A R T I C L E S
Kami n´ ski et al.
Scheme 1. Postulated Mechanism of Coupling with TBCRs
final product) below the energy of the transition state formation
EA (Figure 2, right) required leaving groups capable of an
was undertaken demonstrating the efficacy of triazines not only
in model studies but also in a very broad range of typical
synthetic applications. These studies confirmed the predomi-
nance of the triazine-based “superactive esters” over the series
of the well-known coupling reagents, considered up to now as
the most efficient agents for ester and amide bond formation,
in manual and automatic peptide synthesis, in solution and solid
phase.
A
additional energetically favored process associated with their
departure. It has been postulated that the energetically favored
process of prototropic rearrangement of the enol 4 to the
9
significantly more stable keto form 5 provides sufficient driving
force to change the energetic profile of the coupling reaction
involving TBCRs (Scheme 1).
In fact, triazine esters 1 have already been found more reactive
than any other acylating reagent, including N-hydroxybenzo-
Results and Discussion
Development of New Improved TBCRs. A preliminary
investigation of efficacy of the old generation (chloride salts)
of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
1
7
triazole esters. Moreover, many authors used successfully
18
triazine reagents for the synthesis of peptides, carboxylic acid
1
9
20
21
22
esters, amides, pholic acid antagonists, â-lactames, carote-
3
0
(
DMTMM) chloride evidenced the formation of methyl
2
3
24
25,26
noids, fullerenes, and others compounds.
31
chloride in the demethylation side reaction, which dramatically
distorted stoichiometry, decreased the yield, and caused con-
tamination of the final products. The degradation process was
particularly favored in anhydrous aprotic solvents and during
Sporadic failures in some synthetic applications raised severe
doubts concerning the correctness of the entire concept of
“
superactive esters”. Moreover, in the literature there are some
ambiguities concerning the energetic effects of keto-enol
31
the storage of the salt. The demethylation product of DMTMM
was isolated and unequivocally identified as 4-(4,6-dimethoxy-
isomeric,27 synchronization of both processes, as well as other
28
29
aspects of an acyl transfer mechanism. Therefore, eradication
of all these doubts was essential, and the “proof of concept”
1,3,5-triazin-2-yl)morpholine (6) by X-ray diffraction. The study
showed very strong conjugation of the morpholine nitrogen with
the triazine ring, tested by the shortening of C(2)-N(morpho-
line) bond to 1.350(2) Å, being equal to the two endocyclic
C-N bond lengths of 1.353(2) Å and 1.347(2) Å (Figure 3),
thus making a regular guanidine fragment.
Due to the conjugation, the triazine ring was found coplanar
with the C-N-C fragment of the morpholine ring. The
crystallographic data were fully consistent with the crystal
structure determined by Kaftory et al. and strongly suggested
an attack of a nucleophilic chloride anion on a methyl group
affording compound 6 with elimination of methyl chloride.
To prevent this degradation pathway, the nucleophilic chloride
anion was changed with the less nucleophilic and larger
tetrafluoroborate anion. The modular structure of the TBCRs
(
17) Gł o´ wka, M. L.; Iwanicka, I.; Kami n´ ski, Z. J. Acta Crystallogr. 1990, C46,
2
211-2216.
(18) a) Kami n´ ski, Z. J. Synthesis 1987, 917-920. (b) Garrett, C. E.; Jiang, X.;
Prasad, K.; Repic, O. Tetrahedron Lett. 2002, 43, 4161-4165.
(
(
19) Kami n´ ska, J. E.; Kami n´ ski, Z. J.; G o´ ra, J. Synthesis 1999, 593-596.
20) (a) Rayle, H. L.; Fellmeth, L. Org. Process Res. DeV. 1999, 3, 172-176.
(
b) Bandgar, B. P.; Pandit, S. S. Tetrahedron Lett. 2003, 44, 3855-3858.
(
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21) (a) Barnett, C.; Wilson, T. M.; Wendel, S. R.; Winningham, M. J.; Deeter,
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(
(
22) Lee, H. W.; Kang, T. W.; Cha, K. H.; Kim, E. N.; Choi, N. H. Synth.
(Figure 4) permitted the necessary modifications of the structure
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and a new generation of triazine coupling reagents as tetrafluo-
roborates 9a-d (Scheme 2) has been prepared directly from
the easily accessible precursor 2-chloro-4,6-dimethoxy-1,3,5-
triazine (CDMT).
The synthetic procedure leading to the tetrafluoroborate salts
of TBCRs 9a-d involved in situ formation of N-triazinylam-
monium chlorides by treatment of the triazine 7 with appropriate
tertiary amines 8a-d, followed by replacement of the chloride
anion with the tetrafluoroborate anion by treatment with silver
or lithium tetrafluoroborate (Table 1). Two monocyclic 8a,b
and two bicyclic tertiary amines 8c,d were used for the syntheses
of TBCRs 9a-d.
24) (a) Bahr, J. L.; Kuciauskas, D.; Liddell, P. A.; Moore, A. L.; Moore, T.
A.; Gust, D. Photochem. Photobiol. 2000, 72, 598-611. (b) Kodis, G.;
Liddell, P. A.; Garza, L.; Moore, A. L.; Moore, T. A.; Gust, D. J. Mater.
Chem. 2002, 12, 2100-2108. (c) Liddell, P. A.; Kodis, G.; De la Garza,
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