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Synthesis of unsymmetrical triarylmethanes via Friedel -Crafts reaction of N - Boc or

Burapha University International Conference 2014 July 3-4, 2014, Pattaya , THAILAND. Synthesis of unsymmetrical triarylmethanes via Friedel -Crafts reaction of N - Boc or N - CBz diarylmethylcarbamates. Sureeporn Ruengsangtongkul 3 July 2014. Structure. Unsymmetrical

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Synthesis of unsymmetrical triarylmethanes via Friedel -Crafts reaction of N - Boc or

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  1. Burapha University International Conference 2014 July 3-4, 2014, Pattaya, THAILAND Synthesis of unsymmetrical triarylmethanes viaFriedel-Crafts reaction of N-Boc or N-CBzdiarylmethylcarbamates Sureeporn Ruengsangtongkul 3 July 2014

  2. Structure Unsymmetrical Triarylmethanes Triarylmethanes (TRAMs)

  3. Application of Triarymethanes (TRAMs) A B http://www.ijdvl.com/viewimage.asp?img=ijdvl_2010_76_2_180_60571_u2.jpg Antitubercular agent http://www.987theriver.com/pages/breastcancerawareness.html?feed=463518&article=10448243 C D Anti-breast cancer agent

  4. Application of Triarymethanes (TRAMs) • leuco-dye • protecting group • building blocks of dendimer • photochromic agents Triarylmethanes 4

  5. Literature reviews

  6. Literature reviews Unsymmetrical triarylmethane : Diarylmethylamine 2-pyridylsulfonyl imines (E) N-(diarylmethyl)2-pyridylsulfonylamines (F) 6 Esquivias, J. et al. (2006). Angew. Chem Int. Ed., 45, 629-633.

  7. Literature reviews I G H 7 Zhang, J. et al. (2012). J. Am.Chem. Soc., 134, 13765–13772.

  8. Literature reviews J K 8

  9. Synthetic plans… Carbamate (3) Diarylmethylamine (4) Unsymmetrical Triarylmethane (8) Arene (1) Aldehyde (2) Difference arene (7) R = t-Bu, Bn 9

  10. Results The synthesis of N-Boc or N-benzyl-diarylmethylcarbamate 4a,b as an alkylating agent 3 1 2 4 4b : 66% 4a : 86% 4c : 57% 4d : 25% 4e : 66% 4f : 36% 10 a Reaction conditions : 1 (1 mmol), 2 (1.1 mmol), 3 (1 mmol), FeCl3·6H2O, solvent (1 mL), room temperature. b Isolated yield.

  11. Results Model and optimization studies 6a 1a 4a 1c 7a a Isolated yield.

  12. Results Synthesis of unsymmetrical triarylmethanes 6a 12 a Reaction conditions : 1 (1 mmol), 2 (1 mmol), I2, solvent (10 mL), room temperature. b Isolated yield.

  13. Results Synthesis of unsymmetrical triarylmethanes 6a a Reaction conditions : 1 (1 mmol), 2 (1 mmol), I2, solvent (10 mL), room temperature. b Isolated yield.

  14. Mechanism I II Unsymmetrical triarylmethane

  15. Anti-Inflammatory Activity Screening 6b Anti-inflammatory activity 6a 6c 6e 6f 6g http://www.niox.com/en-US/feno-asthma/, http://www.epyk.com/459/ top-7-anti-inflammatory-foods/, http://www.naturalbodydefense.net/

  16. Anti-Inflammatory Activity Screening Aminoguanidine %NO inhibition= 70.2 ± 5.9 6b 6e 6a % Cell viability : 101.21±2.72 % NO inhibition : 26.68±4.40 % Cell viability : 95.76±2.83 % NO inhibition : 63.74±7.52 % Cell viability : 95.13±3.92 % NO inhibition : 49.69±1.63 6c 6f 6g % Cell viability : 94.86±1.17 % NO inhibition : 74.64±14.00 % Cell viability : 87.40±3.29 % NO inhibition : 75.71±10.94 % Cell viability : 93.63±1.33 % NO inhibition : 47.35±17.26

  17. Conclusions FeCl3.6H2O 3 5 4 6 R = t-Bu, Bn % yield : 8-93 1 2 Mild reaction conditions Low catalytic loading Easy removal of the catalyst 6c 6f % Cell viability : 94.86±1.17 % NO inhibition : 74.64±14.00 % Cell viability : 87.40±3.29 % NO inhibition : 75.71±10.94

  18. Acknowledgements • Advisor: Assistant Professor Dr. JarayJaratjaroonphong • Assistant Professor Dr. KlaokwanSrisook • The Center of Excellence for Innovation in Chemistry (PERCH-CIC) • Department of Chemistry, Faculty of Science, Burapha university

  19. Thank you

  20. Results The synthesis of N-Boc or N-benzyl-diarylmethylcarbamate 4a,b as an alkylating agent 3 1 2 4 4b : 66% 4a : 86% 4c : 57% 5c : 43% 4d : 25% 4e : 66% 4f : 36% 20 a Reaction conditions : 1 (1 mmol), 2 (1.1 mmol), 3 (1 mmol), FeCl3·6H2O, solvent (1 mL), room temperature. b Isolated yield.

  21. 1H-NMR 2.26 (3H, s) 7.52 (2H, d, J = 8.4 Hz) 7.45-7.25 (5H, m) 8.20 (2H, d, J = 8.4 Hz) 5.14 (2H, dd, J = 12.2 Hz) 5.93 (1H, d, J = 2.2 Hz) 5.75 (1H, brd, J = 6.6 Hz) 6.03 (2H, brs)

  22. 13C-NMR 123.8 13.5 127.8 128.6 128.4 128.3 106.4 67.4 109.2 52.8 147.1 153.1 149.7 147.4 135.9

  23. 1H-NMR 2.27 (3H, s) 1.20 (3H, t, J = 7.5 Hz) 5.95 (4H, dd, J = 3.9 Hz 8.19 (2H, d, J = 8.7 Hz) 7.44 (2H, d, J = 8.7 Hz) 5.47 (1H, s) 2.62 (2H, q, J = 7.5 Hz)

  24. 13C-NMR 129.2 123.6 106.2 108.5 44.8 108.7 104.6 21.3 13.5 12.0 146.9 150.8 147.5 151.0 157.8 152.0

  25. Mechanism II I Unsymmetrical triarylmethane II

  26. Inflammation • Inflammation is reaction in tissues of host response to injurious agents such as radiation, CCl4, bacteria (lipopolysaccharides: LPS) and viruses (dsRNA) infection by increase in vascular permeability and activation of leukocytes. • Inflammation can be classified as : • - Acute inflammation • Relatively short duration, lasting for minutes, several hours, or a few days • Main characteristics are the exudation of fluid and plasma proteins (edema) • - Chronic inflammation • Prolonged duration (weeks to months to years) • Associated histologically with the presence of lymphocytes and macrophages

  27. The components of acute and chronic inflammatory responses and their principal functions Kumar V., Abbas A.K., Fausto N. (2010). Robbins and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia: Elsevier Saunders

  28. The role of macrophage in inflammation • Macrophages are white blood cell within tissues and are mononuclear phagocytic cells (monocytes) differentiation from myeloid stem cells in the bone marrow. • It’s play a key role in acute and chronic inflammation and respond to many microbes and are destroyed microbes by phagocytosis • It’s importance effector cells for the elimination of microbes and produce cytokines such as NO and PGE2 as well as activate other inflammatory cells.

  29. The mechanism of phagocytosis Kumar, Abbus & Fausto, 2005

  30. The components of acute and chronic inflammatory responses and their principal functions Kumar V., Abbas A.K., Fausto N. (2010). Robbins and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia: Elsevier Saunders

  31. Inflammatoryresponse of mediators in inflammation

  32. Nitric oxide (NO)  NO is a free radical gas, generated by nitric oxide synthase (NOS). NOS-derived NO production is oxidation of L-Arginine to L-Citrulline. • Endothelial NOS (eNOS) NO plays a role in vasodilation, inhibition of platelet aggregation, etc. • Neuronal NOS (nNOS) NO acts as a neurotransmitter and neuromodulator • Inducible NOS (iNOS) NO acts as a cytotoxic agent during immune and inflammatory responses. Isoforms of the nitric oxide synthase (NOS) Feng C.(2012) Mechanism of Nitric Oxide Synthase Regulation: ElectronTransfer and Interdomain Interactions. Coordination Chemistry Reviews, 256 393-411

  33. Prostaglandins (PGs) It is synthesized from arachidonic acid by cyclooxygenase (COX). Isoforms of the cyclooxygenase (COX) • COX-1: constitutive form COX-1-derived PGs regulate the secretion of gastric mucin. • COX-2: inducible form COX-2-derived prostaglandin E2 (PGE2) production is increasein inflammatory response and caused vasodilation, fever and pain. • COX-3: constitutive form COX-3 is a splice variant of COX-1 predominantly expressed in brain and heart. http://ai.jsaweb.jp/fulltext/054020209/fig01.html

  34. Lipopolysaccharide (LPS) • Major component of the outer cell • wall of gram-negative bacteria • Strongest activator for macrophages via • Toll-like receptor 4 (TLR4) • Activation of inflammatory responses • Initiate multiple intracellular signaling • events, including • : Nuclear factor-κB (NF-κB) pathway • : Mitogen-activated protein (MAP) • kinases Inflammatory-related gene (e.g. iNOS and COX-2) From : Guo, & Friedman, 2010

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