Chemistry:2-Chloro-4,6-dimethoxy-1,3,5-triazine

From HandWiki

2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) is a triazine derivative commonly used in acylation reactions for the synthesis of amides and esters as well as for activation of alcohols in a diverse range of other reactions. Almost exclusively used with N-methylmorpholine (NMM) as a Brønsted base, its reactivity is closely related to DMTMM.

Preparation

CDMT synthesis

CDMT can be prepared from cyanuric chloride in a mixture of methanol, water and sodium bicarbonate.[1] CDMT directly precipitates from this aqueous reaction mixture, but careful control of base stoichiometry and temperature is required to obtain high selectivity between the mono-, di- and trimethoxy-triazines and prepare CDMT in high yield.[2][3] DMTMM is prepared in a nucleophilic aromatic substitution between CDMT and NMM.[4]

Uses

CDMT is a general reagent for acylation of carboxylic acids, providing access to amides and esters in high yields under mild conditions.[5] NMM is almost exclusively used as the Brønsted base in acylation and the reactivity of CDMT is hard to distinguish from DMTMM in the context of acylations.[6] The activated ester intermediate in these reactions is the 2-acyloxy-4,6-dimethoxy-1,3,5-triazine which has been characterized using IR and NMR spectroscopy. CDMT has been shown to form a wide variety of amidations, including peptides, with low risk of epimerization.[7] CMDT has been successfully used at multikilogram scales to prepare the secondary amide in the antitumor agent Pemetrexed.[8] In the case of esterification, broad reactivity is observed but the addition of magnesium chloride is often required.[9]

CDMT reaction

CDMT has been used to activate alcohols, transforming them into electrophiles for a variety of transformations. It has been used in glycosylations.[10] The anomeric position can be activated selectively without protecting the other hydroxyl groups. The isolated CDMT-adduct undergoes stereoselective reaction with alcohols when used as solvent in the presence of catalytic [CuI(CH3CN)4]PF6. Isolated CDMT-adducts have also been used as electrophiles in nickel-catalyzed Suzuki-Miyaura cross couplings.[11]

CDMT reaction
CDMT reaction

Safety

In vivo dermal sensitization studies according to OECD 429[12] confirmed CMDT is a strong skin sensitizer, showing a response at 0.03 wt% in the local lymph node assay (LLNA) placing it in Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Dermal Sensitization Category 1A.[13] These studies confirm that DMTMM is a less sensitizing alternative to CDMT, as suggested by anecdotal observations in the literature.[14] Protective gloves, lab coat, and eye protection should be employed to reduce exposure while using CDMT.

References

  1. ↑ Dudley, James R.; Thurston, Jack T.; Schaefer, Frederic C.; Holm-Hansen, Dagfrid; Hull, Clarence J.; Adams, Pierrepont (1951). "Cyanuric Chloride Derivatives. III. Alkoxy-s-triazines". Journal of the American Chemical Society 73 (7): 2986–2990. doi:10.1021/ja01151a003. ISSN 0002-7863. https://doi.org/10.1021/ja01151a003. 
  2. ↑ Cronin, Jason S.; Ginah, Francis O.; Murray, Angela R.; Copp, James D. (1996). "An Improved Procedure for the Large Scale Preparation of 2-Chloro-4,6-dimethoxy-1,3,5-triazine" (in en). Synthetic Communications 26 (18): 3491–3494. doi:10.1080/00397919608003754. ISSN 0039-7911. http://www.tandfonline.com/doi/abs/10.1080/00397919608003754. 
  3. ↑ , Valentina"Method for the industrial production of 2-halo -4,6-dialkoxy-1,3,5-triazines and their use in the presence of amines" patent WO2016103185A2, issued 2016-06-30
  4. ↑ Kunishima, Munetaka; Kawachi, Chiho; Monta, Jun; Terao, Keiji; Iwasaki, Fumiaki; Tani, Shohei (12 November 1999). "4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride: an efficient condensing agent leading to the formation of amides and esters". Tetrahedron 55 (46): 13159–13170. doi:10.1016/S0040-4020(99)00809-1. ISSN 0040-4020. https://www.sciencedirect.com/science/article/pii/S0040402099008091. 
  5. ↑ Kamiński, Zbigniew J. (1 January 1985). "2-chloro-4,6-disubstituted-1,3,5-triazines a novel group of condensing reagents". Tetrahedron Letters 26 (24): 2901–2904. doi:10.1016/S0040-4039(00)98867-1. ISSN 0040-4039. https://www.sciencedirect.com/science/article/pii/S0040403900988671. 
  6. ↑ Sole, Roberto; Gatto, Vanessa; Conca, Silvia; Bardella, Noemi; Morandini, Andrea; Beghetto, Valentina (2 January 2021). "Sustainable Triazine-Based Dehydro-Condensation Agents for Amide Synthesis" (in en). Molecules 26 (1): 191. doi:10.3390/molecules26010191. ISSN 1420-3049. PMID 33401732. PMC 7795458. https://www.mdpi.com/1420-3049/26/1/191. 
  7. ↑ Kamiński, Zbigniew J. (1987). "2-Chloro-4,6-dimethoxy-1,3,5-triazine. A New Coupling Reagent for Peptide Synthesis" (in en). Synthesis 1987 (10): 917–920. doi:10.1055/s-1987-28122. ISSN 0039-7881. http://www.thieme-connect.de/DOI/DOI?10.1055/s-1987-28122. 
  8. ↑ Barnett, Charles J.; Wilson, Thomas M.; Kobierski, Michael E. (1999). "A Practical Synthesis of Multitargeted Antifolate LY231514". doi:10.1021/op9802172. https://pubs.acs.org/doi/10.1021/op9802172. 
  9. ↑ Kamińska, Janina E.; Kamiński, Zbigniew J.; Góra, Józef (1999). "2-Acyloxy-4,6-dimethoxy-1,3,5-triazine - A New Reagent for Ester Synthesis". Synthesis 1999 (04): 593–596. doi:10.1055/s-1999-3448. http://www.thieme-connect.de/DOI/DOI?10.1055/s-1999-3448. 
  10. ↑ Tanaka, Tomonari; Kikuta, Naoya; Kimura, Yoshiharu; Shoda, Shin-ichiro (5 June 2015). "Metal-catalyzed Stereoselective and Protecting-group-free Synthesis of 1,2- cis -Glycosides Using 4,6-Dimethoxy-1,3,5-triazin-2-yl Glycosides as Glycosyl Donors" (in en). Chemistry Letters 44 (6): 846–848. doi:10.1246/cl.150201. ISSN 0366-7022. https://academic.oup.com/chemlett/article/44/6/846/7394401. 
  11. ↑ Li, Xiao-Jian; Zhang, Jin-Ling; Geng, Yu; Jin, Zhong (2013). "Nickel-Catalyzed Suzuki–Miyaura Coupling of Heteroaryl Ethers with Arylboronic Acids". doi:10.1021/jo4005537. https://doi.org/10.1021/jo4005537. 
  12. ↑ OECD (2010) (in en). Test No. 429: Skin Sensitisation: Local Lymph Node Assay. Paris: Organisation for Economic Co-operation and Development. https://www.oecd-ilibrary.org/environment/test-no-429-skin-sensitisation_9789264071100-en. 
  13. ↑ Graham, Jessica C.; Trejo-Martin, Alejandra; Chilton, Martyn L.; Kostal, Jakub; Bercu, Joel; Beutner, Gregory L.; Bruen, Uma S.; Dolan, David G. et al. (20 June 2022). "An Evaluation of the Occupational Health Hazards of Peptide Couplers" (in en). Chemical Research in Toxicology 35 (6): 1011–1022. doi:10.1021/acs.chemrestox.2c00031. ISSN 0893-228X. PMID 35532537. PMC 9214767. https://pubs.acs.org/doi/10.1021/acs.chemrestox.2c00031. 
  14. ↑ Kunishima, Munetaka; Kawachi, Chiho; Monta, Jun; Terao, Keiji; Iwasaki, Fumiaki; Tani, Shohei (12 November 1999). "4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride: an efficient condensing agent leading to the formation of amides and esters". Tetrahedron 55 (46): 13159–13170. doi:10.1016/S0040-4020(99)00809-1. ISSN 0040-4020. https://www.sciencedirect.com/science/article/pii/S0040402099008091. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:2-Chloro-4,6-dimethoxy-1,3,5-triazine&oldid=4309006"