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Article

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

by
Mezna Saleh Altowyan
1,
Saied M. Soliman
2,
Matti Haukka
3,
Nora H. Al-Shaalan
1,
Aminah A. Alkharboush
1 and
Assem Barakat
4,*
1
Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
2
Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt
3
Department of Chemistry, University of Jyväskylä, P.O. Box 35, FI-40014 Jyvaskyla, Finland
4
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
*
Author to whom correspondence should be addressed.
Crystals 2022, 12(1), 6; https://doi.org/10.3390/cryst12010006
Submission received: 1 December 2021 / Revised: 15 December 2021 / Accepted: 16 December 2021 / Published: 21 December 2021
(This article belongs to the Special Issue New Trends in Crystals at Saudi Arabia)
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Abstract

:
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).

1. 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 silver-catalyzed cycloisomerization/dipolar cycloaddition reported by Porco Jr. et al. [13]. Cascade oxidation/cycloaddition/aromatization catalyzed by copper was described by Wang and co-workers [14]. In addition, a very elegant example disclosed by Xiao in which [Ru(bpy)3]3+ catalyzed the oxidation/cycloaddition/aromatization cascade reactions [15]. Another elegant protocol is the Pd-catalyzed stereoselective four multicomponent synthesis of pyrrolidinyl-,pyrazolidinyl-, and isoxazolidinyl isoquinolines described by Grigg, R. et al. [16]. Among the reported procedures for the synthesis of pyrrolo[2,1-a]isoquinolines was to use the alkaline medium [17] or electrochemical synthesis [18] to generate the azomethine ylide as integral part of the dipolar [3 + 2] cycloaddition reaction.
The application of fused heterocyclic system based on imidazo[2,1-b]thiazole skeleton covers a vast therapeutic area as antimicrobial, anti-inflammatory, diuretic agents and human constitutive androstane receptor (CAR) agonist [19,20,21]. In this context, and in continuation of our interest to construct new heterocyclic systems by [3 + 2] cycloaddition (32CA) reaction [22,23,24,25,26,27,28,29,30], we employed the imidazo[2,1-b] thiazole based chalcone as a dipolarphile for the [3 + 2] cycloaddition (32CA) reaction to construct a new compound derived from pyrrolo[2,1-a]isoquinoline (3). Molecular insights including X-ray single crystal structure combined with Hirshfeld surface analysis of 3 were presented. In addition, DFT calculations were performed in order to compute the NMR chemical shifts and simulate the UV-Vis electronic spectra.

2. Materials and Methods

The synthesis of imidazo[2,1-b]thiazole derivative as a dipolarphile 1 and the monoquaternary salt 2 followed by the reported procedure in literature [31,32].

2.1. Synthesis of Dimethyl 2-(4-Chlorophenyl)-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,3-dicarboxylate 3

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, NEt3 (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.
1H NMR (400 MHz, CDCl3) δ 9.85 (d, J = 8.4 Hz, 1H), 9.35 (d, J = 7.4 Hz, 1H), 8.63–8.56 (m, 1H), 7.75–7.68 (m, 1H), 7.56 (s, 2H), 7.15 (s, 1H), 6.69 (d, J = 6.6 Hz, 2H), 6.28 (d, J = 7.3 Hz, 1H), 4.56 (d, J = 3.0 Hz, 1H), 4.42 (d, J = 3.3 Hz, 1H), 3.83 (s, 2H), 3.53 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 170.72, 166.06, 151.71, 143.31, 136.13, 132.82, 132.20, 131.46, 129.61, 128.99, 128.29, 126.68, 126.16, 123.76, 107.82, 95.40, 71.24, 53.30, 50.73, 50.53; IR (KBr, cm−1): 3428, 2948, 2870, 1710, 1651, 1510, 107; Chemical formula: C22H18ClNO4.

2.2. 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.

2.3. Computational Study

The protocols for the Hirshfeld surface analysis [37], DFT [38,39], NBO [40], self-consistent reaction filed (SCRF) calculations [41,42], as well as NMR computation [43] are provided in Supplementary Materials.

3. Results and Discussion

3.1. Chemistry

The unexpected tricyclic heterocyclic compound based on isoquinoline scaffold has been obtained from the starting material named (Z)-2-(4-chlorobenzylidene)-5,6-diphenylimidazo[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/NEt3) 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 1H-NMR; 13C-NMR; IR; and single crystal X-ray diffraction analysis.

3.2. Crystal Structure Description of 3

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).
The molecular packing of 3 is dominated by three hydrogen bonds shown as red dotted lines in Figure 2 (left part). The molecules are packed via non classical C-H…O interactions such as C8-H8…O4, C12-H12…O2, and C22-H22A…O1 contacts. The distances between the donor (D) and acceptor (A) are 3.245(2), 3.346(2) and 3.520(2) Å, respectively (Table 3). The molecular packing is shown in Figure 2 (right part).
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.

3.3. 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. The molecules are mainly packed by short O…H (19.1%) contacts. These O…H contacts are shorter than the vdWs radii sum of the interacting atoms with red regions in the dnorm maps (Figure 5). The O2…H12 (2.343 Å), O4…H8 (2.332 Å) and O1…H22A (2.499 Å) are the shortest C-H…O interactions. In addition, relatively long H…C (17.1%), Cl…H (10.6%) and C…C (6.1%) interactions are also dominant in the crystal packing (Figure 4). The H…H contacts are the most dominant with contact percentage of 44.8% from the whole fingerprint area. The absence of red/blue triangles in shape index and large green flat area in curvedness revealed the absence of significant π-π stacking interactions.

3.4. 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 straight-line correlations (R2 = 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 sp2 hybridized carbon atom have higher negative charges than the corresponding O-atoms of the ester group attached to the sp3 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 e-density) close to the carbonyl oxygen atoms while the blue region (lowest e-density) closes to the CH proton of the sp3 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 = μ2/2η) 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.

3.5. 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, 272, 286, 298, 358, 397, 414 and 444 nm. Theoretically, the TD-DFT calculations predicted five electronic transitions calculated at 381.4 nm (f = 0.2416), 342.0 nm (f = 0.1837), 271.4 nm (f = 0.1269), 258.2 nm (f = 0.1157) and 220 nm (f = 0.1270) as shown in the upper part of Figure 8. The two bands calculated at 271.4 and 258.2 nm appeared in the theoretical TD-spectrum as one broad band mixed with a shoulder. The shortest wavelength band calculated at 220 nm is experimentally observed at the same wavelength and it was assigned to the H−1→L + 2 (57%) and H−1→L + 4 (14%) mixed excitations. Similarly, the electronic spectral bands observed experimentally at 272, 358 and 397 nm were predicted at 271.4, 342.0 and 381.4 nm, respectively. These spectral bands were assigned to H−1→LUMO (89%), HOMO→L + 1 (93%) and HOMO→LUMO (94%) excitations, respectively (Figure 9).
1H and 13C NMR chemical shifts (CSs) were calculated and compared with the experimental results (Table S3 (Supplementary Materials)) showing high correlation coefficients (R2 = 0.93–0.94) which are close to 1 (Figure S5 Supplementary Materials).

4. 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.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/cryst12010006/s1, Figures S1–S3: 1HNMR, 13CNMR, and IR. Figure S4: Correlations between the optimized and experimental geometric parameters. Figure S5: 1H and 13C NMR correlations between the calculated and experimental data. Tables S1–S3: Computational investigations.

Author Contributions

Conceptualization, A.B.; methodology, M.S.A. and A.A.A.; software, S.M.S. and M.H.; validation, M.S.A., N.H.A.-S. and A.A.A.; formal analysis, M.S.A., N.H.A.-S., M.H. and A.A.A.; investigation, M.S.A.; resources, M.S.A. and A.B.; data curation, A.B. and S.M.S.; writing—original draft preparation, A.B. and S.M.S.; writing—review and editing, A.B. and S.M.S.; visualization, A.B., M.S.A. and N.H.A.-S.; supervision, A.B. and M.S.A.; project administration, A.A.A.; funding acquisition, M.S.A. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University, through the Research Groups Program Grant no. (RGP-1443-0040).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

This work was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University, through the Research Groups Program Grant no. (RGP-1443 -0040).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Roesch, E.S. Isoquinolines. In Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation; Brase, S., Ed.; RSC: Cambridge, UK, 2015; pp. 147–213. [Google Scholar]
  2. Horton, D.A.; Bourne, G.T.; Smythe, M.L. The combinatorial synthesis of bicyclic privileged structures or privileged substructures. Chem. Rev. 2003, 103, 893–930. [Google Scholar] [CrossRef]
  3. García-Castro, M.; Zimmermann, S.; Sankar, M.G.; Kumar, K. Scaffold diversity synthesis and its application in probe and drug discovery. Angew. Chem. Int. Ed. 2016, 55, 7586–7605. [Google Scholar] [CrossRef] [PubMed]
  4. Sau, P.; Santra, S.K.; Rakshit, A.; Patel, B.K. tert-Butyl nitrite-mediated domino synthesis of isoxazolines and isoxazoles from terminal aryl alkenes and alkynes. J. Org. Chem. 2017, 82, 6358–6365. [Google Scholar] [CrossRef]
  5. Gang, M.Y.; Liu, J.Q.; Wang, X.S. CuI-catalyzed Sonogashira reaction for the efficient synthesis of 1H-imidazo[2,1-a]isoquinoline derivatives. Tetrahedron 2017, 73, 4698–4705. [Google Scholar] [CrossRef]
  6. Shi, R.G.; Sun, J.; Yan, C.G. Tandem double [3 + 2] cycloaddition reactions at both C-1 and C-3 atoms of N-cyanomethylisoquinolinium ylide. ACS Omega 2017, 2, 7820–7830. [Google Scholar] [CrossRef] [PubMed]
  7. Leonardi, M.; Villacampa, M.; Menéndez, J.C. Mild and general synthesis of pyrrolo[2,1-a]isoquinolines and related polyheterocyclic frameworks from pyrrole precursors derived from a mechanochemical multicomponent reaction. J. Org. Chem. 2017, 82, 2570–2578. [Google Scholar] [CrossRef]
  8. Al Matarneh, C.M.; Apostu, M.O.; Mangalagiu, I.I.; Danac, R. Reactions of ethylcyanoformate with cycloimmonium salts: A direct pathway to fused or substituted azaheterocycles. Tetrahedron 2016, 72, 4230–4238. [Google Scholar] [CrossRef]
  9. Marco, E.; Laine, W.; Tardy, C.; Lansiaux, A.; Iwao, M.; Ishibashi, F.; Bailly, C.; Gago, F. Molecular determinants of topoisomerase I poisoning by Lamellarins: Comparison with Camptothecin and structure−activity relationships. J. Med. Chem. 2005, 48, 3796–3807. [Google Scholar] [CrossRef]
  10. Reddy, M.V.R.; Rao, M.R.; Rhodes, D.; Hansen, M.S.T.; Rubins, K.; Bushman, F.D.; Venkateswarlu, Y.; Faulkner, D. Lamellarin α 20-sulfate, an inhibitor of HIV-1 integrase active against HIV-1 virus in cell culture. J. Med. Chem. 1999, 42, 1901–1907. [Google Scholar] [CrossRef]
  11. Aubry, A.; Pan, X.-S.; Fisher, L.M.; Jarlier, V.; Cambau, E. Mycobacterium tuberculosis DNA gyrase: Interaction with quinolones and correlation with antimycobacterial drug activity. Antimicrob. Agents Chemother. 2004, 48, 1281–1288. [Google Scholar] [CrossRef]
  12. Ploypradith, P.; Petchmanee, T.; Sahakitpichan, P.; Litvinas, N.D.; Ruchirawat, S. Total synthesis of natural and unnatural Lamellarins with saturated and unsaturated D-rings. J. Org. Chem. 2006, 71, 9440–9448. [Google Scholar] [CrossRef] [PubMed]
  13. Su, S.; Porco, J.A., Jr. Synthesis of pyrrolo-isoquinolines related to the lamellarins using silver-catalyzed cycloisomerization/dipolar cycloaddition. J. Am. Chem. Soc. 2007, 129, 7744–7745. [Google Scholar] [CrossRef]
  14. Yu, C.; Zhang, Y.; Zhang, S.; Li, H.; Wang, W. Cu (II) catalyzed oxidation-[3+ 2] cycloaddition-aromatization cascade: Efficient synthesis of pyrrolo [2,1-a] isoquinolines. Chem. Commun. 2011, 47, 1036–1038. [Google Scholar] [CrossRef]
  15. Zou, Y.-Q.; Lu, L.-Q.; Fu, L.; Chang, N.-J.; Rong, J.; Chen, J.-R.; Xiao, W.-J. Visible-light-induced oxidation/[3 + 2] cycloaddition/oxidative aromatization sequence: A photocatalytic strategy to construct pyrrolo [2,1-a] isoquinolines. Angew. Chem. Int. Ed. 2011, 50, 7171–7175. [Google Scholar] [CrossRef]
  16. Dondas, H.A.; Fishwick, C.W.; Gai, X.; Grigg, R.; Kilner, C.; Dumrongchai, N.; Kongkathip, B.; Kongkathip, N.; Polysuk, C.; Sridharan, V. Stereoselective palladium-catalyzed four-component cascade synthesis of pyrrolidinyl-, pyrazolidinyl-, and isoxazolidinyl isoquinolines. Angew. Chem. Int. Ed. 2005, 44, 7570–7574. [Google Scholar] [CrossRef]
  17. Choi, A.; Morley, R.M.; Coldham, I. Synthesis of pyrrolo [1, 2-a] quinolines by formal 1, 3-dipolar cycloaddition reactions of quinolinium salts. Beilstein J. Org. Chem. 2019, 15, 1480–1484. [Google Scholar] [CrossRef] [PubMed]
  18. Wang, Q.; Yuan, T.; Liu, Q.; Xu, Y.; Xie, G.; Lv, X.; Ding, S.; Wang, X.; Li, C. External oxidant-free oxidation/[3+ 2] cycloaddition/aromatization cascade: Electrochemical synthesis of polycyclic N-heterocycles. Chem. Commun. 2019, 55, 8398–8401. [Google Scholar] [CrossRef]
  19. Andreani, A.; Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi, M. Synthesis and antitubercular activity of imidazo [2, 1-b] thiazoles. Eur. J. Med. Chem. 2001, 36, 743–746. [Google Scholar] [CrossRef]
  20. Maglich, J.M.; Parks, D.J.; Moore, L.B.; Collins, J.L.; Goodwin, B.; Billin, A.N.; Stoltz, C.A.; Kliewer, S.A.; Lambert, M.H.; Willson, T.M.; et al. Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes. J. Biol. Chem. 2003, 278, 17277–17283. [Google Scholar] [CrossRef]
  21. Hozien, Z.A.; Abd El-Wareth, A.S.; El-Sherief, H.A.; Mahmoud, A.M. An efficient route for synthesis of 5, 6-diphenylimidazo-[2,1-b] thiazoles as antibacterial agents. J. Heterocycl. Chem. 2000, 37, 943–949. [Google Scholar] [CrossRef]
  22. Barakat, A.; Islam, M.S.; Ghawas, H.M.; Al-Majid, A.M.; El-Senduny, F.F.; Badria, F.A.; Elshaier, Y.A.; Ghabbour, H.A. Design and synthesis of new substituted spirooxindoles as potential inhibitors of the MDM2–p53 interaction. Bioorg. Chem. 2019, 86, 598–608. [Google Scholar] [CrossRef]
  23. Altowyan, M.S.; Barakat, A.; Al-Majid, A.M.; Al-Ghulikah, H.A. Spiroindolone analogues bearing benzofuran moiety as a selective cyclooxygenase COX-1 with TNF-α and IL-6 inhibitors. Saudi J. Biol. Sci. 2020, 27, 1208–1216. [Google Scholar] [CrossRef]
  24. Altowyan, M.S.; Barakat, A.; Al-Majid, A.M.; Al-Ghulikah, H. Spiroindolone analogues as potential hypoglycemic with dual inhibitory activity on α-amylase and α-glucosidase. Molecules 2019, 24, 2342. [Google Scholar] [CrossRef]
  25. Islam, M.S.; Ghawas, H.M.; El-Senduny, F.F.; Al-Majid, A.M.; Elshaier, Y.A.; Badria, F.A.; Barakat, A. Synthesis of new thiazolo-pyrrolidine-(spirooxindole) tethered to 3-acylindole as anticancer agents. Bioorg. Chem. 2019, 82, 423–430. [Google Scholar] [CrossRef] [PubMed]
  26. Barakat, A.; Islam, M.S.; Al Majid, A.M.; Ghawas, H.M.; El-Senduny, F.F.; Badria, F.A.; Elshaier, Y.A.M.M.; Ghabbour, H.A. Substituted spirooxindole derivatives as potent anticancer agents through inhibition of phosphodiesterase 1. RSC Adv. 2018, 8, 14335. [Google Scholar] [CrossRef]
  27. Lotfy, G.; Aziz, Y.M.A.; Said, M.M.; El Sayed, H.; El Sayed, H.; Abu-Serie, M.M.; Teleb, M.; Dömling, A.; Barakat, A. Molecular hybridization design and synthesis of novel spirooxindole-based MDM2 inhibitors endowed with BCL2 signaling attenuation; a step towards the next generation p53 activators. Bioorg. Chem. 2021, 117, 105427. [Google Scholar] [CrossRef] [PubMed]
  28. Barakat, A.; Soliman, S.M.; Al-majid, A.M.; Ali, M.; Islam, M.S.; Elshaier, Y.A.M.M.; Ghabbour, H.A. Regioselective synthesis of novel spiro-oxindole constructed with pyrrolidine/thioxothiazolidin-4-one derivatives: X-ray crystal structures, Hirshfeld surface analysis, DFT, docking and antimicrobial studies. J. Mol. Struc. 2018, 1152, 101–114. [Google Scholar] [CrossRef]
  29. Aziz, Y.M.A.; Lotfy, G.; Said, M.M.; El Ashry, E.S.H.; El Tamany, E.S.H.; Soliman, S.M.; Abu-Serie, M.M.; Teleb, M.; Yousuf, S.; Dömling, A.; et al. Design, synthesis, chemical and biochemical insights into novel hybrid spirooxindole-based p53-MDM2 inhibitors with potential Bcl2 signaling attenuation. Front. Chem. 2021, 9, 735236. [Google Scholar] [CrossRef]
  30. Al-Majid, A.M.; Soliman, S.M.; Haukka, M.; Ali, M.; Islam, M.S.; Shaik, M.R.; Barakat, A. Design, construction, and characterization of a new regioisomer and diastereomer material based on the spirooxindole scaffold incorporating a sulphone function. Symmetry 2020, 12, 1337. [Google Scholar] [CrossRef]
  31. Mustafa, A.; Ali, M.I.; Abou-State, M.A.; Hammam, A.E.G. Reactions with 4, 5-disubstituted 2-mercaptoimidazoles and their derivatives. J. Für Prakt. Chem. 1972, 314, 785–792. [Google Scholar] [CrossRef]
  32. Gherasim, C.; Airinei, A.; Tigoianu, R.; Craciun, A.M.; Danac, R.; Nicolescu, A.; Isac, D.L.; Mangalagiu, I.I. Synthesis and photophysical insights of new fused N-heterocyclic derivatives with isoquinoline skeleton. J. Mol. Liq. 2020, 310, 113196. [Google Scholar] [CrossRef]
  33. Rikagu Oxford Diffraction. CrysAlisPro; Agilent Technologies Inc.: Yarnton, Oxfordshire, UK, 2018. [Google Scholar]
  34. Sheldrick, G.M. ShelXT-Integrated space-group and crystal-structure determination. Acta Cryst. 2015, A71, 3–8. [Google Scholar] [CrossRef]
  35. Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Cryst. 2015, C71, 3–8. [Google Scholar]
  36. Hübschle, C.B.; Sheldrick, G.M.; Dittrich, B. ShelXle: A Qt graphical user interface for SHELXL. J. Appl. Cryst. 2011, 44, 1281–1284. [Google Scholar] [CrossRef]
  37. Turner, M.J.; McKinnon, J.J.; Wolff, S.K.; Grimwood, D.J.; Spackman, P.R.; Jayatilaka, D.; Spackman, M.A. Crystal Explorer17. 2017, University of Western Australia: Perth, WA, Australia. Available online: http://hirshfeldsurface.net (accessed on 21 July 2017).
  38. Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; et al. GAUSSIAN 09; Revision A02; Gaussian Inc.: Wallingford, CT, USA, 2009. [Google Scholar]
  39. GaussView; Version 4.1; Dennington, R., II; Keith, T.; Millam, J. (Eds.) Semichem Inc.: Shawnee Mission, KS, USA, 2007. [Google Scholar]
  40. Reed, A.E.; Curtiss, L.A.; Weinhold, F. Intermolecular interactions from a natural bond orbital, donor-acceptor viewpoint. Chem. Rev. 1988, 88, 899–926. [Google Scholar] [CrossRef]
  41. Marten, B.; Kim, K.; Cortis, C.; Friesner, R.A.; Murphy, R.B.; Ringnalda, M.N.; Sitkoff, D.; Honig, B. New model for calculation of solvation free energies:  Correction of self-consistent reaction field continuum dielectric theory for short-range hydrogen-bonding effects. J. Phys. Chem. 1996, 100, 11775–11788. [Google Scholar] [CrossRef]
  42. Tannor, D.J.; Marten, B.; Murphy, R.; Friesner, R.A.; Sitkoff, D.; Nicholls, A.; Ringnalda, M.; Goddard, W.A.; Honig, B. Accurate first principles calculation of molecular charge distributions and solvation energies from ab initio quantum mechanics and continuum dielectric theory. J. Am. Chem. Soc. 1994, 116, 11875–11882. [Google Scholar] [CrossRef]
  43. Cheeseman, J.R.; Trucks, G.W.; Keith, T.A.; Frisch, M.J. A comparison of models for calculating nuclear magnetic resonance shielding tensors. J. Chem. Phys. 1996, 104, 5497–5509. [Google Scholar] [CrossRef]
  44. Foresman, J.B.; Frisch, Æ. Exploring Chemistry with Electronic Structure Methods, 2nd ed.; Gaussian: Pittsburgh, PA, USA, 1996. [Google Scholar]
  45. Chang, R. Chemistry, 7th ed.; McGraw-Hill: New York, NY, USA, 2001. [Google Scholar]
  46. Kosar, B.; Albayrak, C. Spectroscopic investigations and quantum chemical computational study of (E)-4-methoxy-2-[(p-tolylimino) methyl] phenol. Spectrochim. Acta 2011, 78, 160–167. [Google Scholar] [CrossRef] [PubMed]
  47. Koopmans, T.A. Ordering of wave functions and eigenenergies to the individual electrons of an atom. Physica 1933, 1, 104–113. [Google Scholar] [CrossRef]
  48. Parr, R.G.; Yang, W. Density-Functional Theory of Atoms and Molecules; Oxford University Press: New York, NY, USA, 1989. [Google Scholar]
  49. Parr, R.G.; Szentpaly, L.V.; Liu, S. Electrophilicity index. J. Am. Chem. Soc. 1999, 121, 1922–1924. [Google Scholar] [CrossRef]
  50. Singh, R.N.; Kumar, A.; Tiwari, R.K.; Rawat, P.; Gupta, V.P. A combined experimental and quantum chemical (DFT and AIM) study on molecular structure, spectroscopic properties, NBO and multiple interaction analysis in a novel ethyl 4-[2-(carbamoyl) hydrazinylidene]-3, 5-dimethyl-1H-pyrrole-2-carboxylate and its dimer. J. Mol. Strut. 2013, 1035, 427–440. [Google Scholar] [CrossRef]
Crystals 12 00006 sch001 550
Scheme 1. Synthesis (upper) and proposed mechanism (lower) for the tricyclic heterocyclic compound based isoquinoline scaffold 3.
Scheme 1. Synthesis (upper) and proposed mechanism (lower) for the tricyclic heterocyclic compound based isoquinoline scaffold 3.
Crystals 12 00006 sch001
Crystals 12 00006 g001 550
Figure 1. X-ray structure of 3.
Figure 1. X-ray structure of 3.
Crystals 12 00006 g001
Crystals 12 00006 g002 550
Figure 2. Hydrogen bonds in 3.
Figure 2. Hydrogen bonds in 3.
Crystals 12 00006 g002
Crystals 12 00006 g003 550
Figure 3. Hirshfeld surfaces of 3.
Figure 3. Hirshfeld surfaces of 3.
Crystals 12 00006 g003
Crystals 12 00006 g004 550
Figure 4. Intermolecular interactions in 3.
Figure 4. Intermolecular interactions in 3.
Crystals 12 00006 g004
Crystals 12 00006 g005 550
Figure 5. Decomposed fingerprint plots and dnorm surfaces in 3.
Figure 5. Decomposed fingerprint plots and dnorm surfaces in 3.
Crystals 12 00006 g005
Crystals 12 00006 g006 550
Figure 6. The calculated structure (left) and its overlay with experimental one, (right) for 3.
Figure 6. The calculated structure (left) and its overlay with experimental one, (right) for 3.
Crystals 12 00006 g006
Crystals 12 00006 g007 550
Figure 7. The MEP, HOMO and LUMO of 3.
Figure 7. The MEP, HOMO and LUMO of 3.
Crystals 12 00006 g007
Crystals 12 00006 g008 550
Figure 8. The calculated (upper) and experimental (lower) electronic spectra of 3.
Figure 8. The calculated (upper) and experimental (lower) electronic spectra of 3.
Crystals 12 00006 g008
Crystals 12 00006 g009 550
Figure 9. MOs included in the electronic absorption bands for the studied system.
Figure 9. MOs included in the electronic absorption bands for the studied system.
Crystals 12 00006 g009
Table
Table 1. Crystal data and structure refinement for 3.
Table 1. Crystal data and structure refinement for 3.
Contact3
CCDC2075387
empirical formulaC22H18ClNO4
fw395.82
temp (K)120(2) K
λ (Å)0.71073 Å
cryst systMonoclinic
space groupP21/c
a (Å)7.9337(3)
b (Å)32.6514(8)
c (Å)7.7034(3)
β (deg)111.687(4)
V (Å3)1854.29(12) Å3
Z4
ρcalc (mg/m3)1.418 mg/m3
μ (Mo Kα) (mm−1)0.236 mm−1
No. reflns.16,269
Unique reflns.4791
GOOF (F2)1.027
Rint0.0434
R1 a (I ≥ 2σ)0.0477
wR2 b (I ≥ 2σ)0.1017
a R1 = Σ||Fo| − |Fc||/Σ|Fo|. b wR2 = [Σ[w(Fo2 − Fc2)2]/Σ[w(Fo2)2]]1/2.
Table
Table 2. Bond lengths (Å) and angles (°) for 3.
Table 2. Bond lengths (Å) and angles (°) for 3.
BondLength/ÅBondLength/Å
Cl1-C31.7425(19)C6-C71.521(2)
O1-C91.338(2)C7-C201.532(2)
O1-C101.455(2)C7-C81.548(2)
O2-C91.194(2)C8-C91.522(3)
O3-C211.370(2)C11-C121.336(2)
O3-C221.436(2)C12-C131.436(2)
O4-C211.223(2)C13-C141.408(2)
N1-C111.376(2)C13-C181.419(2)
N1-C191.382(2)C14-C151.373(2)
N1-C81.457(2)C15-C161.398(3)
C1-C21.388(3)C16-C171.377(2)
C1-C61.389(2)C17-C181.408(2)
C2-C31.385(3)C18-C191.459(2)
C3-C41.379(3)C19-C201.393(2)
C4-C51.392(3)C20-C211.440(2)
BondsAngle/∲∲BondsAngle/∲∲
C9-O1-C10114.88(15)O1-C9-C8110.34(14)
C21-O3-C22115.83(13)C12-C11-N1120.44(15)
C11-N1-C19125.37(14)C11-C12-C13119.38(16)
C11-N1-C8122.19(14)C14-C13-C18119.63(15)
C19-N1-C8111.59(13)C14-C13-C12119.95(15)
C2-C1-C6121.37(16)C18-C13-C12120.42(15)
C3-C2-C1118.70(18)C15-C14-C13120.59(16)
C4-C3-C2121.40(18)C14-C15-C16119.95(16)
C4-C3-Cl1118.83(14)C17-C16-C15120.69(16)
C2-C3-Cl1119.77(15)C16-C17-C18120.64(17)
C3-C4-C5118.86 (17)C17-C18-C13118.48(15)
C6-C5-C4121.23(17)C17-C18-C19122.55(15)
C5-C6-C1118.43(16)C13-C18-C19118.97(14)
C5-C6-C7119.92(16)N1-C19-C20109.02(14)
C1-C6-C7121.62(15)N1-C19-C18115.39(14)
C6-C7-C20114.86(14)C20-C19-C18135.58(15)
C6-C7-C8111.81(13)C19-C20-C21131.92(15)
C20-C7-C8101.56(13)C19-C20-C7109.13(13)
N1-C8-C9109.27(14)C21-C20-C7118.95(14)
N1-C8-C7103.02(13)O4-C21-O3120.31(14)
C9-C8-C7111.47(14)O4-C21-C20130.41(16)
O2-C9-O1124.11(18)O3-C21-C20109.25(14)
O2-C9-C8125.55(16)
Table
Table 3. Hydrogen bond parameters (Å and °) for 3.
Table 3. Hydrogen bond parameters (Å and °) for 3.
D-H…AD-HH…AD…AD-H…A
C8-H8…O4 11.002.403.245(2)142
C12-H12…O2 20.952.463.346(2)155
C17-H17…O40.952.142.980(2)147
C22-H22A…O1 30.982.593.520(2)158
Symm. Code. 1 −1 + x,y,z; 2 x,1/2 − y,1/2 + z and 3 1 + x,y,z.
Table
Table 4. Shortest intermolecular interactions and their distances.
Table 4. Shortest intermolecular interactions and their distances.
ContactDistanceContactDistance
O2…H12 12.343C17…C15 4a3.644
O4…H8 22.332C18…C14 4a3.559
O1…H22A 32.499C21…H10C 5a2.879
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.
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Altowyan, M.S.; Soliman, S.M.; Haukka, M.; Al-Shaalan, N.H.; Alkharboush, A.A.; Barakat, A. 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. Crystals 2022, 12, 6. https://doi.org/10.3390/cryst12010006

AMA Style

Altowyan MS, Soliman SM, Haukka M, Al-Shaalan NH, Alkharboush AA, Barakat A. 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. Crystals. 2022; 12(1):6. https://doi.org/10.3390/cryst12010006

Chicago/Turabian Style

Altowyan, Mezna Saleh, Saied M. Soliman, Matti Haukka, Nora H. Al-Shaalan, Aminah A. Alkharboush, and Assem Barakat. 2022. "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" Crystals 12, no. 1: 6. https://doi.org/10.3390/cryst12010006

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