(peptide coupling reagent; used to prepare active esters which can be used for the preparation of amides and esters;1 used in the reduction of carboxylic acids to aldehydes or alcohols2)
Alternate Name: CDMT, 2-chloro-4,6-dimethoxy-1,3,5-triazine.
Physical Data: mp 71-74°C; bp 125-128°C/66.661 Pa.
Solubility: soluble in most organic solvents.
Form Supplied in: white solid; commercially available.
Preparative Methods: commercially available; prepared from cyanuric chloride and MeOH.3 An improved procedure for a large-scale preparation has been reported.4
Purification: commercial reagent is generally used as received.
Handling, Storage, and Precautions: irritant; sternutator. Avoid inhalation. Should be handled with gloves in a fume hood. Relatively stable but should be stored under anhydrous conditions.
6-Chloro-2,4-dimethoxy-s-triazine (CDMT) is utilized primarily as a coupling reagent in the condensation of amines and carboxylic acids for the preparation of peptides and other amides. Treatment of CDMT with a tertiary amine, preferably N-methylmorpholine (NMM), and a carboxylic acid yields an intermediate 6-acyloxy-2,4-dimethoxy-s-triazine (1) which serves as the acylating agent.1,5 A typical example is shown in eq 1. The procedure involves adding N-methylmorpholine (1.02 equiv) to a solution of the corresponding carboxylic acid (1.02 equiv) and CDMT (1.0 equiv) at -5°C to 0°C in CH2Cl2, CH3CN, THF, or DMF. The mixture is stirred for 1-4 h until formation of 1 is complete. The corresponding amine (1.0 equiv) and NMM (1.0 equiv) are then added, the mixture is allowed to warm to room temperature and stirred until the reaction is complete. Yields typically range from 75-98%. One major advantage offered by CDMT over other peptide coupling reagents, such as the carbodiimide reagents (see 1,3-dicyclohexylcarbodiimide),6 is the ease of purification. Since the triazine ring is weakly basic, a dilute acid wash will remove any by-products as well as any excess reagent from the reaction mixture. Furthermore, protected functional groups, as well as the unprotected hydroxyl group in serine, do not interfere with the coupling reactions, and racemization is not commonly observed. It is also worth noting that CDMT is inexpensive and has been used on kilogram scale.7
Studies directed toward a better understanding of the mechanism of activation of carboxylic acids by CDMT revealed that the reaction proceeds through quarternary triazinylammonium salts such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM) (2)8,9 prior to formation of acyloxytriazines shown in eq 1. In fact, DMTMM, synthesized quantitatively by treatment of CDMT with NMM in THF (eq 2), is a white solid and is stable for a month at ambient temperature. It can be used directly in condensation reactions of amines and carboxylic acids,10,11 thus providing a useful, “one-step” variant of CDMT. The example in eq 2 illustrates the complexity of amines and carboxylic acids that can be coupled using DMTMM or CDMT.11,12 It should be noted that the stability of DMTMM varies in different solvents. For instance, DMTMM completely demethylates in CH2Cl2 in 3 h. Therefore, lower yields of amides are observed when CH2Cl2 is used as solvent for the condensation reactions. DMTMM is, however, very stable in THF and alcoholic solvents. Amides can be obtained from the condensation of carboxylic acids and amines with DMTMM in THF with yields similar to those observed in the CDMT-NMM system. A typical procedure involves adding DMTMM (1.1 equiv) to a mixture of the corresponding acid (1.0 equiv) and amine (1.1 equiv) in THF and stirring at room temperature for 3-24 h. Furthermore, it is not necessary to dry the THF or perform the reaction under a N2 atmosphere.
Alcohols react much more slowly than amines with the 6-acyloxy-2,4-dimethoxy-s-triazine intermediates similar to 1. Using typical CDMT-NMM conditions, ethyl benzoate was prepared by condensation of benzoic acid and ethanol in 65% yield, but the reaction time was 10 days.1 It was later determined that ester formation proceeds much faster and in higher yields when the intermediate acyloxytriazine is isolated.13 It was also determined that the rate of esterification can be increased by catalysis with 5 mol% MgBr2 (eq 3). A typical procedure involves preparing the acyloxytriazine with CDMT, NMM and the corresponding carboxylic acid as described in the previous section. After work-up, the corresponding alcohol (10 equiv) and MgBr2 (0.05 equiv) are then added to the crude, intermediate acyloxytriazine (1.0 equiv), and the mixture is stirred until the reaction is complete. Primary, secondary, and tertiary alcohols can be acylated under these conditions with yields between 44-92%. The reaction conditions are mild, but reaction times are somewhat long (typically 2-4 days), and the alcohol must be used in excess.
Carboxylic acids can also be esterified using DMTMM and the corresponding alcohols.10,11 A typical procedure involves adding NMM (0.1-1.2 equiv) to a mixture of the carboxylic acid (1.0 equiv) and DMTMM (1.1-2.0 equiv) in the corresponding alcohol (solvent). Reaction times range from 4-21 h. The yields are quite good, but in most cases, the alcohol must be used in large excess.
Reduction of Carboxylic Acids
Active esters prepared from CDMT (e.g. 6-acyloxy-2,4-dimethoxy-s-triazines) can be reduced directly to aldehydes by treatment of hydrogen (1 atm) at room temperature in the presence of 10 mol% Pd/C (eq 4).2 A typical procedure involves adding a carboxylic acid (1.0 equiv) to a mixture of DMTMM, prepared from CDMT (1.0 equiv) and NMM (1.02 equiv), in DME. The active ester is filtered, added to a mixture of Pd/C (10 mol%) in ethanol and stirred under a hydrogen atmosphere until the reaction is complete. Yields range from 75-84% when aliphatic carboxylic acids are used, but yields of aldehydes drop dramatically with aromatic carboxylic acids as substrates. The main product in these cases is the corresponding alcohol. Even with aliphatic carboxylic acids, the reactions have to be monitored carefully to avoid further reduction to the corresponding alcohols. In fact, if the hydrogen pressure is increased to 3-5 atm, alcohols can obtained in high yields.
CDMT can be used as a source of 2,4-dimethoxy-s-triazine for the preparation of 6-substituted-2,4-dimethoxy-s-triazine derivatives. In these cases, substitution or coupling reactions occur at the carbon bearing the chlorine. Some examples include modified Sonogashira Pd-mediated couplings to form 6-alkynyl-2,4-dimethoxy-s-triazine derivatives,14 glycosolations of thioglycosides,15 nickel(0)-catalyzed cross-coupling reactions with arylboronic acids16 and addition of amines to form 6-amino-2,4-dimethoxy-s-triazine derivatives.17
benzotriazol-1-yloxytris(dimethylamino)phosphinium hexafluoro-phosphate (BOP),
O-benzotriazol-1-yl-N,N,N´,N´-tetramethyluronium hexafluoro-phosphate (HBTU),
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP),
1,3-dicyclohexylcarbodiimide (DCC), and
1-ethyl-3-(3´-dimethylaminopropyl)carbodiimide hydrochloride (EDCI).
- 1. Kaminski, Z. J., Tetrahedron Lett. 1985, 26, 2901.
- 2. Falorni, M.; Giacomelli, G.; Porcheddu, A.; Taddei, M., J. Org. Chem. 1999, 64, 8962.
- 3. Dudley, J. R.; Thurston, J. T.; Schaefer, F. C.; Holm-Hansen, D.; Hull, C. J.; Adams, P., J. Am. Chem. Soc. 1951, 73, 2986.
- 4. Cronin, J. S.; Ginah, F. O.; Murray, A. R.; Copp, J. D., Synth. Commun. 1996, 26, 3491.
- 5. Kaminski, Z. J., Synthesis 1987, 917.
- 6. Sheehan, J. C.; Hess, G. P., J. Am. Chem. Soc. 1955, 77, 1067.
- 7. Barnett, C. J.; Wilson, T. M.; Kobierski, M. E., Org. Process Res. Dev. 1999, 3, 184.
- 8. Kaminski, Z. J., J. Prakt. Chem. 1990, 332, 579.
- 9. Kaminski, Z. J.; Paneth, P.; Rudzinski, J., J. Org. Chem. 1998, 63, 4248.
- 10. Kunishima, M.; Kawachi, C.; Iwasaki, F.; Terao, K.; Tani, S., Tetrahedron Lett. 1999, 40, 5327.
- 11. Kunishima, M.; Kawachi, C.; Morita, J.; Terao, K.; Iwasaki, F.; Tani, S., Tetrahedron 1999, 55, 13159.
- 12. Lee, H.-W.; Kang, T. W.; Cha, K. H.; Kim, E.-N.; Choi, N.-H.; Kim, J.-W.; Hong, C. I., Synth. Commun. 1998, 28, 1339.
- 13. Kaminska, J. E.; Kaminski, Z. J.; Gora, J., Synthesis 1999, 593.
- 14. Menicagli, R.; Samaritani, S.; Gori, S., Tetrahedron Lett. 1999, 40, 8419.
- 15. Sugimura, H.; Motegi, M.; Sujino, K., Nucleosides Nucleotides 1995, 14, 413.
- 16. Saito, S.; Oh-tani, S.; Miyaura, N., J. Org. Chem. 1997, 62, 8024.
- 17. Tucker, JA.; Allwine, DA.; Grega, KC.; Barbachyn, MR.; Klock, JL.; Adamski, JL.; Brickner, SJ.; Hutchinson, DK.; Ford, CW.; Zurenko, GE.; Conradi, RA.; Burton, PS.; Jensen, RM., J. Med. Chem. 1998, 41, 3727.
Dr D. Scott Coffey
Eli Lilly and Company, Indianapolis, IN, USA
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