Synthesis of 1,2-Dihydro-SubstitutedAnilineAnalogues Involving N-Phenyl-3-aza-Cope Rearrangement Using a Metal-Free Catalytic Approach

An efficient metal-free domino reaction leading to structural/electronically divergent 1,2-dihydropyridines from easily accessible propargyl vinyl anilines via N-phenyl 3-aza-Cope sigmatropic rearrangement is reported with good to excellent yields using 1,2-dichlorobenzene as solvent under thermal conditions. Spirocyclic substitution is also tolerated under the present optimized conditions.


Introduction
Dihydropyridine (DHP) is amongst the most attractive molecules that have gained the attention of pharmaceutical researchers due to its promising biological efficiency mainly against hypertension and angina [1]. A variety of DHPs such as amlodipine and nifedipine are presently in the market as potent antihypertensive drugs. Literature reports on the synthesis of easily accessible 1,2-and 1,4-dihydropyridine intermediates, which have led to a copious library of biological active drug molecules and natural product compounds including alkaloids [2]. e search for new feasible synthetic approaches for the preparation of the derivatives of azaheterocycles, particularly, 1,2-dihydropyridines (1,, is an important study as these compounds can exhibit diverse biological activities such as follows [3,4]: 1,2-DHPs act as starting materials for the synthesis of the 2-azabicyclo[2.2.2]octanes (isoquinuclidines) ring system present in various alkaloids such as ibogaine, dioscorine, and catharanthine (vinca alkaloids) (Figure 1). e anti-influenza drug, oseltamivir phosphate (Tamiflu), is also synthesized from 1,2-DHP via an isoquinuclidine intermediate [5] (Figure 2). Considerable efforts have been directed toward the development of new and efficient methodologies for the synthesis of 1,2-dihydropyridines since the first synthesis started by Fowler [6]. 1,2-DHPs are prepared by hydrogenation involving the redox cycloisomerization approach [7] and via 6π-azaelectrocyclization [8]. More pioneering work particularly in this field is carried out by Tejedor et al. using microwave-assisted domino reaction of a propargyl vinyl ether (secondary or tertiary) and a primary amine (aliphatic or aromatic) in toluene or methanol [9][10][11].
Harschneck and Kirsch have exploited transition metal catalysts such as AuCl 3 for preparation of 1,2-DHPs, wherein propargyl vinyl ethers and amines were used as starting materials [12,13]. In another study, a four-component synthetic approach was employed to prepare derivatives of 1,2-DHPs [14] through a one-pot multicomponent reaction of acetophenone, aldehyde, and ammonium acetate with ethyl cyanoacetate or malononitrile, respectively. Besides these several other transition metals have also been utilized as catalysts, for example, Rh [15], Cu/Mo [16], and low-valent Co complexes [17] for the synthesis of 1,2-DHPs via C-H activation/6π-electrocyclization pathways. Furthermore, various other metal complexes have also been evaluated, including Pt (II)-catalyzed cycloisomerization of aziridinyl propargylic esters [18], Sc(OTf ) 3 -catalyzed imino-Aldol reactions using vinyloxiranes as masked dienolates [19], BF 3 .Et 2 O-catalyzed 6π-electrocyclization of enaminonitriles with α,β-unsaturated aldehydes [20], and N-amino-3-aza-Cope rearrangements [21,22]. Additionally, various other examples of the synthesis of 1,2-dihydropyridines have been comprehensively compiled by Silva et al. in a recent review [4]. Notably, most of the preparation methods of 1,2dihydropyridines are based on nucleophilic addition to Nalkyl or N-acylpyridinium salts which often yield undesirable side products [23]; hence, to overcome these limitations, various alternative reaction strategies have been designed [24]. In most of the already reported methodologies, use of expensive metal catalysts or harsh reaction condition stimulates the need for further improvement in the synthesis of 1,2-DHPs.
In this regard, sigmatropic rearrangement reactions can be an advantageous alternative approach for the synthesis of 1,2-dihydropyridines. ese types of reactions constitute fascinating chemical bond reorganizations reactions, which have been extensively used in organic synthesis [25]. Herein, we present our preliminary results pertaining to an efficient domino reaction, which led to the formation of electronically divergent 1,2-DHPs from easily accessible propargyl vinyl anilines involving a metal-free N-phenyl 3-aza-Cope sigmatropic rearrangement with good to excellent yields using 1,2dichlorobenzene as solvent.

Materials and Methods
General melting points were determined on a Reichert ermovar apparatus and are uncorrected. in-layer chromatography was performed on Merck silica gel 60 F254 0.2 mm thick plates and visualized under UV light or by exposing to iodine vapour. For preparative separation, the plates were 0.51 mm thick. For flash chromatography silica Merck Kieselgel, 60 and 70-230 mesh were used. Infrared (IR) spectra were recorded on a Perkin-Elmer 1000X FT-IR spectrometer. Proton and 13 C NMR spectra were recorded in CDCl 3 on a Bruker ARX 400 spectrometer (400 MHz for 1 H, 100.63 MHz for 13 C). Chemical shifts are reported relative to tetramethylsilane as the internal reference. Mass spectra were recorded on Fisons TRIO 2000 or AEI MS-9 spectrometer. Highresolution MS spectra (HRMS) were obtained on a FT-ICR/MS Finnigan FT/MS 2001-DT spectrometer at 70 eV by electron impact or on a Finnigan MAT 900 ST spectrometer by ESI. Elemental analysis was performed in Hewlett-Packard, model 185 (United States) (HP). Microwave reactions were conducted in sealed glass vessels (capacity 10 mL) using a CEM Discover microwave reactor equipped with a surface sensor to measure the temperature of the reaction mixture.
Oseltamivir ( under reduced pressure. Anhydrous solvents were dried and freshly distilled by standard methods [26].
Aqueous phase of the reaction mixture is extracted with DCM (2×25 ml). Organic phase obtained is washed with 1 ml HCl twice and concentrated using vacuum, which gives the crude compound, which is further purified by flash column chromatography using diethyl ether: n-hexane (1 : 3) to afford b in 91% isolated yield (5.87 g).

Spectral
. Aniline (0.657 ml, 7.21 mmol, 1 equiv.) is slowly added to a stirred solution of b (1 g, 7.93 mmol, 1.1 equiv.), CuCl (70 mg, 0.1 equiv.), and triethyl amine (1.12 ml, 1.1 equiv.) dissolved in THF (10 ml) at room temperature (Scheme 1). en, the reaction mixture is refluxed for 90 min, while monitoring the reaction mixture for the complete consumption of starting material, and the reaction mixture is then concentrated and then dissolved in EtOAc (10 ml). en, the reaction mixture is treated with saturated NH 4 Cl solution (10 mL) twice followed by brine solution (10 ml). e organic layer is then concentrated under reduced pressure to give crude residue, which is then subjected to flash column chromatography using gradient elution system starting from n-hexane to 1 : 5 of ethyl acetate: n-hexane, to afford desired product c in 71% isolated yield (0.83 g).

N-Phenyl-2,2-dimethyl-5-tosyl-1,2-dihydropyridine (F).
Compound D (100 mg) is dissolved in 1,2-dichorobenzene (2 mL) and heated at 180°C, for 20 min, while monitoring the reaction progress by TLC (Scheme 2). After the starting material is almost completely consumed, the crude reaction mixture is subjected to direct flash chromatography using n -hexane as the first eluent to remove the solvent; i.e., 1,2-DCB and then 10% ethyl acetate : n-hexane solution is utilized as eluent to obtain the desired compound F as colourless oil in 95% isolated yield (95 mg).  13
All the compounds obtained were subjected to spectroscopic analysis. e FT-IR of compound D showed an absorption band of approximately 1607 cm −1 , indicating that the product has a double bond conjugated to a heteroatom (enamine) [29]. Furthermore, bands at 1296 cm −1 , 1158 cm −1 , and 1135 cm −1 corresponding to the SO 2 bonds of the tosyl group were also observed. In the 1 H NMR spectra of compound D, doublets were displayed at δ 8.17 (d, J � 12.6 Hz, 1H) and 4.51 (d, J � 12.6 Hz, 1H), confirming the enamine in conjugation with trans-configuration. Both signals are characteristic of the tosyl group. 13  doublet at δ 6.09 (dd, J � 9.8 and 1.4 Hz, 1H) and 4.95 (d, J � 9.8 Hz, 1H), which confirms the complete electrocyclization. 13 C NMR further confirms the formation of the product, as propargylic peaks at δ 85.9 and δ 73.5 disappeared and new peaks at δ 117.6 and δ 122.1 appeared, representing the formation of double bond. HRMS data further confirmed the formation of the desired product F. We propose a mechanism pathway for the above aza-Cope rearrangement, as shown in Scheme 3, which is quiet similar to the one reported previously [30]. In brief, when compound (a) is heated to 180°C, it undergoes a [3,3]-sigmatropic rearrangement yielding the allene (b).
is is followed by proton migration, which isomerizes to triene (c) which through intramolecular electrocyclization gives the final reaction product 1,2-dihydropyridine (d). However, further studies along with experimental and spectroscopic studies must be carried out to authenticate the claim.
Different solvents were tested for optimization, and it was found that, among the various solvents investigated, 1,2-DCB is the best solvent (see Table 1).
From the studies carried out, it is concluded that conventional heating yields better results compared to the same reaction performed employing microwave irradiation under the mentioned parameters (entries 2 and 7, Table 1).
Inspired by the successful formation of F (Scheme 2), the study is extended with electronically divergent anilines, substituted propargyl acetates, and other Michael acceptors such as ethynyl p-tolyl sulfone (a), methyl propargylate (b), and dimethyl acetylene dicarboxylate (c) to synthesize corresponding 1,2-DHPs (Table 2). e study is extended by utilizing five types of propargyl acetates and reacted with electronically divergent anilines to form corresponding propargyl vinyl amines, which in turn were subjected to the aza-Cope sigmatropic rearrangement, yielding the corresponding 1,2-DHPs.
Among the three Michael acceptors utilized in this methodology, the addition reaction employing dimethyl acetylene dicarboxylate (entries 11 and 12, see Table 2) yields the lowest product. is can be attributed to the deactivation of the acceptor due to the presence of two electron withdrawing groups in opposite positions, causing a reduction in the electrophilicity of triple bond as compared to the triple bond of the remaining acceptors employed. Furthermore, under the optimized conditions, cyclopentyl propargyl vinyl aniline or cyclohexyl propargyl vinyl aniline also undergo aza-Cope sigmatropic rearrangement; however, the yield is less compared to the open chain propargyl vinyl anilines (entries 4 and 5, Table 2).
is protocol is unsuccessful with an aniline having electron-withdrawing group, such as NO 2 . However, when propargyl acetate or 1-methyl propargyl Scheme 3: Proposed mechanism for the formation of 1,2-DHPs. Journal of Chemistry acetate are used as precursors, the rearranged product obtained is pyridines instead of desired 1,2dihydropyridines.
Observation of 13 C NMR spectra shows the proximity of all these signals presents very similar chemical deviations. In the case of the proposed structures, it is possible   Journal of Chemistry to draw a plane of symmetry passing along the dihydropyridine ring, and that due to the planarity of all the different functional groups, all obtained molecules extend beyond this ring [30].

Conclusions
In this study, we have successfully demonstrated the synthesis of various substituted 1,2-dihydropyridines from electronically divergent N-propargyl vinyl anilines, using metal-free aza-Cope rearrangement. is improved version delivers these important heterocyclic scaffolds with a wider diversity at the ring, along with mono-and disubstitution at the sp 3 position. Spirosubstituted 1,2-DHPs are also obtained under this reaction conditions albeit in lesser yields. e protocol can be extended to secondary and tertiary propargyl vinyl ethers bearing internal or terminal alkyne moieties and primary aromatic amines. Extension of this protocol to aliphatic amines and other Michael acceptors is also currently underway.
Data Availability e data of the research work carried out are presented in the manuscript and supplementary materials itself, and all the readers of this article shall be able to get the desired information. Further data will be available on request to the corresponding author.

Conflicts of Interest
e authors declare that there are no conflicts of interest.

Supplementary Materials
General melting points were determined on a Reichert ermovar apparatus and are uncorrected. in-layer chromatography was performed on Merck silica gel 60 F254 0.2 mm thick plates, visualized under UV light or by exposing to iodine vapour. For preparative separations, the plates were 0.51 mm thick. For flash chromatography silica Merck Kieselgel, 60 and 70-230 mesh were used. Infrared (IR) spectra were recorded on a Perkin-Elmer 1000X FT-IR spectrometer. Proton and 13 C NMR spectra were recorded in CDCl3 on a Bruker ARX 400 spectrometer (400 MHz for 1H, 100.63 MHz for 13C). Chemical shifts are reported relative to tetramethylsilane as the internal reference (δ H 0.00) for 1H NMR spectra and to CDCl 3 (δ C 77.00) for 13C NMR spectra. Ordinary mass spectra were recorded on Fisons TRIO 2000 or AEI MS-9 spectrometer. High-resolution MS spectra (HRMS) were obtained on a FT-ICR/MS Finnigan FT/MS 2001-DT spectrometer at 70 eV by electron impact or on a Finnigan MAT 900 ST spectrometer by ESI. Elemental analysis was performed in Hewlett-Packard, model 185 (United States) (HP). Microwave reactions were conducted in sealed glass vessels (capacity 10 mL) using a CEM Discover microwave reactor equipped with a surface sensor to measure the temperature of the reaction mixture. (Supplementary Materials)