New Experimental Conditions for Diels–Alder and Friedel-Crafts Alquilation Reactions with Thiophene: A New Selenocyanate with Potent Activity against Cancer
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis Optimization
Reaction Mechanism Discussion
2.2. Biological Evaluation
2.2.1. Cytotoxicity Activity
2.2.2. Compound 15 Induces an Arrest on the G2/M Phase of the Cell Cycle
3. Materials and Methods
3.1. Synthesis
3.1.1. Synthesis of 2-Bromoethyl Maleimide
3.1.2. Synthesis of N-3-Acetoxypropyl Maleimide
3.1.3. Diels–Alder Reaction of Thiophene with N-Phenylmaleimides Promoted by AlCl3
3.1.4. Synthesis of Friedel–Crafts-Type Alquilation Compounds
3.1.5. Synthesis of “Butterfly-Like” Diazatetradecenes
3.1.6. Synthesis of the Selenocyanate Derivative of Thiophene DA Adduct 15
3.2. Characterization Data
3.3. Biological Evaluation
3.3.1. NCI-60 Human Tumor Cell Line 5-Dose-Response
3.3.2. Cell Cycle Assay
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Entry | Solvent | (1):(2) | eq AlCl3 | Temp | Time (h) | Yield (%) 1 (3) | Yield (%) 1 (4) | (3):(4) | Yield (%) 1 (5) |
---|---|---|---|---|---|---|---|---|---|
1 | DCM | 1:1 | 0.5 | RT | 24 | 4.4 | 1.1 | 78:22 | - |
2 | DCM | 1:1 | 1 | RT | 24 | 10.5 | 2.4 | 82:18 | 2.0 |
3 | DCM | 1:1 | 2 | RT | 24 | 11.8 | 0.9 | 94:6 | 21.7 |
4 | DCM | 5:1 | 0.5 | RT | 24 | 11.0 | 2.7 | 80:20 | 2.7 |
5 | DCM | 5:1 | 1 | RT | 24 | 25.9 | 7.4 | 77:23 | 4.6 |
6 | DCM | 5:1 | 2 | RT | 24 | - | - | - | 31.0 |
7 | DCM | 5:1 | 1 | RT | 48 | 33.4 | 6.8 | 83:17 | 4.8 |
8 | DCM | 5:1 | 1 | RT | 72 | 37.3 | 3.9 | 90:10 | 11.6 |
9 | DCM | 5:1 | 1 | RT | 96 | 47.2 | 4.9 | 91:9 | 8.8 |
10 | DCM | 5:1 | 1 | Reflux | 8 | 15.4 | 2.1 | 87:13 | 2.1 |
11 | DCM | 5:1 | 1 | Reflux | 24 | 38.8 | 3.0 | 93:7 | 6.7 |
12 | DCM | 5:1 | 1 | Reflux | 48 | 8.2 | 0.6 | 93:7 | - |
13 | THF | 5:1 | 1 | RT | 24 | - | - | - | - |
14 | Et2O | 5:1 | 1 | RT | 24 | - | - | - | - |
15 | CHCl3 | 5:1 | 1 | RT | 24 | 8 | 3.2 | 72:28 | 12.1 |
16 | DCM | 1:1 | 0.5 | RT | 24 | 4.4 | 1.1 | 78:22 | - |
17 | DCM | 1:1 | 1 | RT | 24 | 10.5 | 2.4 | 82:18 | 2.0 |
18 | DCM | 1:1 | 2 | RT | 24 | 11.8 | 0.9 | 94:6 | 21.7 |
Entry | Lewis Acid | Yield (%) 1 3 | Yield (%) 1 4 | (3):(4) | Yield (%) 1 5 |
---|---|---|---|---|---|
5 | AlCl3 | 25.9 | 7.4 | 77:23 | 4.6 |
16 | Me2AlCl | 0.05 | 0.2 | 66:34 | 0 |
17 | FeCl3 | 0 | 0 | - | 0 |
18 | SnCl4 | 0 | 0 | - | 0 |
19 | TiCl4 | 0.019 | 0.002 | 81:19 | 0 |
20 | BF3·H20 | 0 | 0 | - | 0 |
Dienophile | Adduct | Endo:exo a | Yield (%) exo a | Yield (%) endo a | Isolated Yield (%) exo |
---|---|---|---|---|---|
No | n.d. | n.d. | n.d. | n.d. | |
9:91 | 50 | 4.9 | 33 | ||
31:69 | 32 | 15 | 25 | ||
10:90 | 42 | 3.8 | 36 | ||
19:81 | 10 | 2.4 | 7.1 | ||
No | n.d. | n.d. | n.d. | n.d. | |
No | n.d. | n.d. | n.d. | n.d. | |
No | n.d. | n.d. | n.d. | n.d. |
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Calvo-Martín, G.; Plano, D.; Sanmartín, C. New Experimental Conditions for Diels–Alder and Friedel-Crafts Alquilation Reactions with Thiophene: A New Selenocyanate with Potent Activity against Cancer. Molecules 2022, 27, 982. https://doi.org/10.3390/molecules27030982
Calvo-Martín G, Plano D, Sanmartín C. New Experimental Conditions for Diels–Alder and Friedel-Crafts Alquilation Reactions with Thiophene: A New Selenocyanate with Potent Activity against Cancer. Molecules. 2022; 27(3):982. https://doi.org/10.3390/molecules27030982
Chicago/Turabian StyleCalvo-Martín, Gorka, Daniel Plano, and Carmen Sanmartín. 2022. "New Experimental Conditions for Diels–Alder and Friedel-Crafts Alquilation Reactions with Thiophene: A New Selenocyanate with Potent Activity against Cancer" Molecules 27, no. 3: 982. https://doi.org/10.3390/molecules27030982