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A multicomponent cascade reaction for the synthesis of novel chromenopyranpyrazole scaffolds Manickam Bakthadoss,a,b* Damodharan Kannana and Raman Selvakumara
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Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X DOI: 10.1039/b000000x A catalyst, solvent, work-up and column free synthesis of chromenopyranpyrazole scaffolds via multicomponent cascade reaction has been achieved in excellent yields with high stereoselectivity. Interestingly, this novel reaction creates two N-C bonds, two C-C bonds and one O-C bond linkages through a domino process for the construction of three new rings and three contiguous stereogenic centers. An efficient and elegant assembly of complex structures with multiple stereocenters has become an important topic in organic chemistry. Heterocyclic rings are present as fundamental components in the skeleton of more than half of the biologically active compounds produced by nature.1 Among them, benzopyran and pyrazole heterocyclic ring systems are present in a vast number of natural products and bioactive substances, with a wide application range.2 These heterocycles are privileged structures, constituting pivotal drug like scaffolds in medicinal chemistry and have received much attention.3 An interesting aspect in the field of heterocyclic synthesis is in the use of domino reactions. During the past decade, domino reactions have emerged as a powerful and efficient method for the construction of heterocyclic compounds. Amongst such reactions, the domino Knoevenagel-hetero-Diels–Alder reaction has proven to be a useful tool for the synthesis of poly heterocyclic compounds.4 The progression of new methodologies with the improvement of synthetic efficiency is an important objective in modern organic synthesis.5 Multicomponent reactions (MCR), which encompass numerous bond-forming reactions in a one-pot operation, represent an appealing strategy for the facile construction of novel molecular architecture. These reactions are venerable to create wide libraries of diverse molecules in facile manner by virtue of their convergent nature. Therefore, the development of new multicomponent protocol for the rapid construction of fused molecular frameworks represents one of the frontiers of preparative chemistry. Pyrazole derivatives display a broad spectrum of biological activities and represent an important structural class in pharmaceuticals and agrochemicals. They are present in leading drugs such as viagra, celebrex and therefore, synthesis of pyrazole motifs are considered very important in pharmaceutical industries.6 In particular, 3-methyl-1-phenyl-1H-pyrazol-5-one (edaravone 4), which is a free radical scavenger, provides an interesting medicinal applications, such as potential This journal is © The Royal Society of Chemistry [year]
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neuroprotective agent for recovery of acute brain ischemia and subsequent cerebral infarction.7 The compounds containing a pyrano[2,3-c]pyrazole unit have shown antimicrobial, insecticidal, anti-inflammatory, and molluscicidal activities. On the other hand, photochromic compounds having a benzopyran nucleus have practical applications in the data storage, optical filters, displays, sensor protection, waveguides, and ophthalmic plastic lenses.8
Figure 1. Representative examples of natural products and bioactive molecules containing pyrazoles and benzopyran motifs A representative members of pyrazoles, and benzopyran structural motif containing natural products and biologically active molecules such as pyrano[2,3-c]pyrazole,(I),9a chromenopyrazolylsulfonamide (II),9b suksdorfin (III),9c deguelin (IV), tephrosin (V)9d and edaravone (VI)7 are shown in figure 1. The Baylis-Hillman adducts have become a valuable source for various organic transformations and have been transformed into a number of carbocycles and heterocyclic frameworks of medicinal importance. In fact, due to the close proximity of functional groups the BH-adducts and its derivatives have become an attractive source/ substrates for a number of organic transformations often leading to the synthesis of several bioactive compounds and important frameworks of medicinal relevance.10 In continuation of our ongoing research program in the field of heterocyclic chemistry,[11] we herein report a convenient, facile, and new method for the synthesis of novel tetracyclic chromenopyranpyrazole frameworks through multi component cascade reaction (MCCR). Based on our preliminary report,[11a] we envisaged that the synthesis of chromeno pyranpyrazole scaffolds (5) can be acheived through a multi component cascade reaction. Accordingly, we have taken methyl acetoacetate (1), phenyl hydrazine (2) and the BaylisHillman derivative (3) in a round-bottom flask and heated at 180°C for 1 h in solvent and catalyst-free condition, which successfully led to the desired angularly substituted (ester Journal Name, [year], [vol], 00–00 | 1
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DOI: 10.1039/C3CC45502E
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Table 2. Synthesis of novel tetracyclic chromenopyranpyrazole scaffolds via multicomponent cascade reaction (8a-g)
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All reactions were carried out on 1 mmol scale at 180 ºC for 1 h. Structure of the molecule was further confirmed by single-crystal X-ray data (see Supporting Information).
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All reactions were carried out on 1 mmol scale at 180 ºC for 1 h. Structure of the molecule was further confirmed by single-crystal X-ray data (see Supporting Information).
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Interestingly, this cascade reaction proceeds via an insitu formation of edaravone (4) from phenyl hydrazine and methyl acetoacetate followed by domino Knoevenagel intramolecular hetero Diels-Alder (IMHDA) reaction which creates the annulation of three rings (two six membered rings and one five membered ring) in a stereoselective fashion. A similar results were obtained when we used ethylacetoacetate in the place of methylacetoacetate. Decreasing the reaction temperature (from 180 °C to 140 °C) and time led to the incompletion of the reaction with the formation of intermediate 4, product 5 and a Knoevenagel condensation product derived from 4 and aldehyde 3. This type of novel domino reaction involving hydrazine formation, cyclic amide formation, Knovenegel condensation and intramolecular hetero Diels-Alder reaction is very attractive and not known so far in the literature. To expand the scope of this cascade reaction, we have treated various Baylis-Hillman derivatives (3b-p) under optimized reaction condition which successfully afforded the desired angularly substituted (ester moiety) tetracyclic chromenopyran pyrazoles (5b-p) in excellent yields (92-96%). The isolated yields of the pure products (5a-p) are summarized in table 1. On the basis of these successful results, we examined the various Baylis-Hillman derivatives (i.e.) (E)-2-((2-formyl phenoxy)methyl)-3-arylacrylonitriles (6a-g) with phenyl hydrazine (2) and ethyl/methyl acetoacetate (1) under similar reaction condition, which provided the anticipated angularly substituted (nitrile moiety) tetracyclic chromenopyranpyrazole products (8a-g) in excellent yields (91-95%). The isolated yields of the pure products (8a-g) are summarized in table 2. It is very important to mention here that the high stereoselectivity in the formation of tetracyclic chromenopyran 2 | Journal Name, [year], [vol], 00–00
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Figure 2. ORTEP diagram12 of compound 5f and 8c pyrazole frameworks were clearly evidenced by NMR spectra and X-ray crystal analyses (Figure 2). According to the ORTEP diagram of the tetracyclic chromenopyran pyrazole 5f shown in the figure 2, the relative stereochemistry of the o-methoxy aryl group and the adjacent ester moiety are in anti orientation where as the ester moiety and the ring junction proton exist in syn orientation. Similarly, the X-ray crystal structure (figure 2) of the tetracyclic chromenopyranpyrazole 8c shows that the pmethyl phenyl group, adjacent nitrile moiety and the ring junction proton are in syn orientation. Scheme 1. Plausible pathway for the formation of tetracyclic chromenopyranpyrazoles (5 / 8)
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The plausible pathway for the formation of tetracyclic chromenopyranpyrazole is shown in scheme 1. The geometrical nature and attack of dienophiles control the stereochemistry of the products formed in the reaction. Based on that, we can envisage four possible transition structures. The exo-E-anti and endo-Z-anti proceed towards trans-adduct whereas, the endo-Esyn and exo-Z-syn to a cis-one.4e In this work, the endo-E-syn transition structure likely to provide cis product though two probable pathways exist. Therefore, the starting material 3 having a trans geometry led to the anti product and starting material 6 having a cis geometry led to the syn product which clearly shows the high stereoselective nature of the reaction. This journal is © The Royal Society of Chemistry [year]
Chemical Communications Accepted Manuscript
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moiety) tetracyclic chromenopyranpyrazole (5a) in excellent yield (95%) without column chromatography purification. The pure product was obtained after washing the crude mass with ethylacetate and hexane mixture in a 1:49 ratio. It is surprise to to note that this novel multicomponent cascade reaction provides a single product eventhough multiple reaction sites are present in the reactants with comparable reactivities. Table 1. Synthesis of novel tetracyclic chromenopyranpyrazole scaffolds via multicomponent cascade reaction (5a-p)
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The 2D-NMR also supports the stereoselectivity observed in the reaction. In order to demonstrate the synthetic utility of the newly synthesized tetracyclic chromenopyranpyrazole derivatives, we subjected them under different reaction conditions (Table 3). The hindered ester (5) moiety was reduced into alcohol (9) using LAH followed by cyclization led to the novel angularly fused poly heterocyclic frameworks (10). The hindered ester (5) and nitrile moiety (8) present in the angular position was successfully transformed into corresponding acid (12) and amide moiety (13) respectively. We also transformed the alcohol (9) into corresponding aldehyde (11) using IBX. Table 3. Synthesis of novel angularly fused polyheterocyles
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In conclusion, we have successfully developed an efficient multicomponent cascade protocol for the highly stereoselective constrution of novel tetracyclic chromenopyranpyrazole frameworks via domino reaction involving hydrazine formation, cyclic amide formation, Knoevenagel condensation and intramolecular hetero-Diels-Alder reaction for the first time. The present work provides an attractive strategy for the construction of three rings and three contiguous stereogenic centres in which one of them being an all carbon quarternary center in a unique fashion. Further highlight of this reaction include the following: (a) catalyst and solvent not required for the reaction, (b) Work-up and column chromatography purification not required to obtain pure material (c) The reaction is environmentally benign in nature and carriedout without the exclusion of air and moisture, (d) The reaction is highly efficient and provide products in excellent yields with high stereoselectivity. The present approach also opens new opportunities for the preparation of libraries of a wide variety of chromenopyranpyrazoles for biological screening.
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Acknowledgment We thank DST and CSIR (New Delhi) for the financial support. D.K and R.S thank CSIR for their SRF.
Note and references
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Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai – 600 025, Tamilnadu, India. Fax: 91-44-22352494; b Department of Chemistry, Pondicherry University, R. V. Nagar, Pondicherry – 605 014, India. E-mail: [email protected]
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†Electronic Supplementary Information (ESI) available: Copies of 1H and 13C spectra of all the new compounds. See DOI: 10.1039/b000000x/ 1 A. K. Katritzky, C. W. Rees. In Comprehensive Heterocyclic Chemistry; C. W. Bird, G. W. H. Cheeseman, Eds.; Pergamon: New York, NY, 1984.
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2 (a) M. Radi, V. Bernardo, B. Bechi, D. Castagnolo, M. Pagano, M. Botta, Tetrahedron Lett, 2009, 50, 6572. (b) M. Jha, S. Guy, T-Yi Chou, Tetrahedron Lett, 2011, 52, 4337. 3 (a) K. C. Nicolaou, J. A. Pfefferkorn, A. J. Roecker, G.-Q. Cao, S. Barluenga, H. J. Mitchell, J. Am. Chem. Soc. 2000, 122, 9939. (b) N. Iwata, S. Kitanaka, J. Nat. Prod. 2010, 73, 1203. (c) I. Bouabdallah, L. A. M. Barek, A. Zyad, A. Ramdani, I. Zidane, A. Melhaoui, Natural Product Research, 2006, 20, 1024. 4 (a) L. F. Tietze, Chem. Rev. 1996, 96, 115. (b) L. F. Tietze, H. Evers, E. Töpken, Angew. Chem. Int. Ed. 2001, 40, 903. (c) D. Bello, J. R. Rodríguez, F. Albericio, R. Ramón, R. Lavilla, Eur. J. Org. Chem. 2010, 5373. (d) G. Chouhan H. Alper, Org. Lett., 2010, 12, 192. (e) L. F. Tietze, J. Heterocycl.Chem. 1990, 27, 47. 5 (a) L. F. Tietze, N. Rackelmann, The Domino-Knoevenagel-heteroDiels-Alder Reaction and Related Transformations in "Multicomponent Reactions" 2005, p. 121-168. (b) A. Domling, Chem. Rev. 2006, 106, 17; (c) Z, Xu, F. D. Moliner, A. P. Cappelli, C. Hulme, Org. Lett., 15, 2013. 6. (a) C. Despotopoulou, L. Klier, P. Knochel, Org. Lett., 2009, 11, 3326; (b) T. Eicher, S. Hauptmann, A Speicher in The Chemistry of Heterocycles, 2nd ed., Wiley, New York, 2004, pp. 179. (c) N. K. Terrett, A. S. Bell, D. Brown, P. Ellis, Bioorg. Med. Chem. Lett. 1996, 6, 1819. (d) T. D. Penning, J. J. Talley, S. R. Bertenshaw, J. S. Carter, P. W. Collins, S. Docter, M. J. Graneto, L. F. Lee, J. F. Malecha, J. M. Miyashiro, R. S. Rogers, D. J. Rogier, S. S. Yu, G. D. Anderson, E. G. Burton, J. N. Cogburn, S. A. Gregory, C. M. Koboldt, W. E. Perkins, K. Seibert, A. W. Veenhuizen, Y. Y. Zhang, P. C. Isakson, J. Med. Chem, 1997, 40, 1347. 7 (a) A. Graul.;J. Castaner. Drugs Future, 1996, 21, 1014. (b) N. Sasano, A. Enomoto, Y. Hosoi, Y. Katsumura, Y. Matsumoto, A. Morita, K. Shiraishi, K. Miyagawa, H. Igaki, K. Nakagawa. Cancer Letters, 2010, 293, 52. 8 (a) E. S. El-Tamany, F. A. El-Shahed, B. H. Mohamed, J. Serb.Chem. Soc. 64,1999, 9. (b) Z. H. Ismail, G. M. Aly, M. S. El-Degwi, Egyp. J.Biotechnol, 13, 2003, 73. (c) M. E. A. Zaki, H. A. Soliman, A. E. Z. Rashad,. Naturforsch. C, 61, 2006, 1. (d) F. M. Abdelrazek,P. Metz, O. Kataeva, A. Jaeger, Arch.Pharm. 340, 2007, 543. 9 (a) D. Enders, A. Grossmann, B. Gieraths, M. Deüzdemir, C. Merkens, Org. Lett, 2012, 14, 4254. (b) A. R. Reddy, A. Sampath, G. Goverdhan, B. Yakambaram, K. Mukkanti, P. P. Reddy, Org. Process Res. Dev, 2009, 13, 98. (c) A. D. Patil, A. J. Freyer, D. S. Eggleston, R. C. Haltiwanger, B. Tomcowicz, A. Breen, R. K. Johnson, J. Nat. Prod. 1997, 60, 306. (d) T. T.-Y. Lee, Y. Kashiwada, L. Huang, J. Snider, M. Cosentino, K.-H. Lee, Bioorg. Med. Chem. 1994, 2, 1051. (f) S. R. Belmain, B. A. Amoah, S. P. Nyirenda, J. F. Kamanula, P. C. Stevenson, J. Agric. Food Chem. 2012, 60, 10055. 10 (a) T. Y. Liu, M. Xie, Y. C. Chen, Chem. Soc. Rev., 2012, 41, 4101. (b) D. Basavaiah, G. Veeraraghavaiah, Chem. Soc. Rev., 2012, 41, 68. (c) D. Basavaiah, B. S. Reddy, S. S. Badsara, Chem. Rev., 2010, 110, 5447. (d) V. Declerck, J. Martinez, F. Lamaty, Chem. Rev., 2009, 109, 1. (e) V. Singh, S. Batra, Tetrahedron, 2008, 64, 4511. 11 (a) M. Bakthadoss, G. Sivakumar, D. Kannan, Org. Lett., 2009, 11, 4466-4469. (b) M. Bakthadoss, N. Sivakumar, Synlett, 2011, 1296. (c) M. Bakthadoss, N. Sivakumar, A. Devaraj, Synthesis, 2011, 611. (d) D. Basavaiah, M. Bakthadoss, S. Pandiaraju, Chem. Commun., 1998, 1639. (e) M. Bakthadoss, N. Sivakumar, Synlett, 2009, 1014. (f) M. Bakthadoss, N. Sivakumar, G. Sivakumar, G. Murugan, Tetrahedron Lett., 2008, 49, 820. (g) M. Bakthadoss, N. Sivakumar, A. Devaraj, D. S. Sharada, Synthesis, 2011, 2136. (h) M. Bakthadoss, G. Murugan, Eur. J. Org. Chem., 2010, 5825. (i) M. Bakthadoss, D. Kannan, G. Sivakumar, Synthesis, 2012, 44, 793. M. Bakthadoss, J. Srinivasan, R. Selvakumar, Synthesis, 2012, 44, 793. 12.Structures were confirmed by single-crystal X-ray data. CCDC numbers for 5f and 8c are 780638 and 780639 respectively. 13. Representative procedure for the synthesis of compound (5a): A mixture of (E)-methyl-2-((2-formylphenoxy)methyl)-3-phenyl acrylate (3a, 1mmol), ethyl/methyl acetoacetate (1, 1mmol) and phenyl hydrazine (2, 1mmol) was placed in a round bottom flask and melted at 180 ºC for 1 h. After completion of the reaction as indicated by TLC, the crude product was washed with 5 mL of ethylacetate and hexane mixture (1:49 ratio) which successfully provided the pure product 5a as colorless solid.
Journal Name, [year], [vol], 00–00 | 3
Chemical Communications Accepted Manuscript
DOI: 10.1039/C3CC45502E
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Accepted Manuscript This article can be cited before page numbers have been issued, to do this please use: M. Bakthadoss, D. Kannan and S. Raman, Chem. Commun., 2013, DOI: 10.1039/C3CC45502E.
Volume 46 | Number 32 | 2010
ccess
This is an Accepted Manuscript, which has been through the RSC Publishing peer review process and has been accepted for publication. Chemical Communications www.rsc.org/chemcomm
Volume 46 | Number 32 | 28 August 2010 | Pages 5813–5976
ChemComm
the chemical
to therapeutic
etic and
Accepted Manuscripts are published online shortly after acceptance, which is prior to technical editing, formatting and proof reading. This free service from RSC Publishing allows authors to make their results available to the community, in citable form, before publication of the edited article. This Accepted Manuscript will be replaced by the edited and formatted Advance Article as soon as this is available. To cite this manuscript please use its permanent Digital Object Identifier (DOI®), which is identical for all formats of publication.
analytical ques for use
es and tools to s.
More information about Accepted Manuscripts can be found in the Information for Authors.
inical systems.
and
les. ion
Registered Charity Number 207890
Pages 5813–5976
org/journals
ISSN 1359-7345
COMMUNICATION J. Fraser Stoddart et al. Directed self-assembly of a ring-in-ring complex
FEATURE ARTICLE Wenbin Lin et al. Hybrid nanomaterials for biomedical applications
1359-7345(2010)46:32;1-H
Please note that technical editing may introduce minor changes to the text and/or graphics contained in the manuscript submitted by the author(s) which may alter content, and that the standard Terms & Conditions and the ethical guidelines that apply to the journal are still applicable. In no event shall the RSC be held responsible for any errors or omissions in these Accepted Manuscript manuscripts or any consequences arising from the use of any information contained in them.
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ARTICLE TYPE
A multicomponent cascade reaction for the synthesis of novel chromenopyranpyrazole scaffolds Manickam Bakthadoss,a,b* Damodharan Kannana and Raman Selvakumara
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Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X DOI: 10.1039/b000000x A catalyst, solvent, work-up and column free synthesis of chromenopyranpyrazole scaffolds via multicomponent cascade reaction has been achieved in excellent yields with high stereoselectivity. Interestingly, this novel reaction creates two N-C bonds, two C-C bonds and one O-C bond linkages through a domino process for the construction of three new rings and three contiguous stereogenic centers. An efficient and elegant assembly of complex structures with multiple stereocenters has become an important topic in organic chemistry. Heterocyclic rings are present as fundamental components in the skeleton of more than half of the biologically active compounds produced by nature.1 Among them, benzopyran and pyrazole heterocyclic ring systems are present in a vast number of natural products and bioactive substances, with a wide application range.2 These heterocycles are privileged structures, constituting pivotal drug like scaffolds in medicinal chemistry and have received much attention.3 An interesting aspect in the field of heterocyclic synthesis is in the use of domino reactions. During the past decade, domino reactions have emerged as a powerful and efficient method for the construction of heterocyclic compounds. Amongst such reactions, the domino Knoevenagel-hetero-Diels–Alder reaction has proven to be a useful tool for the synthesis of poly heterocyclic compounds.4 The progression of new methodologies with the improvement of synthetic efficiency is an important objective in modern organic synthesis.5 Multicomponent reactions (MCR), which encompass numerous bond-forming reactions in a one-pot operation, represent an appealing strategy for the facile construction of novel molecular architecture. These reactions are venerable to create wide libraries of diverse molecules in facile manner by virtue of their convergent nature. Therefore, the development of new multicomponent protocol for the rapid construction of fused molecular frameworks represents one of the frontiers of preparative chemistry. Pyrazole derivatives display a broad spectrum of biological activities and represent an important structural class in pharmaceuticals and agrochemicals. They are present in leading drugs such as viagra, celebrex and therefore, synthesis of pyrazole motifs are considered very important in pharmaceutical industries.6 In particular, 3-methyl-1-phenyl-1H-pyrazol-5-one (edaravone 4), which is a free radical scavenger, provides an interesting medicinal applications, such as potential This journal is © The Royal Society of Chemistry [year]
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neuroprotective agent for recovery of acute brain ischemia and subsequent cerebral infarction.7 The compounds containing a pyrano[2,3-c]pyrazole unit have shown antimicrobial, insecticidal, anti-inflammatory, and molluscicidal activities. On the other hand, photochromic compounds having a benzopyran nucleus have practical applications in the data storage, optical filters, displays, sensor protection, waveguides, and ophthalmic plastic lenses.8
Figure 1. Representative examples of natural products and bioactive molecules containing pyrazoles and benzopyran motifs A representative members of pyrazoles, and benzopyran structural motif containing natural products and biologically active molecules such as pyrano[2,3-c]pyrazole,(I),9a chromenopyrazolylsulfonamide (II),9b suksdorfin (III),9c deguelin (IV), tephrosin (V)9d and edaravone (VI)7 are shown in figure 1. The Baylis-Hillman adducts have become a valuable source for various organic transformations and have been transformed into a number of carbocycles and heterocyclic frameworks of medicinal importance. In fact, due to the close proximity of functional groups the BH-adducts and its derivatives have become an attractive source/ substrates for a number of organic transformations often leading to the synthesis of several bioactive compounds and important frameworks of medicinal relevance.10 In continuation of our ongoing research program in the field of heterocyclic chemistry,[11] we herein report a convenient, facile, and new method for the synthesis of novel tetracyclic chromenopyranpyrazole frameworks through multi component cascade reaction (MCCR). Based on our preliminary report,[11a] we envisaged that the synthesis of chromeno pyranpyrazole scaffolds (5) can be acheived through a multi component cascade reaction. Accordingly, we have taken methyl acetoacetate (1), phenyl hydrazine (2) and the BaylisHillman derivative (3) in a round-bottom flask and heated at 180°C for 1 h in solvent and catalyst-free condition, which successfully led to the desired angularly substituted (ester Journal Name, [year], [vol], 00–00 | 1
Chemical Communications Accepted Manuscript
Published on 19 September 2013. Downloaded by University of Minnesota - Twin Cities on 23/09/2013 02:22:18.
www.rsc.org/xxxxxx
ChemComm
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DOI: 10.1039/C3CC45502E
55
Table 2. Synthesis of novel tetracyclic chromenopyranpyrazole scaffolds via multicomponent cascade reaction (8a-g)
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a
All reactions were carried out on 1 mmol scale at 180 ºC for 1 h. Structure of the molecule was further confirmed by single-crystal X-ray data (see Supporting Information).
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20 a
All reactions were carried out on 1 mmol scale at 180 ºC for 1 h. Structure of the molecule was further confirmed by single-crystal X-ray data (see Supporting Information).
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Interestingly, this cascade reaction proceeds via an insitu formation of edaravone (4) from phenyl hydrazine and methyl acetoacetate followed by domino Knoevenagel intramolecular hetero Diels-Alder (IMHDA) reaction which creates the annulation of three rings (two six membered rings and one five membered ring) in a stereoselective fashion. A similar results were obtained when we used ethylacetoacetate in the place of methylacetoacetate. Decreasing the reaction temperature (from 180 °C to 140 °C) and time led to the incompletion of the reaction with the formation of intermediate 4, product 5 and a Knoevenagel condensation product derived from 4 and aldehyde 3. This type of novel domino reaction involving hydrazine formation, cyclic amide formation, Knovenegel condensation and intramolecular hetero Diels-Alder reaction is very attractive and not known so far in the literature. To expand the scope of this cascade reaction, we have treated various Baylis-Hillman derivatives (3b-p) under optimized reaction condition which successfully afforded the desired angularly substituted (ester moiety) tetracyclic chromenopyran pyrazoles (5b-p) in excellent yields (92-96%). The isolated yields of the pure products (5a-p) are summarized in table 1. On the basis of these successful results, we examined the various Baylis-Hillman derivatives (i.e.) (E)-2-((2-formyl phenoxy)methyl)-3-arylacrylonitriles (6a-g) with phenyl hydrazine (2) and ethyl/methyl acetoacetate (1) under similar reaction condition, which provided the anticipated angularly substituted (nitrile moiety) tetracyclic chromenopyranpyrazole products (8a-g) in excellent yields (91-95%). The isolated yields of the pure products (8a-g) are summarized in table 2. It is very important to mention here that the high stereoselectivity in the formation of tetracyclic chromenopyran 2 | Journal Name, [year], [vol], 00–00
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Figure 2. ORTEP diagram12 of compound 5f and 8c pyrazole frameworks were clearly evidenced by NMR spectra and X-ray crystal analyses (Figure 2). According to the ORTEP diagram of the tetracyclic chromenopyran pyrazole 5f shown in the figure 2, the relative stereochemistry of the o-methoxy aryl group and the adjacent ester moiety are in anti orientation where as the ester moiety and the ring junction proton exist in syn orientation. Similarly, the X-ray crystal structure (figure 2) of the tetracyclic chromenopyranpyrazole 8c shows that the pmethyl phenyl group, adjacent nitrile moiety and the ring junction proton are in syn orientation. Scheme 1. Plausible pathway for the formation of tetracyclic chromenopyranpyrazoles (5 / 8)
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The plausible pathway for the formation of tetracyclic chromenopyranpyrazole is shown in scheme 1. The geometrical nature and attack of dienophiles control the stereochemistry of the products formed in the reaction. Based on that, we can envisage four possible transition structures. The exo-E-anti and endo-Z-anti proceed towards trans-adduct whereas, the endo-Esyn and exo-Z-syn to a cis-one.4e In this work, the endo-E-syn transition structure likely to provide cis product though two probable pathways exist. Therefore, the starting material 3 having a trans geometry led to the anti product and starting material 6 having a cis geometry led to the syn product which clearly shows the high stereoselective nature of the reaction. This journal is © The Royal Society of Chemistry [year]
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moiety) tetracyclic chromenopyranpyrazole (5a) in excellent yield (95%) without column chromatography purification. The pure product was obtained after washing the crude mass with ethylacetate and hexane mixture in a 1:49 ratio. It is surprise to to note that this novel multicomponent cascade reaction provides a single product eventhough multiple reaction sites are present in the reactants with comparable reactivities. Table 1. Synthesis of novel tetracyclic chromenopyranpyrazole scaffolds via multicomponent cascade reaction (5a-p)
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The 2D-NMR also supports the stereoselectivity observed in the reaction. In order to demonstrate the synthetic utility of the newly synthesized tetracyclic chromenopyranpyrazole derivatives, we subjected them under different reaction conditions (Table 3). The hindered ester (5) moiety was reduced into alcohol (9) using LAH followed by cyclization led to the novel angularly fused poly heterocyclic frameworks (10). The hindered ester (5) and nitrile moiety (8) present in the angular position was successfully transformed into corresponding acid (12) and amide moiety (13) respectively. We also transformed the alcohol (9) into corresponding aldehyde (11) using IBX. Table 3. Synthesis of novel angularly fused polyheterocyles
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75 O
15
H
Me
MeO2C
N N Ph
O
R1
5
O
Me
H
N
0 °C-rt, 0.5 h
O
R1
Me
H
TFA, DCE
HO
LAH, THF
O
9a-e
N Ph
reflux, 15 h
N N Ph
O
R1
10a-e
80
MeO O
H
Me
O
O
H
N N Ph 10a Me Br O
O
H
Me N
O
10b
O
40
45
H
OHC
N Ph OMe 10e
35
Me
O
H
N
N N Ph
O
N Ph
O
10d
10c
Me N N 20 Ph
85
Cl
O
30
H
Me
Me N
O
11
N Ph
O
H
HO2C
Me N
O
12
N Ph
O
H
H2NOC O
Me N N Ph
25
90
13
In conclusion, we have successfully developed an efficient multicomponent cascade protocol for the highly stereoselective constrution of novel tetracyclic chromenopyranpyrazole frameworks via domino reaction involving hydrazine formation, cyclic amide formation, Knoevenagel condensation and intramolecular hetero-Diels-Alder reaction for the first time. The present work provides an attractive strategy for the construction of three rings and three contiguous stereogenic centres in which one of them being an all carbon quarternary center in a unique fashion. Further highlight of this reaction include the following: (a) catalyst and solvent not required for the reaction, (b) Work-up and column chromatography purification not required to obtain pure material (c) The reaction is environmentally benign in nature and carriedout without the exclusion of air and moisture, (d) The reaction is highly efficient and provide products in excellent yields with high stereoselectivity. The present approach also opens new opportunities for the preparation of libraries of a wide variety of chromenopyranpyrazoles for biological screening.
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Acknowledgment We thank DST and CSIR (New Delhi) for the financial support. D.K and R.S thank CSIR for their SRF.
Note and references
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Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai – 600 025, Tamilnadu, India. Fax: 91-44-22352494; b Department of Chemistry, Pondicherry University, R. V. Nagar, Pondicherry – 605 014, India. E-mail: [email protected]
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†Electronic Supplementary Information (ESI) available: Copies of 1H and 13C spectra of all the new compounds. See DOI: 10.1039/b000000x/ 1 A. K. Katritzky, C. W. Rees. In Comprehensive Heterocyclic Chemistry; C. W. Bird, G. W. H. Cheeseman, Eds.; Pergamon: New York, NY, 1984.
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Journal Name, [year], [vol], 00–00 | 3
Chemical Communications Accepted Manuscript
DOI: 10.1039/C3CC45502E
