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Hantzsch-like three-component synthesis of tetracyclic 10b-azachrysenes: Unambiguous structural elucidation using X-ray crystallography and 2D-HMBC spectroscopy
Journal Pre-proofs Hantzsch-like three-component synthesis of tetracyclic 10b-azachrysenes: unambiguous structural elucidation using X-ray crystallography and 2D-HMBC spectroscopy Fatma M. Saleh, Hamdi M. Hassaneen, Holger Butenschön, Gerald Dräger, Ismail A. Abdelhamid PII: DOI: Reference:
S0040-4039(19)31045-7 https://doi.org/10.1016/j.tetlet.2019.151265 TETL 151265
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
10 August 2019 30 September 2019 10 October 2019
Please cite this article as: Saleh, F.M., Hassaneen, H.M., Butenschön, H., Dräger, G., Abdelhamid, I.A., Hantzschlike three-component synthesis of tetracyclic 10b-azachrysenes: unambiguous structural elucidation using X-ray crystallography and 2D-HMBC spectroscopy, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet. 2019.151265
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Hantzsch-like three-component synthesis of tetracyclic 10b-azachrysenes: unambiguous structural elucidation using X-ray crystallography and 2D-HMBC spectroscopy
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Fatma M. Saleh, a Hamdi M. Hassaneen,a Holger Butenschön,b Gerald Dräger b and Ismail A. Abdelhamid *a
NC MeO MeO
O Ar N
+
+ O
CHO
AcOH, reflux 3h
Ar
O
C N
D
NC MeO
72-82% yield
A MeO
B
Ar = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-O2NC6H4, benzo[d][1,3]dioxol-5-yl
1
Tetrahedron Letters journal homepage: www.elsevier.com
Hantzsch-like three-component synthesis of tetracyclic 10b-azachrysenes: unambiguous structural elucidation using X-ray crystallography and 2D-HMBC spectroscopy Fatma M. Saleh,a Hamdi M. Hassaneen,a Holger Butenschön,b Gerald Drägerb and Ismail A. Abdelhamid *a a b
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt, Email: [email protected], Fax : 002-0235727556 Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
Herein, we report the first synthesis of 10b-azachrysenes via the Hantzsch-like reaction of aldehydes with 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetonitrile and dimedone in the presence of acetic acid. The regioselectivity was established using X-ray crystallography and 2D-HMBC spectroscopy. 2009 Elsevier Ltd. All rights reserved.
Keywords: Hantzsch-like reaction 2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-1yl)acetonitrile Hexahydro-10b-azachrysene X-Ray crystallography
1. Introduction Heterocycles with bridgehead nitrogen atoms such as fused isoquinolines are of significant importance as they comprise the core structures of various alkaloids such as palmatinem,1 columbamine,1 berberine2 and papaverine.3 In addition, fused isoquinolines possess a wide range of biological activities including cardiovascular,4 anticancer,5–7 anti-inflammatory,4,8,9 antidepressant,4,10 anti-HIV11 and antimalarial12 activity. Moreover, the azachrysenes (tetracyclic chrysenes in which one or more carbon atoms is replaced by nitrogen)13,14 are of interest due to their structural rigidity that considerably affects their biological activity,14–18 which includes antitumor activities.15,16 To the best of our knowledge, the synthesis of monoazachrysene derivatives is not common in the literature, and is limited to 2-azachrysenes,13,15,17–20 5-azachrysenes13,18,21–25 and 6-azachrysenes.13,18,26–31 Also, 10b-azachrysenes are much less common, although Pshenichnyi and co-workers,32 Gulyakevich
and co-workers,33 and Mikhalchuk and co-workers34 have reported significant progress in this area. 2. Results and Discussion Taking into account the significance of the azachrysene moiety and in conjunction with our work on multicomponent reactions,35,36 Michael addition37,38 and Hantzsch reactions,36 we report herein the highly efficient one-pot, three-component synthesis of 10b-azachrysenes. Initial studies demonstrated that stirring 2-(6,7-dimethoxy3,4-dihydroisoquinolin-1-yl)acetonitrile 139 with dimedone 2 and substituted aldehydes 3a-f in acetic acid at reflux gave heterocycles 4a-f (ESI). The cyclo-condensation reaction can potentially lead to the formation of either racemic 1-oxo-13arylhexahydro-1H-isoquinolino[2,1-a]quinoline-12-carbonitriles (named as 10b-azachrysene) 4a-f (Route I) or its regioisomeric structure 2,3-dimethoxy-8-aryl-11,11-dimethyl-9-oxo5,8,9,10,11,12-hexahydro-6H-isoquinolino[3,2-a]isoquinoline13-carbonitriles 5a-f (Route II) (Scheme 1).
2 Ar
Route I
O
NC MeO
N
MeO
4a-f
NC MeO
4a, Ar = Ph (82%) 4b, Ar = 4-MeC6H4 (78%) 4c, Ar = 4-MeOC6H4 (72%) 4d, Ar = 4-ClC6H4 (85%) 4e, Ar = 4-O2NC6H4 (87%) O (72%) 4f, Ar = O
O N
+
+ O
MeO 1
Ar
AcOH
CHO
3a-f
2
NC
Route II
Ar
MeO
N
O
H
MeO
5a-f
Scheme 1. Synthesis of 9,10-dimethoxy-1H-isoquinolino[2,1-a]quinoline-12-carbonitriles 4a-f. Compounds 4 are formed via initial addition of the methylene group to the activated double bond with subsequent cyclization involving NH (Route I), while the other proposed isomers 5 result from the initial addition of NH to the activated double bond with subsequent cyclization (Route II) (Scheme 2). Thus, in Route I, the first step encompasses the Knoevenagel condensation reaction of aldehydes 3 and dimedone 2 to generate 2-arylidene-5,5-dimethylcyclohexane-1,3-dione intermediate 6.
Intermediate 6 acts as a Michael acceptor, while compound 1 can be considered as a Michael donor. The Michael addition of compound 1 (which represent rings A and B) with 6 (which represents ring D) leads to the Michael adduct 7 which tautomerizes into 8. Intramolecular cyclization via the nucleophilic addition of NH to the CO group affords intermediate 9 (in which ring C is formed). Dehydration of 8 affords the final products 4, which are obtained in racemic form (Scheme 2). Ar
Ar
O
MeO A
B
N
D
MeO
D
A
O
MeO
B
6
MeO
O
NC
NC
Route I
NC
Ar
O
D
MeO
NO
A
B
NH O
MeO 7
8
1
Ar O Ar CHO
3
MeO
+
A
O
2
O
NC
B
MeO
C N
D
Ar
O
NC
- H 2O MeO
A
B
C N
D OH
MeO 4
9
Scheme 2. Proposed mechanistic pathway. The structures of the formed products were unambiguously proved to be isoquinolino[2,1-a]quinoline-12-carbonitriles 4 through careful inspection of the spectroscopic data. Using the 1H NMR spectra of 4c as a representative example, a characteristic singlet signal was observed at 4.60 ppm for H-13. Moreover, the 13C NMR and APT spectra of compound 4c indicated 27 carbon signals. It featured the pyridine-C13 at 37.4 ppm, the CCN signal at 84.9 ppm, the CN group at 122.1 ppm, C-13a at δ 110.4 ppm and the carbonyl signal at 195.1 ppm. With the aid of
HSQC and HMBC experiments, the structure of compound 4c was assigned as shown in Figure 1. The 2D-HMBC analysis revealed five (3J-CH) and three (2J-CH) correlations between H13 (δ 4.60 ppm) and eight different carbon atoms. The correlations between H-13 with both C-12 (2J-CH) and CN (3JCH) are considered to be the strongest evidence for structure 4c, as these two correlations cannot occur in the case of isomer 5c (Fig. 1 and ESI).
3 OMe
H
NC MeO
O
NC
N
O
X
MeO
X
MeO
N
H OMe
MeO 4c
5c
Figure 1. 2D-HMBC correlations of compound 4c (red arrows represent the correlations between H-13 (δ 4.60 ppm) and the key carbon atoms). Crystals for two derivatives 4c and 4e which were suitable for X-ray crystal structure analyses were obtained by crystallization from acetonitrile (Fig. 2 and 3). The unit cells for 4c and 4e
Figure 2. X-Ray crystal structure of compound 4c (CCDC 1943555).
Figure 3: X-Ray crystal structure of compound 4e (CCDC 1943556). Conclusion
contain both enantiomers of the racemic derivative. For clarity only one enantiomer is shown. The structure clearly shows the constitution and conformation of 4c and 4e.
4 We have reported the first synthesis of 10b-azachrysene derivatives via the Hantzsch-like reaction of aldehydes with 2(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetonitrile and dimedone in the presence of acetic acid. The regioselectivity was established using X-ray crystallography and 2D-HMBC spectroscopy.
19. 20. 21. 22. 23.
3. References and notes
24.
1.
25.
Rueffer, M.; Amann, M.; Zenk, M. H. Plant Cell Rep. 1986, 5 (3), 182–185. Huang, L.; Shi, A.; He, F.; Li, X. Bioorg. Med. Chem. 2010, 18 (3), 1244–1251. Galat, A. J. Am. Chem. Soc. 1951, 73 (8), 3654–3656. Elwan, N. M.; Abdelhadi, H. A.; Abdallah, T. A.; Hassaneen, H. M. Tetrahedron 1996, 52 (10), 3451–3456. Mukherjee, A.; Dutta, S.; Shanmugavel, M.; Mondhe, D. M.; Sharma, P. R.; Singh, S. K.; Saxena, A. K.; Sanyal, U. J. Exp. Clin. Cancer Res. 2010, 29 (1), 175. Mohamed, M. F.; Hassaneen, H. M.; Abdelhamid, I. A. Eur. J. Med. Chem. 2018, 143 (1), 532–541. Yang, X.; Yang, S.; Chai, H.; Yang, Z.; Lee, R. J.; Liao, W.; Teng, L. PLoS One 2015, 10 (8), e0136649. Barbosa-Filho, J. M.; Piuvezam, M. R.; Moura, M. D.; Silva, M. S.; Lima, K. V. B.; da-Cunha, E. V. L.; Fechine, I. M.; Takemura, O. S. Rev. Bras. Farmacogn. 2006, 16 (1), 109–139. Küpeli, E.; Koşar, M.; Yeşilada, E.; Başer, K. H. C. Life Sci. 2002, 72 (6), 645–657. Maryanoff, B. E.; McComsey, D. F.; Costanzo, M. J.; Setler, P. E.; Gardocki, J. F.; Shank, R. P.; Schneider, C. R. J. Med. Chem. 1984, 27 (8), 943–946. Kashiwada, Y.; Aoshima, A.; Ikeshiro, Y.; Chen, Y.-P.; Furukawa, H.; Itoigawa, M.; Fujioka, T.; Mihashi, K.; Cosentino, L. M.; Morris-Natschke, S. L.; et al. Bioorg. Med. Chem. 2005, 13 (2), 443–448. Buchanan, M. S.; Davis, R. A.; Duffy, S.; Avery, V. M.; Quinn, R. J. J. Nat. Prod. 2009, 72 (8), 1541–1543. Hearn, M. J.; Swanson, S. L. J. Heterocycl. Chem. 1981, 18 (2), 207–222. Marinho, E.; Proença, F. Targets Heterocycl. Syst. 2016, 20, 448– 482. Stermitz, F. R.; Gillespie, J. P.; Amoros, L. G.; Romero, R.; Stermitz, T. A.; Larson, K. A.; Earl, S.; Ogg, J. E. J. Med. Chem. 1975, 18 (7), 708–713. Messmer, W. M.; Tin-wa, M.; Fong, H. H. S.; Bevelle, C.; Farnsworth, N. R.; Abraham, D. J.; Trojánek, J. J. Pharm. Sci. 1972, 61 (11), 1858–1859. Zee-Cheng, K.-Y.; Cheng, C. C. J. Heterocycl. Chem. 1973, 10 (1), 85–88. Yapi, A. D.; Desbois, N.; Chezal, J. M.; Chavignon, O.; Teulade, J. C.; Valentin, A.; Blache, Y. Eur. J. Med. Chem. 2010, 45 (7),
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26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39.
Supplementary Material Supplementary material related to this article, including 1H and 13C NMR spectra are available in the online version of the text. Crystal structure analysis of 4c and 4e are also provided.
NC MeO MeO
O Ar N
+
+ O
CHO
AcOH
2-(6,7-Dimethoxy-3,4-dihydroisoquinolin1-yl)acetonitrileNC
MeO Dimedone
A B MeO 10b-Azachrysenes
Ar
O
C N
D
Highlights
Hantzsch-like reaction
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal
5 relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
S0040-4039(19)31045-7 https://doi.org/10.1016/j.tetlet.2019.151265 TETL 151265
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
10 August 2019 30 September 2019 10 October 2019
Please cite this article as: Saleh, F.M., Hassaneen, H.M., Butenschön, H., Dräger, G., Abdelhamid, I.A., Hantzschlike three-component synthesis of tetracyclic 10b-azachrysenes: unambiguous structural elucidation using X-ray crystallography and 2D-HMBC spectroscopy, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet. 2019.151265
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Ltd.
Graphical Abstract
To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
Hantzsch-like three-component synthesis of tetracyclic 10b-azachrysenes: unambiguous structural elucidation using X-ray crystallography and 2D-HMBC spectroscopy
Leave this area blank for abstract info.
Fatma M. Saleh, a Hamdi M. Hassaneen,a Holger Butenschön,b Gerald Dräger b and Ismail A. Abdelhamid *a
NC MeO MeO
O Ar N
+
+ O
CHO
AcOH, reflux 3h
Ar
O
C N
D
NC MeO
72-82% yield
A MeO
B
Ar = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-O2NC6H4, benzo[d][1,3]dioxol-5-yl
1
Tetrahedron Letters journal homepage: www.elsevier.com
Hantzsch-like three-component synthesis of tetracyclic 10b-azachrysenes: unambiguous structural elucidation using X-ray crystallography and 2D-HMBC spectroscopy Fatma M. Saleh,a Hamdi M. Hassaneen,a Holger Butenschön,b Gerald Drägerb and Ismail A. Abdelhamid *a a b
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt, Email: [email protected], Fax : 002-0235727556 Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
Herein, we report the first synthesis of 10b-azachrysenes via the Hantzsch-like reaction of aldehydes with 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetonitrile and dimedone in the presence of acetic acid. The regioselectivity was established using X-ray crystallography and 2D-HMBC spectroscopy. 2009 Elsevier Ltd. All rights reserved.
Keywords: Hantzsch-like reaction 2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-1yl)acetonitrile Hexahydro-10b-azachrysene X-Ray crystallography
1. Introduction Heterocycles with bridgehead nitrogen atoms such as fused isoquinolines are of significant importance as they comprise the core structures of various alkaloids such as palmatinem,1 columbamine,1 berberine2 and papaverine.3 In addition, fused isoquinolines possess a wide range of biological activities including cardiovascular,4 anticancer,5–7 anti-inflammatory,4,8,9 antidepressant,4,10 anti-HIV11 and antimalarial12 activity. Moreover, the azachrysenes (tetracyclic chrysenes in which one or more carbon atoms is replaced by nitrogen)13,14 are of interest due to their structural rigidity that considerably affects their biological activity,14–18 which includes antitumor activities.15,16 To the best of our knowledge, the synthesis of monoazachrysene derivatives is not common in the literature, and is limited to 2-azachrysenes,13,15,17–20 5-azachrysenes13,18,21–25 and 6-azachrysenes.13,18,26–31 Also, 10b-azachrysenes are much less common, although Pshenichnyi and co-workers,32 Gulyakevich
and co-workers,33 and Mikhalchuk and co-workers34 have reported significant progress in this area. 2. Results and Discussion Taking into account the significance of the azachrysene moiety and in conjunction with our work on multicomponent reactions,35,36 Michael addition37,38 and Hantzsch reactions,36 we report herein the highly efficient one-pot, three-component synthesis of 10b-azachrysenes. Initial studies demonstrated that stirring 2-(6,7-dimethoxy3,4-dihydroisoquinolin-1-yl)acetonitrile 139 with dimedone 2 and substituted aldehydes 3a-f in acetic acid at reflux gave heterocycles 4a-f (ESI). The cyclo-condensation reaction can potentially lead to the formation of either racemic 1-oxo-13arylhexahydro-1H-isoquinolino[2,1-a]quinoline-12-carbonitriles (named as 10b-azachrysene) 4a-f (Route I) or its regioisomeric structure 2,3-dimethoxy-8-aryl-11,11-dimethyl-9-oxo5,8,9,10,11,12-hexahydro-6H-isoquinolino[3,2-a]isoquinoline13-carbonitriles 5a-f (Route II) (Scheme 1).
2 Ar
Route I
O
NC MeO
N
MeO
4a-f
NC MeO
4a, Ar = Ph (82%) 4b, Ar = 4-MeC6H4 (78%) 4c, Ar = 4-MeOC6H4 (72%) 4d, Ar = 4-ClC6H4 (85%) 4e, Ar = 4-O2NC6H4 (87%) O (72%) 4f, Ar = O
O N
+
+ O
MeO 1
Ar
AcOH
CHO
3a-f
2
NC
Route II
Ar
MeO
N
O
H
MeO
5a-f
Scheme 1. Synthesis of 9,10-dimethoxy-1H-isoquinolino[2,1-a]quinoline-12-carbonitriles 4a-f. Compounds 4 are formed via initial addition of the methylene group to the activated double bond with subsequent cyclization involving NH (Route I), while the other proposed isomers 5 result from the initial addition of NH to the activated double bond with subsequent cyclization (Route II) (Scheme 2). Thus, in Route I, the first step encompasses the Knoevenagel condensation reaction of aldehydes 3 and dimedone 2 to generate 2-arylidene-5,5-dimethylcyclohexane-1,3-dione intermediate 6.
Intermediate 6 acts as a Michael acceptor, while compound 1 can be considered as a Michael donor. The Michael addition of compound 1 (which represent rings A and B) with 6 (which represents ring D) leads to the Michael adduct 7 which tautomerizes into 8. Intramolecular cyclization via the nucleophilic addition of NH to the CO group affords intermediate 9 (in which ring C is formed). Dehydration of 8 affords the final products 4, which are obtained in racemic form (Scheme 2). Ar
Ar
O
MeO A
B
N
D
MeO
D
A
O
MeO
B
6
MeO
O
NC
NC
Route I
NC
Ar
O
D
MeO
NO
A
B
NH O
MeO 7
8
1
Ar O Ar CHO
3
MeO
+
A
O
2
O
NC
B
MeO
C N
D
Ar
O
NC
- H 2O MeO
A
B
C N
D OH
MeO 4
9
Scheme 2. Proposed mechanistic pathway. The structures of the formed products were unambiguously proved to be isoquinolino[2,1-a]quinoline-12-carbonitriles 4 through careful inspection of the spectroscopic data. Using the 1H NMR spectra of 4c as a representative example, a characteristic singlet signal was observed at 4.60 ppm for H-13. Moreover, the 13C NMR and APT spectra of compound 4c indicated 27 carbon signals. It featured the pyridine-C13 at 37.4 ppm, the CCN signal at 84.9 ppm, the CN group at 122.1 ppm, C-13a at δ 110.4 ppm and the carbonyl signal at 195.1 ppm. With the aid of
HSQC and HMBC experiments, the structure of compound 4c was assigned as shown in Figure 1. The 2D-HMBC analysis revealed five (3J-CH) and three (2J-CH) correlations between H13 (δ 4.60 ppm) and eight different carbon atoms. The correlations between H-13 with both C-12 (2J-CH) and CN (3JCH) are considered to be the strongest evidence for structure 4c, as these two correlations cannot occur in the case of isomer 5c (Fig. 1 and ESI).
3 OMe
H
NC MeO
O
NC
N
O
X
MeO
X
MeO
N
H OMe
MeO 4c
5c
Figure 1. 2D-HMBC correlations of compound 4c (red arrows represent the correlations between H-13 (δ 4.60 ppm) and the key carbon atoms). Crystals for two derivatives 4c and 4e which were suitable for X-ray crystal structure analyses were obtained by crystallization from acetonitrile (Fig. 2 and 3). The unit cells for 4c and 4e
Figure 2. X-Ray crystal structure of compound 4c (CCDC 1943555).
Figure 3: X-Ray crystal structure of compound 4e (CCDC 1943556). Conclusion
contain both enantiomers of the racemic derivative. For clarity only one enantiomer is shown. The structure clearly shows the constitution and conformation of 4c and 4e.
4 We have reported the first synthesis of 10b-azachrysene derivatives via the Hantzsch-like reaction of aldehydes with 2(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetonitrile and dimedone in the presence of acetic acid. The regioselectivity was established using X-ray crystallography and 2D-HMBC spectroscopy.
19. 20. 21. 22. 23.
3. References and notes
24.
1.
25.
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26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39.
Supplementary Material Supplementary material related to this article, including 1H and 13C NMR spectra are available in the online version of the text. Crystal structure analysis of 4c and 4e are also provided.
NC MeO MeO
O Ar N
+
+ O
CHO
AcOH
2-(6,7-Dimethoxy-3,4-dihydroisoquinolin1-yl)acetonitrileNC
MeO Dimedone
A B MeO 10b-Azachrysenes
Ar
O
C N
D
Highlights
Hantzsch-like reaction
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal
5 relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: