Solid-supported chloro[1,3,5]triazine. A versatile new synthetic auxiliary for the synthesis of amide libraries

Article abstract of DOI:10.1021/ol990215h

(equation presented) 2,4,6-Trichloro[1,3,5]triazine was loaded on different types of NH₂-functionalized resins to give a new supported reagent. The best results, in term of yields products, were obtained using the chlorotriazine linked to a polystyrene-poly(ethylene glycol) resin. This reagent was employed for the solution-phase synthesis of different amides and dipeptides.

Full text of DOI:10.1021/ol990215h

ORGANIC
LETTERS
1999
Vol. 1, No. 9
1355-1357
Solid-Supported Chloro[1,3,5]triazine. A
Versatile New Synthetic Auxiliary for the
Synthesis of Amide Libraries
Simonetta Masala and Maurizio Taddei*
Dipartimento di Chimica, UniVersita` degli Studi di Sassari, Via Vienna 2,
07100 Sassari, Italy
mtad@ssmain.uniss.it
Received August 5, 1999
ABSTRACT
2,4,6-Trichloro[1,3,5]triazine was loaded on different types of NH functionalized resins to give a new supported reagent. The best results, in
2-
term of yields products, were obtained using the chlorotriazine linked to a polystyrene−poly(ethylene glycol) resin. This reagent was employed
for the solution-phase synthesis of different amides and dipeptides.
Polymer-supported reagents and auxiliaries have found
increasing applications for the preparation of small organic
molecules during the past few years.1 Recent advances in
the development of new solid-supported reagents2 have
opened new routes to library synthesis in the solution phase
with the aim of implementing the protocol with robotic
systems.
diimides4 have been prepared and used for the formation of
amides, lactames, and related reactions.5
Although very effective, these reagents must be synthe-
sized on the resin in a multistep procedure.3,6 In the few cases
of commercially available immobilized reagents, the resins
are expensive and rather sensitive to prolonged storage.7
Following our interest in the chemistry of triazine deriva-
tives,8 we speculated on the possibility of using a resin-bound
triazine to activate a carboxylic acid for a nucleophilic
substitution at the carbonyl to give an amide or a derivative.
2,4,6-Trichloro[1,3,5]triazine and 2-chloro-4,6-dimethoxy-
[1,3,5]triazine are know to be versatile and selective coupling
reagents for amide synthesis.9 The chlorotriazine is generally
activated with N-methylmorpholine (NMM) to give a mor-
Among several polymeric reagents described, supported
N-hydroxybenzotriazole3 and differently substituted carbo-
(1) Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis 1997, 1217.
(2) Paio, A.; Zaramella, A.; Ferritto, R.; Conti, N.; Marchioro, C.; P.
Seneci J. Comb. Chem. 1999, 1, 317. Hu, Y.; Baudart, S.; Porco, J. A., Jr.
J. Org. Chem. 1999, 64, 1049. Chen, C.; Munoz, B. Tetrahedron Lett. 1999,
40, 3491. Minutolo, F.; Katzenellenbogen J. A. Angew. Chem. Int. Ed. Engl.
1999, 38, 1617. Hamuro, Y.; Scialdone, M. A.; DeGrado, W. F. J. Am.
Chem. Soc. 1999, 121, 1636. Ley, S. V.; Bolli, M. H.; Hinzen, B.; Gervois,
A.-G.; Hall, B. J. J. Chem. Soc., Perkin Trans. 1 1998, 2239.
(3) Pop, J. E.; De´prez, B. P.; Tartar, A. L. J. Org. Chem. 1997, 62, 2594.
(4) Desai, M. C.; Stramiello, L. M. S. Tetrahedron Lett. 1993, 37, 7685.
Sturino, C. F.; Labelle, M. Tetrahedron Lett. 1998, 39, 5891.
(6) Kalir, R.; Warshawsky, A. Fridkin, M.; Patchornik, A. Eur. J.
Biochem. 1975, 59, 55.
(7) The polymer-supported bis(6-carboxy-HOBt)-N-(2-aminoethyl)ami-
nomethyl polystyrene and N-cyclohexylcarbodiimide N′-methyl polystyrene
are now available from Novabiochem, catalog no. 01-64-0179 and 01-64-
0211.
(5) Huang, W.; Kalivretenos, A. G. Tetrahedron Lett. 1995, 36, 9113.
Dendrinos, K.; Jeong, J.; Huang, W.; Kalivretenos, A. G. J. Chem. Soc.,
Chem. Commun. 1998, 499.
(8) Falorni, M.; Porcheddu, A.; Taddei, M. Tetrahedron Lett. 1999, 40,
4395.
10.1021/ol990215h CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/30/1999

pholinium salt that reacts with a carboxylic acid to generate
the activated ester. This ester is relatively stable to oxygen
nucleophiles but reacts easily with amines to give high yields
of the corresponding amides.10
Thus we attempted to anchor 2,4,6-trichloro[1,3,5]triazine
1 onto a polystyrene resin using commercially available
substrates. A Wang type resin loaded with Fmoc-Gly (1.0
mmol/g resin) was used as starting material. After depro-
tection of the Fmoc under standard conditions, the NH2 on
the resin was treated with a THF solution of 1 (5 equiv) in
the presence of DIPEA (Scheme 1). The reaction occurred
reaction was monitored by TLC or GC. At the end (3 h was
generally a long enough reaction time for a high conversion)
the product was recovered by filtration on the sintered glass
plate, followed by elimination of the excess of amine by
acidic workup14 and evaporation of the solvent.
Following this protocol, the synthesis of a variety of
amides was accomplished as reported in Table 1.
Table 1
Scheme 1a
a
(a) (1), DIPEA, THF; (b) NMM, THF; (c) RCOOH, THF.
within 10 min as showed by a negative ninhydrine test.11
After washing several times with THF, the resin was dried
and could be stored at 4 °C for several days. Alternatively
the resin was mixed with THF and the loaded chlorotriazine
activated with a THF solution of NMM (1.5 equiv with
respect to the theoretical loading). After few minutes, a
solution of the carboxylic acid (2 equiv with respect to the
loading) in THF was added and the mixture stirred for 3 h
under a nitrogen stream in a vial equipped with a sintered
glass plate. The excess of the acid and the salts eventually
formed were washed away with THF and DMF. The resin
loaded with the activated carboxylate can be dried and stored
for further applications as, for example, splitting into different
vials for a parallel synthesis.12
a Yields of isolated and fully characterized products. The 1H NMR
analysis of the crude compounds showed the presence 5-10% of byproducts.
The resin, loaded with the appropriate carboxylic acid, was
treated with a THF solution of the amine (1.2 equiv) in the
presence of 1 equiv of NMM.13 The conversion of the
We chose a series of representative aliphatic and aromatic
carboxylic acids with different properties and a series of
simple primary and secondary amines. We observed that the
reaction always gave good yields of the desired products even
when using a lipophilic acid as 4. Isonicotinic acid 6 was
analogously transformed into the amide with an extremely
simple procedure in comparison to the methods generally
employed with this kind of acid. Acceptable results were
(9) Venkataram, K.; Wagle, D. R. Tetrahedron Lett. 1979, 32, 3037.
Kaminski, Z. J. Synthesis 1987, 917. Hipskind, P. A.; Howbert, J.; Cho, S.;
Cronin, J. S.; Fort, S. L.; Ginah, F. O.; Hansen, G. J.; Huff, B. E.; Lobb,
K. L.; Martinelli, M. J.; Murray, A. R.; Nixon, J. A.; Staszak, M.; Copp, J.
D. J. Org. Chem. 1995, 60, 7033. Taylor, E. C.; Dowling, J. E.; J. Org.
Chem. 1997, 62, 1599. Nayar, N. K.; Hutchinson, D. R.; Martinelli, M. J.
J. Org. Chem. 1997, 62, 982.
(10) Kaminski, Z. J.; Paneth, P.; Rudzinski, J. J. Org. Chem. 1998, 63,
4248.
(11) The correct loading of 1 on the resin (one triazine ring for one amino
group) was confirmed by the contents of Cl and N determined by
microanalysis.
(12) The selective substitution of one single chlorine with the carboxylate
was verified by FT-IR analysis of the beads and by micronalysis.
(13) The presence of NMM in the reaction is necessary. Attempts to
use less than 1 equiv of the desired amine and to obtain a solution of the
pure product at the end of the reaction were unsuccessfull (in our hands).
(14) The classical two-phase extraction with an acidic aqueous solution
can be substituted by a passage of the THF solution, coming from the vial,
through a small column filled with an acidic ion-exchange resin. After this
treatment the amide could be recovered by evaporation of the solvent with
an acceptable level of purity. See: Gayo, L. M.; Suto, M. J. Tetrahedron
Lett. 1997, 38, 513.
1356
Org. Lett., Vol. 1, No. 9, 1999

obtained with amino acid 7. Among the amine used, it is
noteworthy to see that tryptamine 12 or unprotected ethanol
amine 11 afforded the corresponding amides in good yields.
The triazine loaded on the Wang-Gly resin displayed good
reactivity in THF or CH2Cl2, solvents that are easy to remove
after the reaction and allow for easy isolation of the products.
Nevertheless, when the amine was insoluble in these solvent
(as 12), 1-methyl-2-pyrolidinone (NMP) was successfully
employed.
Table 3
When we tried to use the triazine loaded on the Wang
resin for the preparation of a dipeptide, (Boc-Val-OH and
H-Phe-OMe), we observed low yields (50%) and the
presence of impurities.
With the aim of improving the yields of the amide, we
explored different possibilities and discovered that the nature
of the polymer employed influenced the results. In Table 2
a Yields of isolated and fully characterized products. The purity of the
products was always about 95% (1H NMR 300 MHz).
a terminal NH2 resin that can be successfully used to prepare
libraries of amides (or peptides) in solution employing
volatile solvents. The loading is possible on several kinds
of commercially available resins and can be done just before
use. This feature if particularly important as the applications
of the reagent can be expanded to different resins with
swelling properties more appropriate to the solvent required
in the reaction. Moreover the reagent employed (1) has no
cost when compared with the resin price and can be used
without any additional auxiliary (DCC or PyBOP are required
in the case of supported HOBt).3 The supported reagent is
stable for days in dry form, and the corresponding activated
ester can be stored in an anhydrous atmosphere for at least
1 week without any appreciable modification of the reactiv-
ity. Finally, although we did not try, the resin could be
recycled at the end of the reaction.15
Table 2
a HPLC analysis of the peptide showed less than 5% of racemization.
b The low yield is due to an uncomplete loading of the triazine on the resin.
We are currently using this reagent for the derivatization
of biologically active amines, as a scavenger for primary
amines, and for the preparation of a small molecule amide
library.
are reported the yields of the reaction of formation of the
dipeptide Boc-Val-PheOMe using the chlorotriazine loaded
on different resins.
The cross-linked polystyrene-poly(ethylene glycol) sys-
tem is more flexible and can accommodate the reagent far
away from the beads, improving the reactivity of the
activated ester that is probably hindered by the groups that
remain close to the carbonyl on the surface of the resin.
The results of some selected couplings carried out with
the triazine loaded on the polystyrene-PEG-CH2-NH2 resin
are reported in Table 3.
Acknowledgment. Support has been provided by the
MURST (Rome) within the Progetti di Ricerca di Rilevante
Interesse NazionalesChimica dei Composti di Interesse
Biologico-Es Fin. 1997.
OL990215H
(15) Chlorotriazines containing one NH group are reported to be
hydrolyzed in acidic aqueous medium. Thurston, J. T.; Dudley, J. R.; Kaiser,
D. W.; Hechenbleikner, I.; Schaefer, F. C.; Holm-Hansen, D. J. Am. Chem.
Soc. 1951, 73, 2981.
In conclusion we have described an effective method for
the preparation of a supported coupling reagent starting from
Org. Lett., Vol. 1, No. 9, 1999
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