300 NMR spectrometer at 300 MHz and 75.5 MHz, respectively. Chemical shifts are recorded in  ppm; coupling constants are given in Hz. Elemental analysis of the isolated quinolines was done by a Perkin Elmer 2400 Series II analyzer and the obtained results were found to be in good agreement with the calculated values.

 

Experimental - General Procedure:

The mixture of aniline /substituted anilines (1-9) [0.02mol] with acetyl acetone (10) [0.03 mol] in the presence of p-tolylsulphonic acid [0.0015mol] was irradiated under microwave irradiation for periods varying from 9-24 minutes. About 0.06 gms of powdered molecular sieves 4Å was added to the reaction mixture. Progress of the reactions was routinely monitored by TLC and 1H–NMR. The crude reaction product revealed the presence of stereoisomeric mixtures of enaminoketones and small amount of acetanilide (as a byproduct). The mixtures of enaminoketones were subjected to microwave irradiation in presence of 80% sulphuric acid for a very short period. The reaction mixture was allowed to cool and slowly poured into ice cooled water. Sodium carbonate was added to the reaction mixture with constant stirring. The corresponding quinolines separated out as oil from the alkaline solution which was extracted with dichloromethane. The products were dried and characterized from NMR spectra.


 

Fig. 1: Reaction between substituted anilines and acetyl acetone


Reaction between Aniline and Acetyl acetone

Cis-[4-(phenylamino)pent-3-en-2-one] (11).  1H-NMR (CDCl3, δ, 300MHz): 1.98 (3H, s, 1-CH3), 2.26 (3H, s, 5-CH3), 5.20 (1H, s, 3-CH), 7.00-7.12 (1H, br, 4΄-CH), 7.25 (2H, dd, J=8.0, 7.0, 3΄,5΄-CH), 7.54 (2H, d, J=8.0, 2΄, 6΄-CH), 12.46 (1H, br s, -NH); 13C-NMR (CDCl3, δ, 75.5MHz):  21.1 (5-CH3), 26.5 (1-CH3), 97.5 (3-CH), 115.1 (2΄,6΄-CH), 128.6 (3΄,5΄-CH), 130.9 (4΄-CH), 138.4 (1΄-C), 160.6 (2-CN), 196.1 (4-CO).

 

Trans-[4-(phenylamino) pent-3-en-2-one] (12). 1H-NMR (CDCl3, δ, 300MHz): 2.05 (3H, s, 5-CH3), 2.32 (3H, s, 1-CH3), 5.51 (1H, s, 3-CH), 7.28-7.39 (3H, m, 3΄,4΄,5΄-CH), 7.97 (2H, d, J=8.0, 2΄,6΄-CH), 8.56 (1H, br s, -NH); 13C-NMR (CDCl3, δ, 75.5MHz): 24.2 (5-CH3), 28.9 (1-CH3), 101.2 (3-CH), 119.9 (2΄,6΄-CH), 129.0 (3΄, 5΄-CH), 131.3 (4΄-CH), 138.4 (1΄-C), 160.7 (2-CN), 191.4 (4-CO).

 

2,4-Dimethylquinoline (38). 1H-NMR (CDCl3, δ,  300MHz):  2.66 (3H, s, 4-CH3), 2.70 (3H, s, 2-CH3), 7.14 (1H, s, 3-H), 7.53 (1H, t  J=8.0, 7-H), 7.70 (1H, t, J=8.0, 6-H), 7.96 (1H, d, J=8.0, 8-H), 8.05 (1H, d, J=8.0, 5-H); 13C-NMR (CDCl3, δ, 75.5MHz): 18.5(4-CH3), 25.06 (2-CH3), 122.7 (3-CH), 123.5 (8-CH), 125.4 (6-CH), 126.5(4a-C), 128.9 (7-CH), 129.1 (5-CH), 144.3 (4-C),  147.5 (8a-C), 158.6 (2-C).

 

Reaction between o-Toluidine and Acetyl acetone

Cis-[4-(o-tolylamino)pent-3-en-2-one] (14) 1H-NMR (CDCl3 δ, 300MHz): 1.89 (3H, s,1-CH3), 2.12 (3H, s, 2΄-CH3), 2.26 (3H, s, 5-CH3),  5.21 (1H, s, 3-CH), 6.76 (1H, d, J=7.6, 3΄-CH), 7.06 -7.12 (3H, m, 4΄,5΄,6΄-CH), 12.31 (1H, br s, -NH); 13C-NMR (CDCl3, δ, 75.5MHz): 17.9 (2΄-CH3), 19.5 (5-CH3), 26.6 (1-CH3), 97.0 (3-CH), 115.8 (6΄-CH), 119.5 (4΄-CH), 126.3 (5΄-CH), 130.6 (3΄-CH), 133.6 (2΄-C), 137.4 (1΄-C), 161.2 (2-CN), 196.0 (4-CO).

Trans-[4-(o-tolylamino)pent-3-en-2-one] (15) 1H-NMR (CDCl3, δ, 300MHz): 2.01 (3H, s, 5-CH3), 2.20 (3H, s, 2΄-CH3), 2.29 (3H, s, 1-CH3),  5.49 (1H, s, 3-CH), 7.13-7.22 (4H, m,  3΄,4΄,5΄,6΄-CH), 9.25 (1H, br s, -NH); 13C-NMR (CDCl3, δ, 75.5MHz): 17.2 (2΄-CH), 24.7 (5-CH3), 28.9 (1-CH3), 101.2 (3-CH), 115.8 (6΄-CH), 119.5 (4΄-CH), 126.3 (5΄-CH), 130.6 (3΄-CH), 133.6 (2΄-C), 137.4 (1΄-C), 161.2 (2-CN), 191.4 (4-CO).

 

2,4,8-Trimethylquinoline (39). 1H-NMR (CDCl3, δ,  300MHz): 2.67 (3H, s, 4-CH3), 2.74 (3H, s, 2-CH3), 2.84 (3H, s, 8-CH3), 7.14 (1H, s, 3-H), 7.43 (1H, t J=9.0, 6.0, 6-H), 7.56 (1H, d, J=9.0, 5-H), 7.83 (1H, d, J=6.0, 7-H); 13C-NMR (CDCl3, δ, 75.5MHz): 18.5 (4-CH3), 18.8 (8-CH3), 25.5 (2-CH3), 121.5 (3-CH), 122.4 (6-CH), 124.9 (5-CH),  126.4 (4a-C), 129.3 (7-CH), 136.9 (8-C), 144.1(4-C), 146.8 (8a-C), 157.4 (2-C).

 

 

Reaction between m-Toluidine and Acetyl acetone 

Cis-[4-(m-tolylamino)pent-3-en-2-one] (17). 1H-NMR (CDCl3, δ, 300MHz): 1.99 (3H, s, 1-CH3), 2.10 (3H, s, 5-CH3), 2.34 (3H, s, 3΄-CH3),  5.18 (1H, s, 3-CH), 6.86 (1H, s, 2΄-CH), 7.02 (1H, d, J=7.4, 6΄-CH), 7.16 (1H, d, J=7.7, 4΄-CH), 7.22 (1H, t, J=8.0, 5΄-CH), 12.44 (1H, br s, -NH); 13C-NMR (CDCl3, δ, 75.5MHz): 19.7 (5-CH3), 20.9 (3΄-CH3), 28.8 (1-CH3),  97.3 (3-CH), 120.4 (4΄-CH), 121.6 (6΄-CH), 125.3 (2΄-CH), 128.7 (5΄-CH), 138.4 (3΄-C), 139.0 (1΄-C), 161.2 (2-CN), 196.0 (4-CO).

 

Trans-[4-(m-tolylamino)pent-3-en-2-one](18). 1H-NMR (CDCl3, δ, 300MHz): 2.06 (3H, s, 5-CH3), 2.28 (3H, s, 1-CH3), 2.34 (3H, s, 3΄-CH3),  5.49 (1H, s, 3-CH), 7.06 (1H, s,  2΄-CH), 7.08-7.15 (3H,m, 4΄,5΄,6΄-CH), 8.48 (1H, br s, -NH); 13C-NMR (CDCl3, δ, 75.5MHz): 20.9 (3΄-CH), 24.6 (5-CH3), 29.6 (1-CH3), 101.1 (3-CH), 116.9 (4΄-CH), 120.5 (6΄-CH), 124.6 (2΄-CH), 128.5 (5΄-CH), 138.3 (3΄-CH), 139.0 (1΄-C), 161.0 (2-CN), 194.2 (4-CO).

 

2,4,7-Trimethylquinoline (40). 1H-NMR (CDCl3, δ,  300MHz): 2.62 (3H, s, 4-CH3),  2.74 (3H, s, 2-CH3), 2.95 (3H, s, 7-CH3), 7.25 (1H, s, 8-H), 7.28 (1H, s, 3-H), 7.53 (1H, d, J=9.0, 6-H), 7.96 (1H, d, J=9.0, 5-H); 13C-NMR (CDCl3, δ, 75.5MHz): 18.4 (4-CH3), 21.7 (8-CH3), 24.8 (2-CH3), 121.8 (3-CH), 123.3 (8-CH),  124.9 (4a-C), 127.5 (6-CH), 127.9 (5-CH), 139.3 (7-C), 144.1 (4-C), 147.5 (8a-C), 158.3 (2-C).

 

Reaction between p-Toluidine and Acetyl acetone

Cis-[4-(p-tolylamino)pent-3-en-2-one] (20). 1H-NMR (CDCl3, δ, 300MHz): 1.97 (3H, s, 1-CH3), 2.11 (3H, s, 5-CH3), 2.35 (3H, s, 4΄-CH3),  5.18 (1H, s, 3-CH), 7.01 (2H, d, J=8.2, 2΄,6΄-CH), 7.40 (2H, d, J=8.2, 3΄,5΄-CH), 12.39 (1H, br s, -NH); 13C-NMR (CDCl3, δ, 75.5MHz): 19.7 (5-CH3), 21.0 (4΄-CH3), 28.9 (1-CH3), 97.2 (3-CH), 125.0 (2΄,6΄-CH), 129.6 (3΄,5΄-CH), 133.7 (4΄-C), 136.0 (1΄-C), 161.0 (2-CN), 196.0 (4-CO).

Trans-[4-(p-tolylamino)pent-3-en-2-one] (21).1H-NMR (CDCl3, δ, 300MHz): 2.00 (3H, s, 5-CH3),  2.25 (3H, s, 1-CH3), 2.33 (3H, s, 4΄-CH3),  5.51 (1H, s, 3-CH), 7.09-7.17 (4H, m, 2΄,3΄, 5΄,6΄-CH), 7.70 (1H, br s, -NH); 13C-NMR (CDCl3, δ, 75.5MHz): 21.1 (4΄-CH3), 24.4 (5-CH3), 29.8 (1-CH3), 101.0 (3-CH), 125.0 (2΄,6΄-CH), 129.6 (3΄,5΄-CH), 133.7 (4΄-C), 136.0 (1΄-C), 161.0 (2-CN), 191.0 (4-CO).

 

2,4,6-Trimethylquinoline (41). 1H-NMR (CDCl3, δ,  300MHz):  2.54 (3H, s, 6-CH3), 2.63 (3H, s, 4-CH3), 2.68 (3H, s, 2-CH3), 7.11 (1H, s, 3-H), 7.50 (1H, dd,  J=8.6, 1.7,  7-H),  7.70 (1H, br s,  5-H), 7.94 (1H, d, J=8.6, 8-H); 13C-NMR (CDCl3, δ, 75.5MHz): 18.5 (4-CH3), 21.7 (6-CH3), 24.9 (2-CH3), 120.0 (3-CH), 122.7 (8-CH),  126.4 (4a- C), 128.7 (7-CH), 131.3 (5-CH), 135.1 (6-C), 143.6 (8a-C), 146.0 (4-C), 157.5 (2-C).

 

 

Reaction between o-Anisidine and Acetyl acetone

Cis-[4-(o-methoxyphenylamino)pent-3-en-2-one] (23). 1H-NMR (CDCl3, δ, 300MHz): 1.89 (3H, s, 1-CH3),  2.11 (3H, s, 5-CH3),  3.74 (3H, s, 2΄-OCH3),  5.11 (1H, s, 3-CH),  6.67-6.78 (3H, m, 4΄,5΄,6΄-CH),  6.83 (1H, d, J=7.8, 3΄-CH), 12.26 (1H, br s, -NH); 13C-NMR (CDCl3,  δ, 75.5MHz): 19.4 (5-CH3), 28.9 (1-CH3), 55.6 (2΄-OCH3), 97.4 (3-CH), 119.5 (3΄-CH),  120.4 (5΄-CH), 123.2 (4΄-CH), 124.4 (6΄-CH), 127.4 (1΄-C), 152.3 (2΄-C), 160.0 (2-CN), 195.2 (4-CO).

 

Trans-[4-(o-methoxyphenylamino)pent-3-en-2-one] (24). 1H-NMR (CDCl3, δ, 300MHz): 2.09 (3H, s, 5-CH3),  2.21 (3H, s, 1-CH3),  3.72 (3H, s, 2΄-OCH3),  5.40 (1H, s, 3-CH),  6.71-6.87 (4H, m,  3΄,4΄,5΄,6΄-CH),  7.93 (1H, br s,-NH); 13C-NMR (CDCl3, δ, 75.5MHz): 20.6 (5-CH3), 26.2 (1-CH3), 55.6 (2΄-OCH3),  100.6 (3-CH), 117.9 (3΄-CH), 119.8 (5΄-CH), 120.6 (4΄-CH), 125.6 (6΄-CH), 127.9 (1΄-C), 152.3 (2΄-C), 160.0 (2-CN), 191.0 (4-CO).

 

2,4-Dimethyl-8-methoxyquinoline (42). 1H-NMR (CDCl3, δ,  300MHz):  2.64 (3H, s, 4-CH3), 2.75 (3H, s, 2-CH3), 3.86 (3H, s, 8-OCH3),  7.04 (1H, d, J=7.5, 5-H), 7.17 (1H, s, 3-H), 7.44 (1H, t, J=8.0, 6-H), 7.53 (1H, d, J=8.0, 7-H); 13C-NMR (CDCl3, δ, 75.5MHz): 18.9 (4-CH3), 25.4 (2-CH3), 55.7 (8-OCH3), 115.3 (7-CH), 120.2 (3-CH), 123.3 (5-CH), 125.0 (4a- C), 129.3 (6-CH), 139.3 (4-C), 144.1 (8a-C), 155.0 (2-C), 157.5 (8-C).

 

Reaction between p-Anisidine and Acetylacetone

Cis-[4-(p-methoxyphenylamino)pent-3-en-2-one] (26). 1H-NMR (CDCl3, δ, 300MHz): 1.93 (3H, s, 1-CH3),  2.20 (3H, s, 5-CH3),  3.73 (3H, s, 4΄-OCH3),  5.06 (1H, s, 3-CH), 6.76 (2H, d,  J=7.1, 3΄,5΄-CH),  6.91 (2H, d, J=8.7, 2΄,6΄-CH), 12.20 (1H, br s, -NH); 13C-NMR (CDCl3, δ, 75.5MHz):  19.1 (5-CH3),  28.4 (1-CH3), 55.0 (4΄-OCH3), 96.5 (3-CH), 114.3 (3΄,5΄-CH), 126.7 (2΄,6΄-CH), 131.4 (1΄-C), 155.6 (4΄-C), 161.5 (2-CN), 195.2 (4-CO).

 

Trans-[4-(p-methoxyphenylamino)pent-3-en-2-one] (27). 1H-NMR (CDCl3, δ, 300MHz): 1.88 (3H, s, 5-CH3),  2.26 (3H, s, 1-CH3), 3.66 (3H, s, 4΄-OCH3), 5.40 (1H, s, 3-CH), 6.65 (2H, d, J=8.6, 3΄,5΄-CH),  7.37 (2H, d, J=8.9, 2΄,6΄-CH), 9.10 (1H, br s, -NH); 13C-NMR (CDCl3, δ, 75.5MHz): 20.0 (5-CH3), 26.2 (1-CH3), 55.3 (4΄-OCH3), 100.8 (3-CH), 113.9 (3΄,5΄-CH), 126.1(2΄,6΄-CH), 131.4 (1΄-C), 155.2 (4΄-C), 161.0 (2-CN), 191.1 (4-CO).

 

2,4-Dimethyl-6-methoxyquinoline (43). 1H-NMR (CDCl3, δ,  300MHz): 2.63 (3H, s, 4-CH3), 2.76 (3H, s, 2-CH3), 3.79 (3H, s, 6-OCH3), 7.18 (1H, s, 3-H),  7.28 (1H, d, J=8.0, 7-H), 7.34 (1H, s, 5-H), 7.81 (1H, d, J=8.0, 8-H); 13C-NMR (CDCl3, δ, 75.5MHz): 19.8 (4-CH3), 24.8 (2-CH3), 55.6 (6-OCH3), 102.6 (5-CH), 122.1 (7-CH), 122.7 (3-CH), 128.8 (4a-C), 130.8 (8-CH), 139.3 (4-C), 144.5 (8a-C), 155.9 (6-C),  159.5 (2-C).

 

Reaction between o-Chloroaniline and Acetyl acetone

Cis-[4-(o-chlorophenylamino)pent-3-en-2-one] (29). 1H-NMR (CDCl3, δ, 300MHz): 1.96 (3H, s, 1-CH3),  2.24 (3H, s, 5-CH3),  5.24 (1H, s, 3-CH),  6.67-6.78 (3H, m, 4΄,5΄,6΄-CH),  7.40 (1H, d,  J=7.8,  3΄-CH),  12.36 (1H, br s, -NH); 13C-NMR (CDCl3,  δ,  75.5MHz): 19.7 (5-CH3), 26.6 (1-CH3), 98.4 (3-CH), 119.5 (3΄-CH), 124.0 (6΄-CH), 124.8 (5΄-CH), 125.4 (4΄-CH), 127.4 (1΄-C), 152.3 (2΄-C), 160.1 (2-CN), 196.8 (4-CO).

 

Trans-[4-(o-chlorophenylamino)pent-3-en-2-one] (30). 1H-NMR (CDCl3, δ, 300MHz): 2.09 (3H, s, 5-CH3),  2.30 (3H, s, 1-CH3),  5.46 (1H, s, 3-CH), 6.71-6.87 (4H, m,  3΄,4΄,5΄,6΄-CH),  8.30 (1H, br s, -NH);  13C-NMR (CDCl3, δ, 75.5MHz): 20.8 (5-CH3), 29.1 (1-CH3), 100.4 (3-CH), 117.9 (3΄-CH), 119.8 (5΄-CH), 120.6 (4΄-CH), 125.6 (6΄-CH), 127.9 (1΄-C), 152.3(2΄-C), 160.1 (2-CN), 191.3 (4-CO).

 

2,4-Dimethyl-8-chloroquinoline (44). 1H-NMR (CDCl3, δ, 300MHz): 2.57 (3H, s, 4-CH3), 2.68 (3H, s, 2-CH3), 7.10 (1H, s, 3-H), 7.58 (1H, d, J=8.4, 7-H), 7.69 (1H, t, J=8.4, 6-H), 7.78 (1H, d, J=8.4, 5-H); 13C-NMR (CDCl3, δ, 75.5MHz): 18.8 (4-CH3), 25.5 (2-CH3), 122.3 (3-CH), 123.6 (5-CH), 125.1 (6-CH),  126.3 (4a-C), 129.3 (7-CH), 135.1 (8-C), 142.9 (4-C), 143 (8a-C), 152.9 (2-C).

 

Reaction between p-Chloroaniline and Acetyl acetone

Cis-[4-(p-chlorophenylamino)pent-3-en-2-one] (32). 1H-NMR (CDCl3, δ, 300MHz): 1.98 (3H, s, 1-CH3),  2.01 (3H, s, 5-CH3),  5.12 (1H, s, 3-CH),  6.93 (2H, d,  J=6.7, 2΄,6΄-CH), 7.22 (2H, d,  J=6.7, 3΄,5΄-CH),  12.34 (1H,  br s, -NH); 13C-NMR (CDCl3, δ, 75.5MHz): 19.6 (5-CH3), 26.5 (1-CH3), 98.0 (3-CH), 125.7 (2΄,6΄-CH), 128.6 (4΄-C), 129.1 (3΄,5΄-CH),  137.2 (1΄-C), 160.0 (2-CN), 196.4 (4-CO).

 

Trans-[4-(p-chlorophenylamino)pent-3-en-2-one] (33). 1H-NMR (CDCl3, δ, 300MHz): 1.95 (3H, s, 5-CH3), 2.05 (3H, s, 1-CH3),  5.41 (1H, s, 3-CH),  6.52 (2H, d,  J=6.7, 2΄,6΄-CH), 6.98 (2H, d, J=6.7, 3΄,5΄-CH), 8.61 (1H, br s, -NH); 13C-NMR (CDCl3, δ, 75.5MHz): 24.2 (5-CH3), 29.1 (1-CH3), 100.1 (3-CH), 125.6 (2΄,6΄-CH), 128.5 (4΄-C), 130.9 (3΄,5΄-CH),  137.0 (1΄-C), 160.0  (2-CN), 191.4 (4-CO).

 

2,4-Dimethyl-6-chloroquinoline (45). 1H-NMR (CDCl3, δ, 300MHz):  2.23 (3H, s, 4-CH3), 2.63 (3H, s, 2-CH3), 7.14 (1H, s, 3-H), 7.27 (1H, s, 5-H), 7.58 (1H, d, J=9.0, 7-H), 7.95 (1H, d, J=9.0, 8-H); 13C-NMR (CDCl3, δ, 75.5MHz): 19.7 (4-CH3), 24.9 (2-CH3), 122.6 (3-CH), 122.8 (5-CH), 127.2 (4a-C), 129.8 (7-CH), 130.4 (8-CH), 137.2 (6-C), 143.5 (4-C), 145.6 (8a-C), 159.7 (2-C).

 

 

 

Reaction between m-Nitroaniline and Acetyl acetone

Cis-[4-(m-nitrophenylamino)pent-3-en-2-one] (35). 1H-NMR (CDCl3, δ, 300MHz): 1.98 (3H, s, 1-CH3), 2.21 (3H, s, 5-CH3), 5.31 (1H, s, 3-CH), 6.85 (1H, d, J=8.1, 6΄-CH), 7.28 (1H, d, J=7.7, 5΄-CH), 7.88 (1H, d, J=8.1, 4΄-CH), 8.41 (1H, s, 2΄-CH), 12.63 (1H, br s,-NH); 13C-NMR (CDCl3, δ, 75.5MHz): 19.9 (5-CH3), 29.3 (1-CH3), 99.5 (3-CH), 109.0 (2΄-CH), 113.0 (4΄-CH), 120.6 (6΄-CH), 130.0 (5΄-CH), 148.4 (1΄-C), 149.2 (3΄-C), 158.7 (2-CN), 197.5 (4-CO).

 

Trans-[4-(m-nitrophenylamino)pent-3-en-2-one] (36). 1H-NMR (CDCl3, δ, 300MHz): 2.08 (3H, s, 5-CH3), 2.25 (3H, s, 1-CH3), 5.51 (1H, s, 3-CH), 7.12 (1H, d, J=8.0, 6΄-CH), 7.65 (3H, s, 5΄-CH), 7.70 (1H, d, J=8.0, 4΄-CH), 8.41 (1H, s, 2΄-CH),  8.71 (1H, br s, -NH); 13C-NMR (CDCl3, δ, 75.5MHz):  20.6 (5-CH3), 26.6 (1-CH3), 100.4 (3-CH), 109.0 (2΄-CH), 113.0 (4΄-CH), 120.6 (6΄-CH), 130.0 (5΄-CH), 147.5 (1΄-C), 149.2 (3΄-C), 158.7 (2-CN), 191.5 (4-CO).

 

Computational methods:

Geometries of reactants, orientation complexes, transition states, and products were optimized using the hybrid density functional B3LYP13 method, i.e., Becke’s three parameter non-local-exchange functional with the non-local correlation functional of Lee, Yang, and Parr14, with the 6–311 ++G(2d,p) basis set which incorporates the diffuse functions for C, N, and O atoms, and the polarization functions for all the main group elements. The stationary points were characterized through vibrational frequencies analysis at DFT/B3LYP/6–311 ++G(2d,p) level of theory. All the thermochemical calculations reported were performed at 298.15 K. All the stationary points were definitely identified either from minima (number of imaginary frequencies = 0) or from transition states (number of imaginary frequencies =1). Intrinsic reaction coordinate (IRC15,16) calculations were started from the saddle points and were performed to verify that the potential energy curve connecting the optimized reactants and the products passes through the correct and the lowest TS which must be a first-order saddle point. Theoretical calculations of NMR typically benefit from an accurate geometry and a large basis set. Cheeseman17 and coworkers have considered the B3LYP (6–31G (d)) optimized structures to be the minimum recommended model chemistry for predicting NMR properties. Hence, GIAO/SCF 1H NMR calculations of the DFT/B3LYP/6–311++G(2d,p) optimized enaminoketones were performed at B3LYP/6–311++G (2d,p) level of approximation. Solvent effects are considered at DFT/B3LYP/6–311++G(2d,p) level of theory using the Polarized Continuum Model of Tomasi and coworkers18,19 (CPCM20) in chloroform. All calculations were carried out using a Gaussian 200321 set of programs along with the graphical interface Gauss View 2003.

 

Results and Discussion:

The procedure developed consists of a two-step pathway. The first step is the reaction of acetylacetone with an aromatic amine under microwave irradiation conditions as shown in Fig. 1 to form enaminoketones. The second step consists in conversion of the enaminoketones formed in the first step to substituted quinolines. The reactants, reaction conditions and products of both steps are shown in Fig. 1. The first step, shown in Fig. 1, consists of reacting 1.5 molar excess of acetyl acetone with aniline/substituted anilines in the presence of a catalytic amount of p-toluene sulphonic acid and molecular sieve 4Å (to remove the water formed in the condensation step) under microwave irradiation at a power setting of ~1000 watts for 9-24 minutes in a modified BPL-Sanyo domestic oven. The reactions were monitored at few minutes interval by 1H-NMR analysis. 1H-NMR spectral analysis indicated the formation ofenaminoketones along with small quantity of acetanilide derivative.The degree of conversion was assessed from relative signal intensities in the spectra.The enaminoketone is formed in both trans- and cis- forms.The relative proportions of products 32: 33: 34 (derived from p- chloroaniline) at different time intervals as determined from 1H-NMR spectrum have been listed in Table 1. After 3 minutes, the trans-enaminoketone is generated as the major product. However, after 9 minutes, the proportion of cis isomer increases. After 18 minutes, the relative proportion of cis-enaminoketone: trans- enaminoketone: acetanilide derivative was 79:13:8. The cis- form is stabilized by intramolecular hydrogen bonding. On refluxing the mixture of products in concentrated hydrochloric acid, it was found that the trans- product was converted almost completely to the cis- isomer. The enamino-ketones and substituted quinolines were characterized from their FT- IR, 1H-NMR and 13C-NMR spectra. In cis- series of isomers the chemical shift of proton of –NH is very much deshielded and varies from d12.19 - d12.99 ppm. This is due to the formation of intramolecular hydrogen bonding between oxygen of carbonyl and hydrogen of NH (CO----H—N) in cis- isomer. For trans- isomers, the values vary from d7.98 - d9.73 ppm. The more intense signals corresponded to the cis-isomer.

Use of a large proportion of p-toluene sulphonic acid and longer reaction times in the first step gave substantially the same results.

 

Table 1: The relative proportions of products (32, 33, 34) obtained with time determined from 1H-NMR spectrum.

Time in minutes

Relative Proportion of Products

Overall Yield (%)

32

33

34

3

12

78

10

34

6

17

76

7

58

9

74

20

6

72

12

80

15

5

84

18

79

13

8

89

 

The second step consists of the acid-catalysed cyclisation of the N-aryl enaminoketones to give the corresponding quinolines (Fig. 1). The mixture of enaminoketones was subjected to microwave irradiation, at comparatively low power (200W) in presence of 80% sulphuric acid for a very short period (1-5 minutes) to obtain the substituted quinolines (38-45).This step could be proceeded with the crude reaction mixture obtained after microwave irradiation, as the by-product acetanilides did not interfere in this step. The percentage yields and the time required for the synthesis of N-aryl enamino-ketones and their conversion to substituted quinolines have been given in Table 2.

 

The substituted quinolines were characterized from their 300MHz 1H-NMR and 75.5 MHz 13C-NMR spectra. The chemical shifts and coupling patterns of the 1H-NMR signals indicated the substitution patterns in the quinolines formed.


 

Table 2: Yields of N-aryl enamino-ketones and their corresponding quinolines.

S. No.

Primary Aromatic Amines

Reaction  Time

In minutes

PercentageYields of Enamino-ketones

Reaction Time of  Cyclisation in minutes

Percentage Yields of substituted Quinolines

1.

Aniline

24

53

2

93

2.

2-Toluidine

18

85

1

85

3.

3-Toluidine

18

90

1

91

4.

4-Toluidine

18

95

3

78

5.

4-Chloroaniline

18

82

5

92

6.

2-Chloroaniline

18

85

2

84

7.

2-Anisidine

24

90

2

78

8.

4-Anisidine

24

78

2½

75

9.

3- Nitroaniline

9

94

*

*

*Did not cyclise.


 

Theoretical studies:

Theoretical studies were performed to study the formation of enaminoketones 11 and 12 derived from aniline and acetyl acetone. The GIAO nuclear magnetic shielding tensors of the enaminoketones 11 and 12 are computed at DFT/B3LYP/6-311++G(2d,p) level of theory in gas phase and chloroform. These are collected in Table 3. The chemical shift values of cis (11) and trans (12) enaminoketones are calculated at d12.99 and d6.18 ppm respectively in chloroform. Theexperimentally recorded chemical shift values also indicate a more deshielded signal at d12.46ppm for the N-H proton of 11 compared to that at d8.56 ppm for the trans enaminoketone 12.This can be considered supportive to ascertain the correct stereochemistry of the enaminoketones.


 

Table 3: DFT/B3LYP/6-311++G(2d,p) calculated GIAO nuclear magnetic shielding tensors of enaminoketones 11 and 12

1H

11

12

Expt

DFT/B3LYP/6-311++G(d,p)

Expt

DFT/B3LYP/6-311++G(d,p)

Gas phase

Chloroform

Gas phase

Chloroform

NH

12.46

13.59

12.99

8.56

5.07

6.18

=CH

5.20

5.26

5.54

5.51

6.12

5.96

COCH3

2.26

1.93

2.13

1.92

1.99

 

1.99

2.02

2.03

2.01

 

2.05

2.13

2.17

1.70

2.00

 

2.24

2.25

1.53

2.01

 

-CH3

1.98

2.10

2.47

1.69

2.09

 

2.00

2.57

1.75

2.11

 

2.32

2.42

3.77

1.04

2.41

 

2.60

3.14

1.36

2.37

 

Phenyl ring

H2; H6

7.51

7.31

7.31

7.31

 

7.54

7.57

7.56

 

7.97

7.04

7.77

7.41

 

7.47

7.88

7.68

 

H3; H5

7.25

7.58

7.50

7.54

 

7.86

7.79

7.83

7.28-7.39

7.56

7.56

7.56

 

7.87

7.85

7.86

 

H4

7.00-7.12 (br.)

7.30

7.67

7.28-7.39

7.26

7.63

 


The generation pathways of cis and trans enaminoketones are separately followed during the study. DFT/B3LYP/6-311++G(2d,p) calculated relative energies and enthalpies have been listed in Table 4. The mechanistic scheme for the two steps is outlined in Fig. 2 for the reaction between aniline (1) and acetylacetone (10). We successfully located two transition states (TSI, TSII, TSIII, TSIV) and an intermediate (I, II) in each reaction channel (Fig. 2). The optimized geometries of the reactants, products, intermediates and transition states are shown in Fig. 3.

 

The first step can occur via two stereochemically distinct transition states (TSI and TSII) to yield the carbinolamines I and II. These intermediates undergo dehydration through TSIII and TSIV respectively to yield the cis and trans enaminoketones 11 and 12.

 

 

 

 

 

Table 4: DFT/B3LYP/6-311++G(2d,p) calculated total energies (E) and relative enthalpies of the reactants, intermediates, transition states and products for the generation of enaminoketones 11 and 12

 

 

E (au)

∆E (KJ/mol)

∆H(KJ/mol)

1

-287.694972

--------------------

--------------------

10

-345.920161

--------------------

--------------------

TSI

-633.532445

217.097

209.103

I

-633.598141

44.612

52.019

TSII

-633.532937

215.806

208.215

11

-557.149171

--------------------

--------------------

11 + H2O

-633.611659

9.121

14.081

TSIII

-633.540813

195.127

187.718

II

-633.600435

38.590

46.330

TSIV

-633.530971

220.967

213.099

12

-557.138180

--------------------

--------------------

12 + H2O

-633.607245

20.710

23.461

 

TSI and TSII indicate the first transition states for the generation of cis and trans enaminoketones respectively. The corresponding second transition states are denoted respectively by TSIII and TSIV. I and II are the intermediates for the cis and trans reaction channels. The cisenaminoketone11 is energetically stabilized by 28.857 KJ/mole compared to the trans isomer 12. ∆E and ∆H values of TSI and TSII differ minimally by 1.291 and 0.888 KJ/mole. Therefore, we cannot draw any inference from these activation energies. However, the intermediate II corresponding to the trans product is stabilized by ∆H value of 5.689 KJ/mole compared to intermediate I of the cis isomer.

 

∆E and ∆H values of TSIII and TSIV differ by 25.840 and 25.381 KJ/mole. The activation energy and enthalpy change for TSIII is lowest among all the located transition states. Therefore, the preferential generation of cis enaminoketone at the end of the reaction can be predicted. This is in conformity with the experimental findings.

 


Fig. 2: Mechanistic outline for the generation of cis and trans enaminoketones 11 and 12

 


The bond lengths and Wiberg bond orders of the reactants, intermediates, transition states and the products have been collected in Table 5. Bond order values provide an idea of bond breaking and bond making in the transition states and intermediates. The Wiberg bond order of the two N-H bonds in aniline is 0.846. It varies to 0.381 and 0.375 for the N-H2 bond in TSI and TSII respectively. The Wiberg bond order values of C3-H2 are 0.363 and 0.366 respectively for the transition states TSI and TSII. It is thus reflected from the bond order values that N-H2 bond gets weakened and C3-H2 bond formation starts in these transition states. In case of the intermediates I and II, the bond orders of C3-H2 bond are calculated as 0.907 and 0.888 respectively. For the second transition state, TSIII, the bond orders for two C3-H bonds are 0.906 and 0.616 respectively. Similarly, the corresponding bonds in TSIV show values of 0.911 and 0.609. It predicts that one C3-H bond gets weakened in TSIII and TSIV. Subsequently, after C3-H bond breaking and loss of H2O, the cis and trans enaminoketones are generated with the formation of C2-C3 double bond.


Fig. 3: DFT/B3LYP/6-311++G(2d,p) optimized reactants (1,10); transition states (TSI, TSII, TSIII, TSIV); intermediates (I, II) and products (11,12)

 

Table 5: DFT/B3LYP/6-311++G(2d,p) calculated bond lengths and bond orders of the reactants, intermediates, transition states and products for the generation of enaminoketones 11 and 12

 

Bond lengths (in Angstroms)

Wiberg bond order

 

C2-N

N-H1

N-H2

C2-O

C2-C3

C3-H’1

C3-H2

C2-N

N-H1

N-H2

C2-O

C2-C3

C3-H’1

C3-H2

1

-----

1.010

1.010

-----

-----

-----

-----

-----

0.846

0.846

-----

-----

-----

-----

10

-----

-----

-----

1.324

1.368

1.081

-----

-----

-----

-----

1.165

1.550

0.920

-----

TS I

1.679

1.018

1.294

1.365

1.530

1.085

1.454

0.710

0.811

0.381

1.048

0.991

0.912

0.363

I

1.431

1.011

-----

1.453

1.554

1.092

1.091

1.006

0.784

-----

0.866

0.966

0.927

0.907

TS II

1.692

1.017

1.300

1.354

1.528

1.085

1.450

0.695

0.830

0.375

1.069

0.994

0.913

0.366

II

1.461

1.009

-----

1.424

1.543

1.096

1.097

0.966

0.834

-----

0.914

0.979

0.913

0.888

TS III

1.314

1.028

-----

2.262

1.485

1.185

1.089

1.432

0.706

-----

0.224

1.060

0.616

0.906

11

1.353

1.031

-----

-----

1.381

-----

1.081

1.252

0.703

-----

-----

1.492

-----

0.925

TS IV

1.324

1.013

-----

2.310

1.476

1.190

1.092

1.397

0.790

-----

0.213

1.077

0.609

0.911

12

1.377

1.008

-----

-----

1.362

-----

1.082

1.164

0.812

-----

-----

1.591

-----

0.918

 


Conclusion:

A new microwave irradiation assisted procedure has been developed for preparation of N-aryl enaminoketones and their subsequent microwave irradiation assisted acid-catalyzed conversion to quinolines. This method is a significant improvement on the existing methods of preparation of substituted quinolines from 1,3-diketones particularly in view of the short times taken and high yields. The first step used an excess of acetylacetone and the appropriate aromatic amine, in the presence of p-toluenesulphonic acid as catalyst and molecular sieves to remove the water formed. Progress of the reactions was monitored by 1H-NMR, which revealed the presence of stereoisomeric mixtures of enaminoketones. The mixtures of enaminoketones were subjected to microwave irradiation in presence of 80% sulphuric acid for a very short period to generate the quinoline products. Computational studies at the DFT/B3LYP/6-311++G(2d,p) level were performed to analyze the reactions. The computed GIAO nuclear magnetic shielding tensors of the cis and trans enaminoketones were compared with the experimental data. This was used to confirm the correct stereochemistry of the intermediate enaminoketones. The transition states and intermediates for the generation of cis and trans enaminoketones have been successfully located at DFT/B3LYP/6-311++G(2d,p) level of theory and the relative energies were evaluated to rationalize the selectivity of the process - the preferential generation of cis enaminoketone could be predicted.  These computational studies, undertaken by us, are the first contribution to computational calculations of this type of reactions, and constitute an important contribution to the theoretical analysis of methodologies for the generation of ring-fused nitrogen heterocycles.

 

Acknowledgement:

Avijit Banerji expresses thanks to University of Calcutta for providing laboratory infrastructure facilities before his retirement as Professor of Chemistry. He thanks the Indian Science Congress Association-Department of Science and Technology for the award of the Sir Asutosh Mookerjee Fellowship for senior scientists; and the Director-General, CCRAS, for extending the facilities of the Central Ayurveda Research Institute for Drug Development, Kolkata for him to avail this Fellowship. Nivedita Acharjee expresses thanks to University of Calcutta and Durgapur Government College for extending computational support and also kind cooperation of Professor Manas Banerjee, Retired Professor of  the University of Burdwan, West Bengal, India. Rina Saha expresses thanks to University Grants Commission for financial support and University of Calcutta for laboratory facilities.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Received on 03.03.2019                    Modified on 20.03.2019

Accepted on 04.04.2019                   ©AJRC All right reserved

Asian J. Research Chem. 2019; 12(2):103-111.

DOI: 10.5958/0974-4150.2019.00023.3