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Cyanuric Chloride:
A Useful Reagent for Converting Carboxylic Acids into Chlorides, Esters, Amides and Peptides1

K. Venkatamaran & D. R. Wagle
Tet. Lett., No. 32, 3037-3040 (1979)

Recent examples of the sustained interest in reagents for the conversion of carboxylic acids to chlorides, esters, amides and peptides are;

  1. 2,4,6-Trinitrofluorobenzene for the preparation of amides and esters2
  2. Isocyahides for peptide synthesis3
  3. Oxalyl chloride and catalytic DMF for the conversion of carboxylic acids to chlorides via the TBDMS esters4
  4. Esterification of carboxylic acids in the presence of DCC and a catalytic 4-dialkylaminopyridine5

Another useful regent for these purposes is cyanuric chloride (CC), readily available as an intermediate for the (manufacture of reactive dyes, fluorescent brightening agents and agricultural pesticides.

Senier recorded in 1886 the preparation of acetyl and benzoyl chlorides by heating the sodium salts with cyanuric chloride at 100C for 8 hours6. Refluxing CC with a large excess of glacial acetic acid has been suggested as a method for the preparation of cyanuric acid, acetyl chloride being simultaneously formed. In the method now described the reaction is carried out at room temperature and CC separates as an insoluble product; the solution containing the acid chloride and any unconverted acid can be used directly for further reactions.

When CC in acetone is treated with 1 or 2 mol of carboxylic acid and 1-2 mols of triethylamine (TEA), the acid chloride is rapidly formed, presumably via the σ-adduct (I) resulting from a nucleophilic attack of RCOO- on CC. CC is converted into insoluble dichlorohydroxy- or chlorodihydroxy-s-triazine8, which have also been characterized as the corresponding dianilino or monoanilino derivatives9.

Experimental

General procedure

Add TEA (0.02mol) to a solution of the carboxylic acid (0.02mol or 0.01 mol of a dicarboxylic acid, etc.) and CC (0.01 mol) in acetone (20ml or minimum volume required for clear solution) at 20-30C. After stirring for 3hrs when no CC remains in solution, acetone is remove under reduced pressure and the acid chloride taken up in carbon tetrachloride. Alternatively, when the desired product is an ester or amide, the alcohol, phenol or amine (0.02mol) is added to the reaction mixture, which is then stirred for 2hrs. The triazine derivative is filtered off and the acetone solution worked up as usual.

Acids converted to chlorides, amides or esters
Acid RNH2/ArOH/ROH Product10
Yield
AceticAnilineAnilide
84%
p-Aminophenol p-Hydroxyacetanilide
55%
p-acetoxyacetanilide
35%
TrifluoroaceticAniline Anilide11
64%
L-Valine N-Trifluoroacetyl-
L-valine12
50%
OxalicAnilineAnilide
52%
Malonic - / Aniline Chloride or Anilide
 0%
SuccinicAnilineAnilide
55%
Z-glycine2,4,5-Trichloro-
phenol
Trichlorophenyl
ester13
41%
Z-glycineGly-OEt Z-Gly-Gly-OEt14
40%
Z-L-valineGly-OEt Z-L-Val -Gly-OEt15
45%
Boc-L-valineGly-OEt Boc-L-Val-Gly-OEt16
38%
PhenylaceticAnilineAnilide
86%
Benzoic -Chloride
81%
AnilineAnilide
87%
o-Phenylene-
diamine
N,N-Dibenzoyl-
o-phenylenediamine
68%
o-AminophenolN,O-Dibenzoyl-
o-aminophenol
73%
MethanolMethyl benzoate
82%
p-Nitrobenzoic -Chloride
58%
CinnamicAnilineAnilide
93%
AspirinMethanolMethyl ester
45%
3-Hydroxy-2-naphthoicAniline Anilide17
61%

Three dipeptides were prepared from (1) Z-glycine, (2) Z-L-valine and (3) boc-L-valine. After treatment with CC and TEA, glycine ethyl ester hydrochloride is added as a suspension in acetone (10 ml) and TEA (0.04 mol). The reaction mixture is added to ice-water and extracted with chloroform. The dipeptide, recovered from the chloroform solution after the removal of unconverted acid and amine, is then crystallized14-16. The three peptides and Z-glycine trichlorophenyl ester were characterized by their NMR and mass spectra in addition to their melting points.

The yields recorded in the Table are of the isolated products after purification by acid and base washing, when they were chromatographically homogenous and had mp's about 5C lower than the literature values, but before the crystallization; the recovery uncovered acid was not taken into account. A simple routine procedure using the regenerated TEA was followed for the preparation of esters and amides, and no attempt was made to optimize conditions for maximum yields.


References and Footnotes

  1. NCL Communication No. 2441.
  2. K. Inomata et al., Bull. Chem. Soc. Japan, 51, 1866 (1978).
  3. H. Aigner and D. Marquarding, Tetrahedron Lett., 3325 (1978).
  4. A. Wissner and C.V. Grudzinskas, J. Org. Chem., 43, 3972 (1978).
  5. A. Hassner and V. Alexanian, Tetrahedron Lett., 4475 (1378).
  6. A. Senier, Ber. 13, 311 (1886)
  7. E. Smolin and L. Rapoport, s-Triazines and Derivatives, Interscience, New York, 1959, pp. 24, 59.
  8. S. Horrobin, J. Chem. Soc. 413O (1963).
  9. N. V. Kozlova et al., J. Gen. Chem. USSR, Eng. Trans., 33, 3232 (1963).
  10. Dict. Org. Compounds, 4th ed., 1965.
  11. E. J. Bourne et al., J. Chem. Soc. 4014 (1952), prepared this compound by treatment of aniline with trifluoroacetic anhydride.
  12. C. A. Panetta, Org. Synth. 56, 122 (1977), has described the "trifluoroacetylation of amines and amino acids under neutral, mild conditions: N-trifluoroacetanilide and N-trifluoroacetyl-L-tyrosine" by the action of 1,1,1-trichloro-3,3,3-trifluoroacetone in DMSO at 25-35C. Panetta has also discussed the disadvantages of the nsnal procedure using trifluoroacetic anhydride. ln the present work a minor modification in our general procedure was to add L-valine in DMSO (10 mL); the product was worked up as described by Panetta.
  13. J. Pless and R. A. Boissonnas, Helv. Chim. Acta, 46, 1609 (1963). 2,4,5-Trichlorophenyl esters of N-protected amino acids, valuable as active esters in peptide synthesis, have been prepared by condensing the acid with (a) the phenol in presence of DCC or (b) the triphenylphosphite.
  14. S. P. Greenstein and M. Winitz, Chemistry of the Amino Acids, Vol. 2, p. 1128, Wiley, 1961.
  15. S. P. Greenstein and M. Winitz, Chemistry of the Amino Acids, Vol. 2, p. 1138, Wiley, 1961.
  16. E. Schnabel, Ann. 688, 238 (1965)
  17. Separation through carbon tetrachloride before adding aniline showed that the reaction mixture contained the acid, chloride and depside, cf. E. N. Abrahart, J. Chem. Soc. 424 (1938) R. V. Bhat, R. B. Forster and K. Venkataraman, J. Soc. Dyers Col., 56, 166 (1940). The anilide, which is sparingly soluble in acetone, was taken up in 2 N sodium hydroxide.