Thiol-ene reactions of 1,3,5-triacryloylhexahydro-1,3,5-triazine (TAT): facile access to functional tripodal thioethers

Article abstract of DOI:10.1016/j.tetlet.2008.11.094

Efficient syntheses of tripodal thioethers have been achieved by ionic thiol-ene reactions of 1,3,5-triacryloylhexahydro-1,3,5-triazine (TAT) with a variety of commercially available thiols. The reactions are complete within minutes and give the products

Full text of DOI:10.1016/j.tetlet.2008.11.094

Tetrahedron Letters 50 (2009) 745–747
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Thiol-ene reactions of 1,3,5-triacryloylhexahydro-1,3,5-triazine (TAT): facile
access to functional tripodal thioethers
*
Chinwon Rim, Lauren J. Lahey, Vijita G. Patel, Hongming Zhang, David Y. Son
Department of Chemistry, Southern Methodist University, Dallas, TX 75275-0314, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient syntheses of tripodal thioethers have been achieved by ionic thiol-ene reactions of 1,3,5-triacry-
loylhexahydro-1,3,5-triazine (TAT) with a variety of commercially available thiols. The reactions are com-
plete within minutes and give the products in high yields (63ꢀ96%) and high purity without a complex
workup. The thiol-ene reactions tolerate a wide range of functionality, including hydroxy, amino, carbox-
ylate, and trimethoxylsilyl groups. The amino acid cysteine is also an excellent substrate for this reaction.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 11 November 2008
Revised 19 November 2008
Accepted 21 November 2008
Available online 28 November 2008
1. Introduction
The basic reaction scheme and the compounds synthesized are
shown in Scheme 1. Reaction conditions and product yields are re-
The thiol-ene reaction is an excellent synthetic tool for the cre-
ation of sulfur–carbon bonds.1 Due to the high yields of products,
lack of byproducts, and tolerance of air and water, the thiol-ene
reaction is rapidly gaining acceptance as a ‘click’ reaction.2–6
Although the thiol-ene reaction has been known for many years,7,8
it is only recently that more research groups have exploited its ver-
satility. The groups of Hoyle3,9–12 and Bowman,13–18 for example,
have extensively utilized the thiol-ene reaction in polymer and
materials chemistry.
ported in Table 1. As described below, the reaction conditions var-
ied somewhat depending on the starting thiol. However, some
features were common to all of the reactions. In all cases, it was
not necessary to use more than an exact stoichiometric equivalent
of the thiol for the reaction to reach completion. The progress of
the reactions could be noted by observing the TAT in the reaction
mixture. TAT was relatively insoluble in the solvent systems we
utilized, but disappearance of the TAT would occur within several
The thiol-ene reaction proceeds by either a free-radical or ionic
mechanism. Free-radical reactions typically involve AIBN or UV
irradiation to generate the thiyl radicals necessary for the reaction
to occur.1 Ionic thiol-ene reactions generally occur in the presence
of a base such as an amine, and are limited to compounds possess-
O
O
O
O
R
R
S
N
N
O
S
N
N
O
R
SH
3.0
N
N
10-25 min
ing electron-deficient unsaturation, for example,
a,b-unsaturated
carbonyl compounds.10,15,17,19–25 Thus, the ionic thiol-ene reaction
can essentially be viewed as a Michael-type addition reaction.
On the basis of our interest in organosilicon dendrimers,26,27 we
recently reported the synthesis of various functionalized organosil-
icon thioethers via free-radical thiol-ene reactions of tetravinylsi-
lane.28 As part of another line of investigation concerning
multidentate N- and S-containing ligands,29–34 we identified
1,3,5-triacryloylhexahydro-1,3,5-triazine (TAT) as a potentially
useful starting material for the synthesis of tripodal thioether com-
pounds, which are of value as chelating ligands35–47 and in nano-
particle assembly.48–52 TAT is an inexpensive, stable, and
symmetrical compound that possesses three electron-deficient
olefin groups. Herein, we describe the facile synthesis of a series
of functionalized tripodal thioethers from ionic thiol-ene reactions
of TAT.
S
R
"TAT"
1, R = -CH2CH2OH
2, R = -CH2CH(OH)CH2(OH)
3, R = -CH2CO2CH3
4, R = -CH2CH2CH2Si(OCH3)3
5, R = -CH2CH2NH2
H2N
6, R =
7, R = -CH2CH2CO2H
HO2C
8, R =
9, R = -CH2CH(NH2)CO2H
* Corresponding author. Tel.: +1 214 768 8813; fax: +1 214 768 4089.
E-mail address: dson@smu.edu (D.Y. Son).
Scheme 1. Thiol-ene synthesis of 1ꢀ9.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.094

746
C. Rim et al. / Tetrahedron Letters 50 (2009) 745–747
Table 1
Product yields and reaction conditions (all reactions conducted at room temperature)
Product
Reaction conditions
Yield (%)
1
2
3
4
5
6
7
8
9
MeOH, cat. n-PrNH2
MeOH, cat. n-PrNH2
MeOH/CHCl3, cat. n-PrNH2
MeOH, cat. n-PrNH2
MeOH
MeOH/CHCl3
MeOH, KHCO3
MeOH, KHCO3
MeOH/H2O
92
96
94
93
95
82
63
90
88
minutes of the start of the reactions. Most reactions were complete
within 10 min. After the reactions were complete, the solutions
were gravity filtered and all volatiles were removed under reduced
pressure to give the products in high yields, typically not requiring
further purification. All products were characterized by 1D and 2D
NMR spectroscopy, and elemental analysis.
For the synthesis of compounds 1ꢀ4, the appropriate thiol was
added to a stirred suspension of TAT (1.0 g) in 10 mL of methanol.
A single drop of n-propylamine (10 mg) was then added and the
reaction was worked up as described above to give 1ꢀ4 in high
yields and excellent purity. Alcohol derivatives 1 and 2 were ob-
tained as a crystalline and hard, transparent solid, respectively.
Both compounds are somewhat hygroscopic and are best stored
in a dessicator. For the synthesis of 3, a second liquid layer formed
during the reaction at the bottom of the vessel. 1H NMR experi-
ments indicated that this layer was primarily 3. In order to obtain
higher yields of 3, a small amount of chloroform was added to cre-
ate a uniform solution and then the reaction was worked up in the
normal manner to give 3 as an oil. The synthesis of 4 was straight-
forward and gave the product as a clear, colorless viscous oil. This
oil proved to be unstable; on standing it slowly hardened to a clear
insoluble solid. Since we made no effort to dry the methanol or ex-
clude moisture during the reaction, we speculate that the combi-
nation of trace moisture and residual amine catalyst causes 4 to
undergo a sol–gel crosslinking process.53
Compounds 5 and 6 were synthesized in the same way as 1ꢀ4,
except no amine catalyst was added. The starting thiols, cyste-
amine and o-aminothiophenol, both contain amino groups and
thus ‘self-catalyze’ their own reactions. For the synthesis of 6, chlo-
roform was added to the reaction mixture after 10 min in order to
dissolve the crude product oil that precipitated out of solution.
Compounds 5 and 6 were isolated as yellow solids. It should be
noted that in neither case was addition of the amino groups to
TAT observed.
Figure 1. ORTEP plot of 7 (50% ellipsoids).
nation of intra- and intermolecular hydrogen bonding, the ex-
tended structure consists of a linear chain of dimeric capsules in
which triazine rings constitute the ends of the capsules (see Sup-
plementary data for diagram).
Compound 9 is the product of the thiol-ene reaction of TAT with
the amino acid DL-cysteine, which is known to add to double bonds
through the thiol group.55–58 In our experiments, we found it nec-
essary to use a methanol/water solvent system to aid in the solu-
bility of the cysteine. In this case, the thiol-ene reaction
proceeded without amine catalysis to give 9 as a white solid after
workup.
The attractive features of this general synthetic scheme are
numerous. Firstly, the starting thiols are commercially available
and inexpensive and allow a wide range of functionalization to
be present in the final products. Secondly, there is no need to ex-
clude air or moisture from the reaction mixtures; all reactions
can be carried out in open vessels on the benchtop. Thirdly, the
reaction times are extremely short. Finally, product yields are high
and, as mentioned above, little if any workup is necessary.
In conclusion, we have synthesized a series of highly function-
alized thioethers from thiol-ene reactions of commercially avail-
able thiols with 1,3,5-triacryloylhexahydro-1,3,5-triazine (TAT).
We are currently investigating the application of these compounds
as dendrimer cores and as metal chelating agents.
The standard amine-catalyzed thiol-ene reaction conditions
were ineffective for the syntheses of 7 and 8, presumably because
the added amine was protonated by the carboxyl groups in the thi-
ols. For these thiols, the carboxyl groups were deprotonated by
heating methanol solutions of the thiols in the presence of potas-
sium bicarbonate. TAT was then added to the resulting clear solu-
tions at room temperature. Under these conditions, the thiol-ene
reactions occurred spontaneously without amine catalysis to give
the potassium salts in quantitative yield. The free acids could be
obtained by acidifying aqueous solutions of the salt products.
Although compound 8 precipitated as a white solid on acidification
and was easily isolable, compound 7 separated as an oil. On cool-
ing, the oil crystallized to give pure 7 as a colorless crystalline solid
in 63% yield. We attribute the relatively low yield of 7 to incom-
plete crystallization of the oil from the aqueous medium. Some
of the crystals of 7 were large, colorless blocks which were suitable
for X-ray structural analysis (Fig. 1).54 The triazine ring exists in the
chair conformation with the three ‘arms’ pointing out toward the
same side of the ring to create a bowl-like cavity. Due to a combi-
2. Experimental
2.1. Synthesis of 1,10,100-(1,3,5-triazinane-1,3,5-triyl)tris(3-(2-
hydroxyethylthio)propan-1-one) (1)
The synthesis of 1 is representative of the general synthetic
procedure. Certain products required slightly modified procedures
which are detailed in the Supplementary data. A 100-mL round-bot-
tomed flask was charged with 1,3,5-triacryloylhexahydro-1,3,5-tri-
azine (TAT) (1.0 g, 4.0 mmol), methanol (10 mL), and a magnetic
stirring bar. To this stirred suspension was added 2-mercaptoethanol
(0.94 g, 12 mmol) and a single drop of n-propylamine (10 mg). The
suspension ofTAT disappeared within several minutes, leaving a clear
solution. After a total of 10 min stirring, the solution was filtered
through a fluted filter paper and all volatiles were removed under
reduced pressure to give 1 as a white solid (1.8 g, 92%). Mp
49ꢀ52 °C. 1H NMR (500 MHz, CDCl3): d 2.72 (t, HOCH2CH2–, 6H,
3J = 6.6 Hz), 2.82 (t, –SCH2CH2C(O)–, 6H, 3J = 6.0 Hz), 2.86

C. Rim et al. / Tetrahedron Letters 50 (2009) 745–747
747
(t, –CH2C(O)–, 6H, 3J = 6.0 Hz), 3.73 (t, HOCH2CH2–, 6H, 3J = 6.0 Hz),
5.30 (s, –C(O)NH2N–, 6H). 13C NMR (125 MHz, CDCl3): d 26.7 (–
CH2CH2C(O)–), 33.4 (–CH2C(O)–), 35.5 (HOCH2CH2S–), 56.4 (–
NCH2N–), 61.2 (HOCH2CH2S–), 171 (–C(O)–). Calcd for C18H33O6N3S3:
C, 44.70; H, 6.88; N, 8.69. Found: C, 44.64; H, 6.81; N, 8.43.
25. Clark, T. S.; Hoyle, C. E.; Jönsson, S. Polym. Prepr. 2004, 45, 57–58.
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Acknowledgments
This work was supported by the Robert A. Welch Foundation
(Grant No. N-1375) and Southern Methodist University.
Supplementary data
37. DuPont, J. A.; Coxey, M. B.; Schebler, P. J.; Incarvito, C. D.; Dougherty, W. B.; Yap,
G. P. A.; Rheingold, A. L.; Riordan, C. G. Organometallics 2007, 26, 971–979.
38. Weidner, T.; Kraemer, A.; Bruhn, C.; Zharnikov, M.; Shaporenko, A.; Siemeling,
U.; Traeger, F. J. Chem. Soc., Dalton Trans. 2006, 2767–2777.
39. Yim, H. W.; Tran, L. M.; Dobbin, E. D.; Rabinovich, D.; Liable-Sands, L. M.;
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Complete experimental and characterization details for all com-
pounds reported; 1H and 13C NMR spectra of 1ꢀ9; extended crystal
structural diagram of 7 are available. Supplementary data associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.11.094.
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ꢀ
54. Compound 7: C21H33N3O9S3, FW 567.68, space group P2, a = 10.1945(8),
b = 11.8087(9),
c
c = 12.6371(10) Å,
a
= 64.895(1)°,
b = 82.421(1)°,
= 71.751(1)°, V = 1308.30(18) Å3, Z = 2, D = 1.441 Mg/m3,
l
= 0.338 mmꢀ1. R1
[I > 2r(I)] = 0.045, and wR2 [all data] = 0.130. Crystallographic data (excluding
structure factors) for compound 7 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication CCDC 708858.
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