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

2-Chloro-4,6-dimethoxy-1,3,5-triazine
Names
IUPAC name
2-chloro-4,6-dimethoxy-1,3,5-triazine
Other names
CDMT
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.019.583
EC Number
  • 221-541-0
UNII
  • InChI=1S/C5H6ClN3O2/c1-10-4-7-3(6)8-5(9-4)11-2/h1-2H3
    Key: GPIQOFWTZXXOOV-UHFFFAOYSA-N
  • COc1nc(Cl)nc(OC)n1
Properties
C5H6ClN3O2
Molar mass 175.57 g·mol−1
Appearance White crystalline solid
Melting point 71–74 °C (160–165 °F; 344–347 K)[1]
Hazards
GHS labelling:
Danger
H302, H315, H317, H318, H319, H335, H411
P261, P264, P264+P265, P270, P271, P272, P273, P281, P301+P317, P302+P352, P304+P340, P304+P354+P338, P305+P351+P338, P317, P319, P321, P330, P333+P317, P337+P317, P362+P364, P391, P403+P233, P405, P501
Safety data sheet (SDS) Sigma-Aldrich
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

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 can be prepared from cyanuric chloride in a mixture of methanol, water and sodium bicarbonate.[2] 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.[3][4] DMTMM is prepared in a nucleophilic aromatic substitution between CDMT and NMM.[5]

Uses

CDMT is a general reagent for acylation of carboxylic acids, providing access to amides and esters in high yields under mild conditions.[6] 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.[7] 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.[8] CMDT has been successfully used at multikilogram scales to prepare the secondary amide in the antitumor agent Pemetrexed.[9] In the case of esterification, broad reactivity is observed but the addition of magnesium chloride is often required.[10]

CDMT has been used to activate alcohols, transforming them into electrophiles for a variety of transformations. It has been used in glycosylations.[11] 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.[12]

Safety

In vivo dermal sensitization studies according to OECD 429[13] 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.[14] These studies confirm that DMTMM is a less sensitizing alternative to CDMT, as suggested by anecdotal observations in the literature.[15] Protective gloves, lab coat, and eye protection should be employed to reduce exposure while using CDMT.

References

  1. ^ Recl. Trav. Chim. Pays-Bas, 1978, 97, 107. https://doi.org/10.1002/recl.19780970406
  2. ^ 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.
  3. ^ 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". Synthetic Communications. 26 (18): 3491–3494. doi:10.1080/00397919608003754. ISSN 0039-7911.
  4. ^ WO2016103185A2, BEGHETTO, Valentina, "Method for the industrial production of 2-halo -4,6-dialkoxy-1,3,5-triazines and their use in the presence of amines", issued 30 June 2016 
  5. ^ 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.
  6. ^ 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.
  7. ^ Sole, Roberto; Gatto, Vanessa; Conca, Silvia; Bardella, Noemi; Morandini, Andrea; Beghetto, Valentina (2 January 2021). "Sustainable Triazine-Based Dehydro-Condensation Agents for Amide Synthesis". Molecules. 26 (1): 191. doi:10.3390/molecules26010191. ISSN 1420-3049. PMC 7795458. PMID 33401732.
  8. ^ Kamiński, Zbigniew J. (1987). "2-Chloro-4,6-dimethoxy-1,3,5-triazine. A New Coupling Reagent for Peptide Synthesis". Synthesis. 1987 (10): 917–920. doi:10.1055/s-1987-28122. ISSN 0039-7881.
  9. ^ Barnett, Charles J.; Wilson, Thomas M.; Kobierski, Michael E. (1999). "A Practical Synthesis of Multitargeted Antifolate LY231514". pubs.acs.org. doi:10.1021/op9802172. Retrieved 23 February 2026.
  10. ^ 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.
  11. ^ 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". Chemistry Letters. 44 (6): 846–848. doi:10.1246/cl.150201. ISSN 0366-7022.
  12. ^ Li, Xiao-Jian; Zhang, Jin-Ling; Geng, Yu; Jin, Zhong (2013). "Nickel-Catalyzed Suzuki–Miyaura Coupling of Heteroaryl Ethers with Arylboronic Acids". pubs.acs.org. doi:10.1021/jo4005537. Retrieved 23 February 2026.
  13. ^ OECD (2010). Test No. 429: Skin Sensitisation: Local Lymph Node Assay. Paris: Organisation for Economic Co-operation and Development.
  14. ^ Graham, Jessica C.; Trejo-Martin, Alejandra; Chilton, Martyn L.; Kostal, Jakub; Bercu, Joel; Beutner, Gregory L.; Bruen, Uma S.; Dolan, David G.; Gomez, Stephen; Hillegass, Jedd; Nicolette, John; Schmitz, Matthew (20 June 2022). "An Evaluation of the Occupational Health Hazards of Peptide Couplers". Chemical Research in Toxicology. 35 (6): 1011–1022. doi:10.1021/acs.chemrestox.2c00031. ISSN 0893-228X. PMC 9214767. PMID 35532537.
  15. ^ 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.
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