Microwave-assisted SNAr reaction of 2,4,6-trichloro-1,3,5- triazine for the rapid synthesis of C3-symmetrical polycarboxylate ligands

Article abstract of DOI:10.1016/j.tetlet.2012.04.124

The microwave-assisted S_NAr reaction of 2,4,6-trichloro-1,3,5- triazine with various unprotected amino acids was developed for the synthesis of C₃-symmetrical polycarboxylate ligands which can be used as structural directing units in

Full text of DOI:10.1016/j.tetlet.2012.04.124

Tetrahedron Letters 53 (2012) 3486–3489
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted SNAr reaction of 2,4,6-trichloro-1,3,5-triazine for the
rapid synthesis of C3-symmetrical polycarboxylate ligands
⇑
Weeranuch Karuehanon, Watcharee Fanfuenha, Apinpus Rujiwatra, Mookda Pattarawarapan
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
The microwave-assisted SNAr reaction of 2,4,6-trichloro-1,3,5-triazine with various unprotected amino
acids was developed for the synthesis of C3-symmetrical polycarboxylate ligands which can be used as
structural directing units in metal–organic frameworks. The reactions were performed in water using a
domestic microwave oven as the heating device. In comparison to the reactions performed under conven-
tional heating, the reactions under microwave irradiation proceeded much more rapidly within 20 min to
afford the desired ligands in comparative yields to those obtained by conventional heating.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 23 December 2011
Revised 18 April 2012
Accepted 27 April 2012
Available online 2 May 2012
Keywords:
Microwave-assisted synthesis
1,3,5-Triazine
Polycarboxylate ligand
Metal–organic frameworks
Rational design of new polymeric coordination compounds, also
known as metal–organic frameworks (MOFs), has become an
increasingly important research field due to the intriguing struc-
tural diversity and potential applications of these functional mate-
rials.1–3 Based on self-assembly of metallic centers and bridging
organic linkers, the precisely controlled formation of complex
structural architectures can be achieved depending on the shapes
of the organic molecules and the specific interactions within the
frameworks.
Recently, many studies have focused on the use of polycarboxyl-
ate triazine-based ligands as the structural directing units in the
construction of novel functional MOFs.4–14 Due to the stability of
the triazine ring and the reactivity of chlorine substituents atoms
toward nucleophiles,15 new ligands can be synthesized by substitu-
tion of 2,4,6-trichloro-1,3,5-triazine (TCT) with various types of
nucleophiles containing carboxyl groups. Tri-substituted C3-sym-
metrical triazine derivatives such as N,N0,N00-1,3,5-triazine-2,4,
6-triyltris-glycine (TTG),9,10,13 1,3,5-triazine-2,4,6-triamine hexa-
acetic acid (TTHA),5,7,11 1,10,100-(benzene-1,3,5-triyl)tripiperidine-
4-carboxylic acid,12 1,3,5-triazine-2,4,6-trithiotri-3-benzoic acid,6
and 1,3,5-triazine-2,4,6-triaminetri-4-benzoic acid4,8 have been ap-
plied successfully in the construction of MOFs with new structural
architectures and unique properties. Generally, the syntheses of
C3-symmetrical triazine carboxylate ligands were performed at high
temperature over a long period of time. New energy and time effi-
cient methods are thus potentially useful for the synthesis of highly
structurally diverse ligands having unique properties.
Microwave-assisted organic synthesis has proved to be a useful
technique in enhancing the reaction rate relative to conventional
heating.16,17 By taking advantage of the ability of some liquids
and solids to transform electromagnetic radiation into heat, the
heating rate under microwave irradiation is several-fold higher
than heating with traditional equipment. In addition, since the
heat generated by microwave irradiation is proportional to the
dielectric constant (e) of the media, water (e = 78) is an excellent
solvent for microwave synthesis which can lead to cleaner and
more environmentally benign processes.18,19
Although microwave-assisted synthesis has been applied to a
variety of reactions,16,17 it has not been explored in the SNAr reac-
tion of TCT, neither in organic solvents nor in aqueous media. To
our surprise, only one example has reported the SNAr reaction of
aryl halides with amino acids in water under microwave irradia-
tion.20 The reactions of highly activated 2,4-dinitrofluorobenzene
with natural amino acids in a monomode microwave reactor were
complete within 40 s at 80 °C to afford the N-arylated amino acids
in excellent yields using 2 equiv of NaHCO3 as base.
Herein, we report the microwave-assisted synthesis of C3-sym-
metrical polycarboxylate triazine-based ligands via SNAr reaction
of TCT with unprotected amino acids. All the reactions were carried
out in a domestic microwave oven (Samsung GB872, 850 W,
2.54 GHz) using water as the solvent in an open-vessel.
In a preliminary study, the effects of the microwave conditions
including microwave power and exposure time were investigated
on the synthesis of the known ligand, TTG. For safety consider-
ations and ease of manipulation, irradiation of the reaction mixture
was performed repeatedly over a short period of time to avoid vig-
orous boiling and superheating of the solution which may cause an
⇑
Corresponding author. Tel.: +66 5394 3341; fax: +66 5389 2277.
E-mail address: mookdap55@gmail.com (M. Pattarawarapan).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.124

W. Karuehanon et al. / Tetrahedron Letters 53 (2012) 3486–3489
3487
Table 2
explosion. After each MW irradiation period, the sample was
Effect of base on the percentage yield of TTGa
cooled for 1 min in a water bath. The synthetic conditions were
adapted from the previously reported procedure for the synthesis
of TTHA.5 Typically, a mixture of 1.0 equiv of TCT, 3.6 equiv of gly-
cine, and 10 equiv of NaOH in water was irradiated using a micro-
wave oven according to the conditions listed in Table 1. Upon
completion of the reaction as monitored by TLC, the cooled reac-
tion mixture was acidified with concentrated hydrochloric acid
and filtered. The filtrate was washed several times with water then
ethanol to afford the tri-substituted product in high purity; no fur-
ther purification was necessary.
Entry
Base (equiv)
Isolated yield (%)
1
2
3
4
5
6
NaOH (10)
NaOH (7.2)
NaOH (3.6)
Na2CO3 (10)
K2CO3 (10)
81
32
13
63
56
51
NaOH/NaHCO3 (5/3.3)
a
All reactions were carried out with TCT (0.54 mmol) and glycine (1.94 mmol) in
H2O (2 mL) at 180 W, 5 ꢀ 2 min.
As shown in Table 1, slightly lower yields of TTG were obtained
at low irradiation power (100 W, entries 1 and 2). The highest yield
(81%) was produced with a minimum exposure time of 5 ꢀ 2 min
at 180 W (entry 3). Prolonged irradiation at the same microwave
power resulted in product loss through vigorous boiling of the
reaction mixture (entry 4). At 300 W, the reaction mixture goes
to complete boiling within 1 min and again a low yield was iso-
lated due to escape of the reaction mixture (entry 5).
The microwave conditions were further optimized by varying
the type and quantity of base (Table 2). The highest yield of TTG
was generated using 10 equiv of NaOH. Attempts to lower the
amount of NaOH or use a weaker base such as sodium carbonate
or potassium carbonate resulted in poorer conversion which com-
plicated the reaction work-up. An excess of strong base is presum-
ably required to shift the equilibrium toward the reactive amino
acid anions through deprotonation of the –NHþ3 group of the amino
acid zwitterions.
Table 3
Synthesis of polycarboxylate ligands containing a 1,3,5-triazine core
R1
R2
N
Cl
N
R1
R2
N
N
NaOH, H2O
MW 180 W
N
N
N
H
R2
R1
N
N
N
Cl
Cl
R1
R2
1
Entry
NHR1R2
ProductRef.
Isolated yield (%)
Microwave
81
Reflux
1
2
1a21
1b
80
H2N
CO2H
CO2H
NH2
78a
80
73
The efficiency of the microwave method was compared with
that of conventional heating. TCT was reacted with glycine in the
presence of 10 equiv of NaOH under reflux in an oil bath for
10 min. In this case, the reaction was incomplete and TTG was iso-
lated in only 32% yield. As expected, an enhancement in the reac-
CO2H
3
1c
83
NH2
HO
CO2H
HO2C
4
5
1d
1e
54a
87
67
86
NH2
tion rate and
a shorter reaction time were achieved under
HO2C
CO2H
microwave heating.
To expand the scope of this reaction, a variety of amino acids
were employed in the synthesis of polycarboxylate triazine-based
ligands under the optimized microwave conditions. Unless other-
wise specified, all the reactions were carried out in water with
TCT (0.54 mmol), amino acid (1.94 mmol), and NaOH (5.4 mmol)
at 180 W for 5 ꢀ 2 min. For comparison, the same reactions were
conducted under reflux conditions for 12 h. The isolated yields
from both methods are summarized in Table 3.
NH2
6
7
1f21
89a
78a
87
70
H2N
CO2H
CO2H
1g21
H2N
8
9
1h5
89
86
75
HO2C
N
H
CO2H
CO2H
1i22
28a
It was found that under MW irradiation, the reaction time was
reduced by several-fold when compared with reactions performed
under conventional heating. Diverse amino acids containing pri-
mary, secondary, or aromatic amino groups were sufficiently reac-
tive to afford the corresponding tri-substituted products in good
NH2
CO2H
10
11
1j
7a
85
80
NH2
H2N
1k4,23
87
CO2H
Table 1
Effect of microwave conditions on the percentage yield of TTGa
a
180 W, 10 ꢀ 2 min.
HN
CO2H
N
N
yields. Racemic a-amino acids such as tyrosine, aspartic acid, and
HO2C
N
H
N
N
H
CO2H
glutamic acid (entries 3–5) could be applied directly in the substi-
tution reaction without side-chain protection. However, when
using phenylalanine and proline as the nucleophiles, the desired
products could not be isolated from the residual starting amino
acids, while histidine gave complicated product mixtures possibly
through side reactions from the side-chain imidazole (data not
shown).
Nevertheless, the yields of the tri-substituted products from
microwave heating were in most cases comparable to those of
the standard heating method, except for compound 1i where a
TTG
Entry
Microwave power (W)
Exposure time (min)
Isolated yield (%)
1
2
3
4
5
100
100
180
180
300
5 ꢀ 2
5 ꢀ 3
5 ꢀ 2
2 ꢀ 5
5 ꢀ 1
76
80
81
72
78
a
All reactions were carried out with TCT (0.54 mmol), glycine (1.94 mmol), and
NaOH (5.4 mmol) in H2O (2 mL).

3488
W. Karuehanon et al. / Tetrahedron Letters 53 (2012) 3486–3489
significantly lower yield was produced under microwave irradia-
tion (entry 9). Attempts to drive the reaction to completion by rais-
ing the microwave power under prolonged irradiation failed to
give good conversion. Intramolecular hydrogen bonding is seem-
ingly responsible for the poor nucleophilicity of 2-aminobenzoic
acid. Under microwave conditions, where the reaction was heated
and cooled down intermittently, the amount of free amino group
may be insufficient to react with TCT and thus leads to a slower
rate of reaction. It should be noted also that although TCT has a
tendency to hydrolyze under aqueous alkaline conditions,24 by-
products such as 2,4-dichloro-6-hydroxy-1,3,5-triazine, 2-chloro-
4,6-dihydroxy-1,3,5-triazine, and 2,4,6-dihydroxy-1,3,5-triazine
(cyanuric acid) were not observed suggesting that the rate of TCT
hydrolysis was much slower than amine substitution.
To demonstrate the practicality of the developed microwave
protocol, large-scale experiments (5.0 g, 27 mmol of TCT) were car-
ried out in the synthesis of TTG and TTHA using a 250 mL Erlen-
meyer flask as the reaction vessel. High yields of TTG (82%) and
TTHA (91%) were afforded under microwave irradiation at 180 W
with exposure times of 10 ꢀ 3 min.
N,N0,N00-1,3,5-Triazine-2,4,6-triyltris-aspartic acid (1d)
White powder; mp (dec) P270 °C; Rf = 0.08 (60% MeOH/EtOAc);
1H NMR (D2O, 400 MHz): d 1.96 (dd J = 15.3, 9.1 Hz, 3H), 2.23 (dd,
J = 15.2, 4.4 Hz, 3H), 3.16 (dd, J = 9.1, 4.4 Hz, 3H) ppm; 13C NMR
(D2O, 100 MHz) d 32.2, 62.1, 168.3, 181.0, 183.4 ppm. IR (KBr)
3021, 1692, 1645, 1600, 1512, 1423, 1326, 1250 cmꢁ1. HRMS Calcd
for C15H17N6O12 [MꢁH]ꢁ 473.0910. Found 473.0906.
N,N0,N00-1,3,5-Triazine-2,4,6-triyltris-glutamic acid (1e)
White powder; mp 240–242 °C; Rf = 0.12 (80% MeOH/EtOAc);
1H NMR (D2O, 400 MHz): d 1.93–2.31 (m, 6H), 2.45 (t, J = 6.9 Hz,
6H) 4.43–4.55 (m, 3H) ppm; 13C NMR (D2O, 100 MHz) d 26.8,
30.7, 56.0, 155.8, 176.5, 178.0. IR (KBr) 3563, 1739, 1631, 1412,
1231 cmꢁ1. HRMS Calcd For C18H23N6O2 [MꢁH]ꢁ 515.1379. Found
515.1382.
N,N0,N00-1,3,5-Triazine-2,4,6-triaminetri-3-benzoic acid (1j)
In summary, a straightforward and effective method to synthe-
size C3-symmetrical polycarboxylate triazine-based ligands has
been developed using microwave-assisted synthesis. The ligands
were obtained in good yields and in short reaction times. Compared
to conventional heating, the microwave technique provides a rapid,
simple, and effective method to generate a variety of polycarboxyl-
ate ligands with potential applications in the design of MOFs.
Further efforts toward this end will be reported in due course.
White powder; mp (dec) P300 °C; Rf = 0.08 (60% MeOH/
EtOAc); 1H NMR (D2O, 400 MHz): d 7.24 (t, J = 7.9 Hz, 3H), 7.43
(d, J = 7.7 Hz, 3H), 7.51 (d, J = 7.9 Hz, 3H), 7.74 (s, 3H) ppm; 13C
NMR (DMSO-d6, 100 MHz) d 171.6, 165.9, 138.5, 136.8, 128.6,
124.5, 123.8, 122.0. IR (KBr) 3294, 1697, 1542, 1397, 1271,
1008 cmꢁ1. HRMS Calcd for C24H19N6O6 [M+H]+ 487.1366. Found
487.1363.
Caution! The level of the filled solvent line should not exceed 1/
3 of the reaction vessel. Heating under microwave irradiation can
produce superheating and explosions. All experiments should thus
be performed in a fume hood with an explosion shield.
General procedure for the microwave-assisted synthesis
A solution of amino acid (1.94 mmol) and NaOH (0.22 g,
5.40 mmol) in H2O (1 mL) was added dropwise into a 20 mL test
tube containing a 1 mL aqueous solution of TCT (0.1 g, 0.54 mmol)
at 0 °C. The mixture was allowed to warm to room temperature,
boiling chips were added and the reaction vessel was placed on
the center of the turn-table in a domestic microwave oven (Sam-
sung GB872, 850 W, 2.54 GHz). The mixture was then irradiated
at the specified power for the prescribed time. After the microwave
was switched off, the reaction mixture was cooled and acidified
with concentrated HCl. The precipitate was collected by filtration,
washed successively with H2O and EtOH before drying at 80 °C to
afford the pure product. Novel compounds 1b–e and 1j were fully
characterized by 1H NMR, 13C NMR, FT-IR, and HRMS analyses.
Spectroscopic data for known compounds 1a, 1f–i and 1k were
consistent with those reported in the literature.
Acknowledgements
This research was supported by a grant under the program Stra-
tegic Scholarships for Frontier Research Network for the Ph.D. Pro-
gram Thai Doctoral degree from the Commission on Higher
Education (CHE), Thailand (to W. Karuehanon). The authors also
gratefully acknowledge the Center of Excellence for Innovation in
Chemistry (PERCH-CIC), the National Research University Project
under Thailand’s Office of the Higher Education Commission, and
the Graduate School, Chiang Mai University for financial support
of this research.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
04.124.
N,N0,N00-1,3,5-Triazine-2,4,6-triyltris-valine (1b)
White powder; mp 267–270 °C; Rf = 0.49 (60% MeOH/EtOAc);
1H NMR (D2O, 400 MHz): d 0.67 (dd, J = 28.6, 6.8, 18H), 1.65–1.70
(m, 3H) 2.82 (dd, J = 5.2 Hz, 3H) ppm; 13C NMR (D2O, 100 MHz) d
17.0, 31.8, 61.7, 168.5, 183.1 IR (KBr) 2969, 1727, 1615, 1510,
1397 cmꢁ1. HRMS Calcd for C18H29N6O6 [MꢁH]ꢁ 425.2154. Found
425.2134.
References and notes
1. James, S. L. Chem. Soc. Rev. 2003, 32, 276–288.
2. Das, M. C.; Xiang, S.; Zhang, Z.; Chen, B. Angew. Chem., Int. Ed. 2011, 50, 10510–
10520.
3. Meek, S. T.; Greathouse, J. A.; Allendorf, M. D. Adv. Mater. 2011, 23, 249–267.
4. Fang, Q.-R.; Yuan, D.-Q.; Sculley, J.; Li, J.-R.; Han, Z.-B.; Zhou, H.-C. Inorg. Chem.
2010, 49, 11637–11642.
5. Zhu, Q.; Sheng, T.; Fu, R.; Hu, S.; Chen, J.; Xiang, S.; Shen, C.; Wu, X. Cryst. Growth
Des. 2009, 9, 5128–5134.
N,N0,N00-1,3,5-Triazine-2,4,6-triyltris-tyrosine (1c)
6. Shen, C.; Sheng, T.; Fu, R.; Hu, S.; Zhu, Q.; Ma, X.; Huang, Y.; Wu, X. Inorg. Chem.
Commun. 2011, 14, 1119–1123.
7. Zhu, Q.; Sheng, T.; Fu, R.; Hu, S.; Shen, C.; Ma, X.; Wu, X. CrystEngComm 2011,
13, 2096–2105.
8. Wang, X. S.; Ma, S.; Sun, D.; Parkin, S.; Zhou, H. C. J. Am. Chem. Soc. 2006, 128,
16474–16475.
9. Wang, S.; Bai, J.; Xing, H.; Li, Y.; Song, Y.; Pan, Y.; Scheer, M.; You, X. Cryst.
Growth Des. 2007, 7, 747–754.
White powder; mp (dec) P270 °C; Rf = 0.09 (80% MeOH/EtOAc);
1H NMR (D2O, 400 MHz): d 2.30 (dd, J = 13.7, 7.4 Hz, 3H), 2.48 (dd,
J = 13.6, 5.2 Hz, 3H), 3.05 (t, J = 8.7 Hz, 3H), 6.22 (d, J = 8.3 Hz, 6H),
6.63 (d, J = 8.3 Hz, 6H) ppm; 13C NMR (D2O, 100 MHz) d 39.9, 57.9,
117.9, 123.7, 131.1, 164.4, 168.4, 182.9 ppm. IR (KBr) 3207, 2935,
1588, 1454, 1451, 1412, 1246 cmꢁ1. HRMS Calcd for C30H29N6O9
[MꢁH]ꢁ 617.2002. Found 617.2007.
10. Wang, S.-N.; Bai, J.; Li, Y.-Z.; Pan, Y.; Scheer, M.; You, X.-Z. CrystEngComm 2007,
9, 1084–1095.

W. Karuehanon et al. / Tetrahedron Letters 53 (2012) 3486–3489
3489
11. Ghanashyam Acharya, S. N.; Srinivasa Gopalan, R.; Kulkarni, G. U.; Venkatesan,
K.; Bhattacharya, S. Chem. Commun. 2000, 1, 1351–1352.
12. Zhao, X.; He, H.; Hu, T.; Dai, F.; Sun, D. Inorg. Chem. 2009, 48, 8057–
8059.
13. Wang, S. N.; Xing, H.; Li, Y. Z.; Bai, J.; Scheer, M.; Pan, Y.; You, X. Z. Chem.
Commun. 2007, 2293–2295.
14. Sun, C. Y.; Wang, S.; Yang, G. S.; Wang, X. L.; Shao, K. Z.; Su, Z. M. Inorg. Chem.
Commun. 2011, 14, 893–896.
15. Blotny, G. Tetrahedron 2006, 62, 9507–9522.
17. Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225–
9283.
18. Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563–2591.
19. Polshettiwar, V.; Varma, R. S. Acc. Chem. Res. 2008, 41, 629–639.
20. Cherng, Y. J. Tetrahedron 2000, 56, 8287–8289.
21. Clark, D. R. EP 1981-810317; Chem. Abstr. 1982, 97, 131683.
22. Schinzel, E.; Pelster, M. DE 1983-333457; Chem. Abstr. 1985, 103, 106260.
23. Kolmakov, K. A. J. Heterocycl. Chem. 2008, 45, 533–539.
24. Yan, Z.; Xue, W. L.; Zeng, Z. X.; Gu, M. R. Ind. Eng. Chem. Res. 2008, 47, 5318–
5322.
16. Caddick, S.; Fitzmaurice, R. Tetrahedron 2009, 65, 3325–3355.