Synthesis of Unexpected Dimethyl 2-(4-Chlorophenyl)-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,3-dicarboxylate via Hydrolysis/Cycloaddition/Elimination Cascades: Single Crystal X-ray and Chemical Structure Insights

Hydrolysis/[3 + 2] cycloaddition/elimination cascades employed for the synthesis of unexpected tricyclic compound derived from isoquinoline. Reaction of ethylene derivative 1 with the isoquinoline ester iminium ion 2 in alkaline medium (MeOH/NEt3) under reflux for 1 h resulted in the formation of the fused pyrrolo[2,1-a]isoquinoline derivative 3. Its structure was elucidated by X-ray single crystal and other spectrophotometric tools. Hirshfeld calculations for 3 and its crystal structure analysis revealed the importance of the short O. . . H (19.1%) contacts and the relatively long H. . . C (17.1%), Cl. . . H (10.6%) and C. . . C (6.1%) interactions in the molecular packing. DFT calculations were used to compute the electronic and spectroscopic properties of the studied system. The studied compound has polar nature (3.5953 Debye). TD-DFT calculations assigned the shortest wavelength band (220 nm) to the HOMO−1→LUMO+2 (57%), HOMO−1→LUMO+4 (14%) mixed excitations. The calculated NMR chemical shifts correlated very well with the experimental data (R2 = 0.93–0.94).


Introduction
Quinoline and isoquinoline analogues are privileged structures which exploited for the synthesis of polyheterocycles for the applications in the therapeutic area [1][2][3]. Fused isoquinoline moiety with other heterocyles gained much attention in the drug discovery community, however many efficient synthetic protocols being reported in the last decade [4][5][6][7][8]. Pyrrolo [2,1-a]isoquinoline is a core structure in many natural products with pharmaceutical targets including human topoisomerase I inhibitors and anti-HIV-1 activities as lamellarins [9][10][11], and others such as trollines, crispines, and oleraceins [1]. Indeed, this framework remarks as a skeleton for many synthesized molecules as important, interesting and attractive goal in organic synthesis. [3 + 2] Cycloaddition reaction via azomethine ylide is one of the most straightforward, powerful, and efficient reactions that offered the construction of fused tricyclic compound based on pyrrolo[2,1-a]isoquinoline [12]. Many examples described in the literature for the synthesis of pyrrolo[2,1-a]isoquinolines using metal mediated syntheses such as The monoquaternary salt 2 (1 mmol, 1 eq., 296 mg) and ethylene derivative 1 (1.0 mmol, 1.0 eq. 464 mg) were dissolved in MeOH (10 mL). Then, NEt 3 (1 mmol, 1 eq., 0.14 mL) was partially added under magnetic stirring, subsequently the reaction mixture was refluxed for 1 h which the progress of the reaction monitored by TLC (nHexane-EtOAc (3:1). Evaporation the solvent and the crude product was purified by column chromatography on silica gel, eluting with petrol. ether-EtOAc (3:1), to give ester 3 (347 mg, 88%) as pale-yellow needles. 1 3.53 (s, 3H). 13

X-ray Single Crystal Measurements of 3
The technical experimental data for the synthesized compound 3 and the software [33][34][35][36] employed for data processing was amended in the Supplementary Materials. The crystallographic details are summarized in Table 1.

Chemistry
The unexpected tricyclic heterocyclic compound based on isoquinoline scaffold has been obtained from the starting material named (Z)-2-(4-chlorobenzylidene)-5,6diphenylimidazo[2,1-b]thiazol-3(2H)-one 1 with the bromide salt of isoquinoline ester 2 in MeOH using basic medium and under reflux for 1 h. The generated azomethine ylide was involved in the reaction as intermediate which further move to [3 + 2] cycloaddition (32CA) reaction with the ethylene derivative 1 to afford the new constructed fused pyrrolidine ring. Initially, we expected to obtain either the two diastereisomers 5 or 6 but surprisingly the reaction afforded the tricyclic heterocyclic derivative 3. A proposed mechanism for this unexpected reaction was presented in Scheme 1. First, the isoquinoline ester iminium ion in alkaline medium could be deprotonated to yield isoquinolinium ylide. The amidic bond of the dipolarphile could be hydrolyzed under the same condition to afford the corresponding dipolarphile-ester 7. Subsequently, [3 + 2] cycloaddition (32CA) reaction between the isoquinolinium ylide and dipolarphile-ester affords dimethyl 2-(4-chlorophenyl)-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,3-dicarboxylate 3 in which the 4,5-diphenyl-1H-imidazole-2-thiol 4 serve as a good leaving group. To understand this reaction mechanism, a control experiment was carried out subsequently. The dipolarphile 1 was taken in alkaline medium (MeOH/NEt 3 ) under reflux for 2 h monitored by TLC (Ethyl acetate: nHexane 20%), the reaction proceeded to give the corresponding ester 7 (Scheme 1). The chemical feature of the tricyclic heterocyclic compound 3 was assigned based on 1 H-NMR; 13 C-NMR; IR; and single crystal X-ray diffraction analysis. Figure 1 presents the structure of 3 based on the X-ray diffraction analysis. Crystallographic details are depicted in Table 1 while the reported geometric parameters are listed in Table 2 Figure 1). In ring C, the N1C19C20C7 atoms are located in the same plane while C8 atom located out of this plane by 0.365 Å. Additionally, the N1C19C20C9 plane is slightly deviated from the mean plan passing through rings A and B by only 3.5 • while deviated from the mean plane of ring D by 86.7 • indicating that rings C and D are nearly perpendicular to one another. The molecular conformation structure of this compound is stabilized by weak intramolecular C17-H17. . . O4 with donor-acceptor distances of 2.980(2) Å. For better clarity, this intramolecular hydrogen bonding interaction is presented as turquoise dotted color line in the left part of Figure 2 (left part).  Figure 1 presents the structure of 3 based on the X-ray diffraction analysis. Crystallographic details are depicted in Table 1 while the reported geometric parameters are listed in Table 2. The lattice parameters are a = 7.9337(3) Å, b = 32.6514(8) Å, c = 7.7034(3), β = 111.687(4)°. The molecule comprised three fused rings where the two rings A and B are perfectly planar to one another ( Figure 1). In ring C, the N1C19C20C7 atoms are located in the same plane while C8 atom located out of this plane by 0.365 Å. Additionally, the N1C19C20C9 plane is slightly deviated from the mean plan passing through rings A and B by only 3.5° while deviated from the mean plane of ring D by 86.7° indicating that rings C and D are nearly perpendicular to one another. The molecular conformation structure of this compound is stabilized by weak intramolecular C17-H17...O4 with donor-acceptor distances of 2.980(2) Å. For better clarity, this intramolecular hydrogen bonding interaction is presented as turquoise dotted color line in the left part of Figure 2 (left part).  Table 3). The molecular packing is shown in Figure 2 (right part).

Crystal Structure Description of 3
Interestingly, the molecules are stacked to one another via aromatic π-π interactions of rings A with each other. This fact is clearly seen in the right part of Figure 2. The centroid-centroid distance between two stacked rings A is 3.882 Å and shortest C. . . C interaction of 3.521 and 3.559 Å for C11. . . C16 and C14. . . C18, respectively.

Analysis of Molecular Packing
The Hirshfeld surfaces of 3 is shown in Figure 3 while the whole set of intermolecular contacts contributing in the molecular packing are listed in Figure 4. In addition, summary of the shortest contacts is listed in Table 4  Bond   Table 3). The molecular packing is shown in Figure 2 (right part).  Table 2. Bond lengths (Å) and angles ( • ) for 3.

Bond
Length 114.88 (15)   Interestingly, the molecules are stacked to one another via aromatic π-π interactions of rings A with each other. This fact is clearly seen in the right part of Figure 2. The centroid-centroid distance between two stacked rings A is 3.882 Å and shortest C…C interaction of 3.521 and 3.559 Å for C11…C16 and C14…C18, respectively.

Analysis of Molecular Packing
The Hirshfeld surfaces of 3 is shown in Figure 3 while the whole set of intermolecular contacts contributing in the molecular packing are listed in Figure 4. In addition, summary of the shortest contacts is listed in Table 4 1 x,1/2 − y,1/2 + z; 2 −1 + x,y,z; 3 1 + x,y,z; 4 x,1/2 − y, −1/2 + z; 5 1 + x,y,1 + z a longer distances than the vdWs radii sum.

DFT Studies
The structure of 3 was optimized and the resulting optimized geometry is compared with the experimental one ( Figure 6). There is good matching between the calculated and

DFT Studies
The structure of 3 was optimized and the resulting optimized geometry is compared with the experimental one ( Figure 6). There is good matching between the calculated and experimental data (Table S1, Supplementary Materials). There are excellent straightline correlations (R 2 = 0.9939-0.9599) between the calculated and experimental geometric parameters ( Figure S4; Supplementary Materials). Crystal packing effects are main reason for the little differences between the computed and experimental structures. The natural atomic charges were calculated and the results are depicted in Table S2 (Supplementary Materials). The results indicated the slight electronegative nature of chlorine atom (−0.0116 e). On the other hand, the nitrogen and oxygen atomic sites are electronegative where the two carbonyl oxygen atoms have higher charges than the two oxygen atoms bonded to the methyl groups. It is clear that the two oxygen atoms of the ester group attached to the sp 2 hybridized carbon atom have higher negative charges than the corresponding O-atoms of the ester group attached to the sp 3 hybridized carbon atom. The majority of carbon atoms have electronegative nature where the only exceptions are those C-atoms bonded either to N or O atoms. As a consequence of the presence of different charged regions in the studied molecule, the compound has polar nature (3.5953 Debye) and the dipole moment vector is presented in Figure 7. In molecular electrostatic potential (MEP), there are intense red regions (highest edensity) close to the carbonyl oxygen atoms while the blue region (lowest e-density) closes to the CH proton of the sp 3 hybridized carbon atom bonded to the ester group (Figure 7). In the same figure, the HOMO and LUMO are located over the π-system of 3. Hence, the HOMO→LUMO excitation is mainly π-π* transition. Based on the HOMO and LUMO energies, the reactivity indices such as ionization potential (I = −EHOMO), electron affinity (A = −ELUMO), chemical potential (μ = −(I + A)/2), hardness (η = (I−A)/2) as well as electrophilicity index (ω = μ 2 /2η) were calculated [44][45][46][47][48][49][50]. The calculated parameters are 5.0279, 1.3350, −3.1814, 3.6929 and 1.3704 eV, respectively.

UV-Vis and NMR Spectra
The experimental UV-Vis spectra of the studied molecule were measured in different The natural atomic charges were calculated and the results are depicted in Table S2 (Supplementary Materials). The results indicated the slight electronegative nature of chlorine atom (−0.0116 e). On the other hand, the nitrogen and oxygen atomic sites are electronegative where the two carbonyl oxygen atoms have higher charges than the two oxygen atoms bonded to the methyl groups. It is clear that the two oxygen atoms of the ester group attached to the sp 2 hybridized carbon atom have higher negative charges than the corresponding O-atoms of the ester group attached to the sp 3 hybridized carbon atom. The majority of carbon atoms have electronegative nature where the only exceptions are those C-atoms bonded either to N or O atoms. As a consequence of the presence of different charged regions in the studied molecule, the compound has polar nature (3.5953 Debye) and the dipole moment vector is presented in Figure 7.
In molecular electrostatic potential (MEP), there are intense red regions (highest edensity) close to the carbonyl oxygen atoms while the blue region (lowest e-density) closes to the CH proton of the sp 3 hybridized carbon atom bonded to the ester group (Figure 7). In the same figure, the HOMO and LUMO are located over the π-system of 3. Hence, the HOMO→LUMO excitation is mainly π-π* transition. Based on the HOMO and LUMO energies, the reactivity indices such as ionization potential (I = −E HOMO ), electron affinity (A = −E LUMO ), chemical potential (µ = −(I + A)/2), hardness (η = (I−A)/2) as well as electrophilicity index (ω = µ 2 /2η) were calculated [44][45][46][47][48][49][50]. The calculated parameters are 5.0279, 1.3350, −3.1814, 3.6929 and 1.3704 eV, respectively. The natural atomic charges were calculated and the results are depicted in Table S2 (Supplementary Materials). The results indicated the slight electronegative nature of chlorine atom (−0.0116 e). On the other hand, the nitrogen and oxygen atomic sites are electronegative where the two carbonyl oxygen atoms have higher charges than the two oxygen atoms bonded to the methyl groups. It is clear that the two oxygen atoms of the ester group attached to the sp 2 hybridized carbon atom have higher negative charges than the corresponding O-atoms of the ester group attached to the sp 3 hybridized carbon atom. The majority of carbon atoms have electronegative nature where the only exceptions are those C-atoms bonded either to N or O atoms. As a consequence of the presence of different charged regions in the studied molecule, the compound has polar nature (3.5953 Debye) and the dipole moment vector is presented in Figure 7. In molecular electrostatic potential (MEP), there are intense red regions (highest edensity) close to the carbonyl oxygen atoms while the blue region (lowest e-density) closes to the CH proton of the sp 3 hybridized carbon atom bonded to the ester group (Figure 7). In the same figure, the HOMO and LUMO are located over the π-system of 3. Hence, the HOMO→LUMO excitation is mainly π-π* transition. Based on the HOMO and LUMO energies, the reactivity indices such as ionization potential (I = −EHOMO), electron affinity (A = −ELUMO), chemical potential (μ = −(I + A)/2), hardness (η = (I−A)/2) as well as electrophilicity index (ω = μ 2 /2η) were calculated [44][45][46][47][48][49][50]. The calculated parameters are 5.0279,

UV-Vis and NMR Spectra
The experimental UV-Vis spectra of the studied molecule were measured in different solvents as shown in the lower part of Figure 8. Obviously, the electronic spectra showed very little changes due to solvent effects. The UV-Vis spectra of the studied molecule exhibited several electronic transitions at 220 . Figure 8. The calculated (upper) and experimental (lower) electronic spectra of 3. Figure 8. The calculated (upper) and experimental (lower) electronic spectra of 3.

Conclusions
In conclusion, we have been demonstrated the synthesis of a new pyrrolo[2,1-a]isoquinoline derivative via hydrolysis/[3+2] cycloaddition/elimination reactions incorporation cascades that proceed via azomthine ylide intermediate. Analysis of Hirshfeld surfaces indicated that the short O…H and the relatively long H…C, Cl...H and C…C interactions are the most significant while the H…H contacts are the most frequently occurring close interactions. DFT calculations were used to compute the electronic and spectroscopic properties of the studied system. The studied compound has polar nature (3.5953 Debye). The NMR chemical shifts and the UV-Vis spectral bands were calculated using GIAO and TD-DFT methods, respectively. This hypothesis could be useful and open insight to substrate scope with different substituents and examine the application of the new set of compounds against different targets.

Conclusions
In conclusion, we have been demonstrated the synthesis of a new pyrrolo[2,1a]isoquinoline derivative via hydrolysis/[3 + 2] cycloaddition/elimination reactions incorporation cascades that proceed via azomthine ylide intermediate. Analysis of Hirshfeld surfaces indicated that the short O. . . H and the relatively long H. . . C, Cl. . . H and C. . . C interactions are the most significant while the H. . . H contacts are the most frequently occurring close interactions. DFT calculations were used to compute the electronic and spectroscopic properties of the studied system. The studied compound has polar nature (3.5953 Debye). The NMR chemical shifts and the UV-Vis spectral bands were calculated using GIAO and TD-DFT methods, respectively. This hypothesis could be useful and open insight to substrate scope with different substituents and examine the application of the new set of compounds against different targets.