Synthesis of electron-deficient 1,3,5-triazines as potential azadienes for inverse-electron-demand Diels-Alder reactions

Article abstract of DOI:10.1080/00397910902978031

Various 1,3,5-triazines with electron-withdrawing groups such as esters, thioesters, and amides were prepared. These triazines were synthesized using acyl chloride coupling methods from triazine 1a and various alcohols, ethanethiol, and amines. Lowest unoccupied molecular orbital (LUMO) energy and solubility for these 1,3,5-triazines were determined to assess their potential as azadienes in inverse-electron-demand Diels-Alder reactions (IDA). The thioester 8 showed less LUMO energy and more solubility than triazine 1, suggesting that it may be a better azadiene to study triazine IDA reactions.

Full text of DOI:10.1080/00397910902978031

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Synthesis of Electron-Deficient 1,3,5-
Triazines as Potential Azadienes for
Inverse-Electron-Demand Diels–Alder
Reactions
Guoxing Xu a , Lianyou Zheng a , Shixue Wang a , Qun Dang a & Xu Bai
a
a The Center for Combinatorial Chemistry and Drug Discovery,
College of Chemistry and School of Pharmaceutical Sciences, Jilin
University, Changchun, China
Version of record first published: 06 Jan 2010.
To cite this article: Guoxing Xu , Lianyou Zheng , Shixue Wang , Qun Dang & Xu Bai (2010): Synthesis
of Electron-Deficient 1,3,5-Triazines as Potential Azadienes for Inverse-Electron-Demand Diels–Alder
Reactions, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 40:3, 361-369
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Synthetic Communications1, 40: 361–369, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902978031
SYNTHESIS OF ELECTRON-DEFICIENT 1,3,5-TRIAZINES
AS POTENTIAL AZADIENES FOR INVERSE-ELECTRON-
DEMAND DIELS–ALDER REACTIONS
Guoxing Xu, Lianyou Zheng, Shixue Wang,
Qun Dang, and Xu Bai
The Center for Combinatorial Chemistry and Drug Discovery, College of
Chemistry and School of Pharmaceutical Sciences, Jilin University,
Changchun, China
Various 1,3,5-triazines with electron-withdrawing groups such as esters, thioesters, and
amides were prepared. These triazines were synthesized using acyl chloride coupling
methods from triazine 1a and various alcohols, ethanethiol, and amines. Lowest unoccupied
molecular orbital (LUMO) energy and solubility for these 1,3,5-triazines were determined
to assess their potential as azadienes in inverse-electron-demand Diels–Alder reactions
(IDA). The thioester 8 showed less LUMO energy and more solubility than triazine 1,
suggesting that it may be a better azadiene to study triazine IDA reactions.
Keywords: Inverse-electron-demand Diels–Alder reaction; LUMO energies; solubility; 1,3,5-triazines
INTRODUCTION
Azadiene inverse-electron-demand Diels–Alder (IDA) reactions have been
established as a powerful method to prepare various heterocyclic scaffolds
efficiently.[1–4] Since the initial report by Neunhoeffer and Bachman using 1,3,5-
triazine as an effective azadiene in IDA reactions producing pyrimidines,[5] others
have expanded the scope of 1,3,5-triazine IDA reactions and established this method
as an efficient way to prepare pyrimidines.[6–8] Our recent reports further extended
the scope of this type of IDA reaction, leading to useful methods for the efficient syn-
thesis of fused pyrimidines.[9–11] Most studies of 1,3,5-triazine IDA reactions tend to
focus on investigation of the scope of dienophiles but only a limited number of
1,3,5-triazines have been studied to date. Therefore, a systemic study of various
1,3,5-triazines as potential azadienes and investigation of the effects of various Lewis
acids should contribute to the further development of 1,3,5-triazine IDA method-
ology. Another reason to investigate the scope of 1,3,5-triaizne IDA reactions is that
the IDA products are often highly functionalized and thus are considered useful
building blocks for libraries of fused pyrimidine scaffolds. For example, IDA
Received January 10, 2009.
Address correspondence to Qun Dang, Center for Combinatorial Chemistry and Drug Discovery,
College of Chemistry and School of Pharmaceutical Sciences, Jilin University, 75 Haiwai St., Changchun,
Jilin 130012, China. E-mail: qdang@jlu.edu.cn or xbai@jlu.edu.cn
361

362
G. XU ET AL.
products derived from 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine present two ester
groups that could be selectively functionalized,[12,13] therefore creating two diversity
points at the 2- and 4-positions of the pyrimidine nucleus. 1,3,5-Triazines with
electron-donating groups such as amino and alkoxy groups are readily prepared
from cyanuric chloride via direct substitution reactions, whereas alkyl- or aryl-
substituted 1,3,5-triazines are either prepared via trimerization of nitriles or cross-
coupling reactions with cyanuric chloride.[14–17] However, 1,3,5-triazines with
electron-withdrawing groups have limited scope and are less frequently reported.
Herein, the synthesis, solubility, and theoretical calculation of lowest unoccupied
molecular orbital (LUMO) energies of various 1,3,5-triazines with electron-
withdrawing groups such as various esters, thioesters, and amides are reported.
RESULTS AND DISCUSSION
Several groups used the commercially available 2,4,6-tris(ethoxycarbonyl)-
1,3,5-triazine (1) to study IDA reactions and demonstrated that it is a productive
azadiene. These reactions were often conducted in polar solvents such as acetonitrile,
dimethylformamide (DMF), and dimethylsulfoxide (DMSO) under thermal con-
ditions. In our attempts to study a Lewis acid–catalyzed IDA reaction using triazine
1, we noticed that 1 has poor solubility in tetrahydrofuran (THF) and dichloro-
methane (DCM) at ambient temperature. Given that reaction conditions entailing
polar solvents and elevated temperature are likely incompatible with most Lewis
acids, we decided to investigate the conversion of triazine 1 to other derivatives in
order to identify a triazine with acceptable solubility in most organic solvents such
as DCM, THF, and toluene. The most direct strategy is to use transesterification
reactions to explore other esters of 1,3,5-triazines.[18] First, various alcohols were
explored under acid-catalyzed reaction conditions to prepare various 1,3,5-triazine
Scheme 1. Synthesis of various 1,3,5-triazines. Reagents and conditions: (i) XH, p-TsOH, toluene, reflux;
(ii) KOH, EtOH-H2O; (iii) XH, CDI, DMF; (iv) POCl3; and (v) XH, TEA, Et2O.

ELECTRON-DEFICIENT 1,3,5-TRIAZINES
363
Table 1. Transesterification of triazine 1
Entry
X¼
Conditionsa
Yieldb (%)
1
2
3
4
5
6
MeO
nBuO
iPrO
PhO
BnO
EtS
MeOH, reflux
nBuOH, reflux
iPrOH, reflux
PhOH, 150ꢀC
BnOH, 150ꢀC
EtSH, PhMe, reflux
35
56
NAc
NA
NA
NA
aReactions were conducted with 0.1 equiv of p-TsOH.
bYields are based on pure products isolated by chromatography.
cNA denotes no reaction or that no desired product was isolated.
triesters from triazine 1 (Scheme 1). Unfortunately, this approach has very limited
scope because only reactions with methanol and n-butanol gave the desired triazines
2 and 3 in moderate yields (entries 1 and 2, Table 1).
Attempts with other alcohols and ethanethiol did not produce the desired trie-
sters. Consequently, a stepwise approach was envisioned via the tri-acid form (1a),[19]
which could be prepared via saponification of triazine 1. Direct coupling of 1a with
benzylamine using carbonyl diimidazole (3.3 equiv) in DMF gave the desired amide
9 in good yield (54% for the two steps of ester hydrolysis and amide formation).
However, the same condition did not produce the desired products with other
coupling partners, such as alcohols and secondary amines (Table 2).
Finally, we turned our attention to Grundmann and Kober’s work[19] with acyl
chloride 1b, which was used to prepare a few triazine derivatives with very limited
scope. Thus, triazine 1a was converted to 1b using phosphorus oxychloride, and
subsequent coupling with alcohols, ethanethiol, and amines produced the desired
1,3,5-triazine derivatives in moderate to good yields (Table 3).
With a set of triazines (1–11) in hand, a screen was performed to assess the
relative solubility of these triazines in three common organic solvents: DMF,
THF, and chloroform.
The thioester 8 exhibited excellent solubility in all three organic solvents tested,
whereas most other triazines showed comparable solubility in the polar solvent
DMF with the exception of the triamide 9. The tris(isopropyloxycarbonyl)-triazine
4 also showed better solubility in chloroform compared other esters (1–3, 5–7) and
amides (9–11).
Table 2. Attempted direct couplings with triazine 1aa
Entry
XH¼
Conditionsa
Yield (%)
1
2
3
4
5
BnNH2
MeOH
CDI, DMF, 20 h
CDI, DMF, 48 h
CDI, DMF, 48 h
CDI, DMF, 48 h
CDI, DMF, 48 h
54b
NAc
NA
NA
NA
Morpholine
Et2NH
EtSH
aReactions were conducted at room temperature.
bProduct isolated via crystallization.
cNA denotes no reaction or that no desired product was isolated.

364
G. XU ET AL.
Table 3. Preparation of s-triazines via triazine 1b
Entry
X¼
Triazines
Mp (ꢀC)
Yielda (%)
1
2
MeO
nBuO
iPrO
2
3
155–157
50–52
92–94
63
60
45
49
50
48
45
72
59
51
3
4
4
Allyl-O
PhO
BnO
5
Oil
5
6
164–166
102–104
84–86
6
7
7
EtS
BnNH
8
8
9
170–172
103–106
241–243
9
10
Me(MeO)N
N-Morpholinyl
10
11
aYields were calculated for the three-step sequence and are based on pure products
isolated via chromatography.
It is well established that IDA reactions are controlled by the LUMO energies
of dienes. Therefore, to better understand the relative reactivity of triazines 1–11, we
decided to calculate their LUMO energies, and results are summarized in Table 5.
The unsubstituted triazine 13 has greater LUMO energy compared to triazine
1, which is consistent with experimental observed reactivity of the two triazines. The
amides (10 and 11) also showed greater energy than triazine 1 and therefore are
expected to be less reactive in IDA reactions. It is encouraging to us that the most
soluble triazine 8 showed less LUMO energy than 1, suggesting that it may be a
better model compound to study triazine IDA reactions. It is noted that the
tris-cyano-triazine 12[20] gives the least calculated LUMO energy, thus, it would be
interesting to explore its reactivity in IDA reactions.
EXPERIMENTAL
Diethyl ether was dried with Na2SO4, POCl3 was distilled before use, and other
commercial reagents were used as received without additional purification. Melting
Table 4. Solubility of 1,3,5-triazines (1–11)a
Triazines
DMF
THF
CHCl3
1
2
0.09
0.13
0.27
0.10
0.24
0.24
0.10
1.53
0.05
0.15
0.06
0.01
0.09
0.10
0.04
0.29
0.26
0.07
1.67
0.01
0.08
0.01
0.12
0.13
0.26
0.60
0.36
0.23
0.10
1.47
0.005
0.005
0.06
3
4
5
6
7
8
9
10
11
aSolubility reported as mmol=ml; see the Experimental section for details.

ELECTRON-DEFICIENT 1,3,5-TRIAZINES
365
Table 5. LUMO energies of triazinesa
Entry
Triazines
X¼
ELUMO
1
2
3
4
5
6
7
8
1
5
EtO
Allyl-O
PhO
ꢂ2.78
ꢂ2.75
ꢂ2.94
ꢂ3.11
ꢂ2.21
ꢂ2.28
ꢂ4.16
ꢂ1.46
6
8
EtS
10
11
12
13
Me(MeO)N
N-Morpholinyl
CN
H
aLUMO energy was calculated using Spartan (B3LYP at 6-31Gꢃ
level) and reported as eV.
points are uncorrected. Mass spectra (MS) and high-performance liquid chromato-
graphy (HPLC) evaporative light scattering detector (ELSD) data were recorded
on an LC=MS system, using a 4.6 ꢁ 50-mm column (C-18 AQþ, 5 mm) with a linear
gradient of 30–90% (v=v) acetonitrile–water with 0.035% trifluoro-acetic acid over
5 min with a flow rate of 3.5 mL=min. Analytical thin-layer chromatography (TLC)
was performed using a 2.5 ꢁ 5-cm plate coated with 0.25 mm of silica gel GF254
.
Column chromatography was performed using silica gel G (200–300 mesh). 1H
NMR spectra (300 MHz) are reported as follows: chemical shifts in parts per million
(ppm) referenced to TMS as internal standard (d scale). Multiplicities are indicated
as the following: br ¼ broad, s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼
multiplet, with integration and coupling constant (Hz). 13C NMR spectra (75 MHz)
were determined with complete proton decoupling and are reported in ppm.
Typical Procedure for Preparation of Compound 8
The powdered triazine 1a[19] (15.9 g, 48.6 mmol) was added in small portions
into POCl3 (100 mL) with stirring at room temperature, and the resulting reaction
mixture was refluxed for 16 h. The cooled reaction mixture was extracted with ether
(3 ꢁ 100 mL), and the combined ethereal extracts were evaporated to dryness under
vacuum to give the crude acid chloride 1b (31.4 g). A suspension of 1b (2 g) in anhy-
drous ether (10 mL) was treated with EtSH (0.93 mL, 12.4 mmol) and Et3N (1.73 mL,
12.4 mmol) at 0ꢀC. After 3 h, the reaction was quenched with water (20 mL), and the
pH was adjusted to 5–6 with saturated NaHCO3. The layers were separated, and the
aqueous phase was extracted with EtOAc (2 ꢁ 20 mL). The combined organic
extracts were washed with brine, dried (Na2SO4), and evaporated to dryness. The
residue was purified by flash chromatography [SiO2, eluting with petroleum ether
1
and EtOAc (15:1)] to give 8 as a yellow solid. Mp 84–86ꢀC; H NMR (300 MHz,
CDCl3) d 3.18 (q, J ¼ 7.5 Hz, 2H), 1.41 (t, J ¼ 7.5 Hz, 3H). 13C NMR (75 MHz,
CDCl3): d 188.7, 168.1, 24.5, 14.1. ES-MS: m=z 346 [M þH]þ.
General Procedure to Compare Solubility of 1,3,5-Triazines
Solubility of 1,3,5-triazines (1–11) was estimated by adding solvents
(DMF, THF or chloroform) dropwise to an accurately weighed 2-mg sample of

366
G. XU ET AL.
a 1,3,5-triazine until full solubilization was achieved. The number of drops of
solvents was recorded, and the volume (mL) was estimated based on a control
experiment in which the number of drops was determined for achieving 1 mL of
volume.
CONCLUSION
In summary, the acyl chloride coupling proved to be a good general method for
the preparation of various 1,3,5-triazines. Solubility studies of triazines 1–11 showed
that triazine 8 has excellent solubility in common organic solvents such as DMF,
THF, and chloroform. Moreover, calculation of LUMO energies for several
1,3,5-triazine suggests that the most soluble triazine 8 should also be more reactive
than the commonly used triazine 1. The 2,4,6-tricyano-1,3,5-triazine 12 appears to
have the lowest LUMO energy among all triazines investigated and thus is identified
as a potential new azadiene for IDA reactions. Currently, we are using the solubility
and LUMO energy data reported here to study the application of various IDA reac-
tions to synthesize of diverse pyrimidine-fused heterocycles, and results from these
studies will be reported in due course.
DATA
2,4,6-Tris(methoxycarbonyl)-1,3,5-triazine (2)[21]
1
Yield 63%; straw-yellow solid; mp 155–157ꢀC; H NMR (300 MHz, DMSO-
d6): d 4.12 (s, 3H); 13C NMR (75 MHz, DMSO-d6): d 165.7, 161.9, 54.0; ES-MS:
m=z 256 [M þHþ].
2,4,6-Tris(butoxycarbonyl)-1,3,5-triazine (3)
1
Yield 60%; white solid; mp 50–52ꢀC; H NMR (300 MHz, CDCl3): d 4.51(t,
J ¼ 6.9 Hz, 2H), 1.87–1.78 (m, 2H), 1.52–1.42 (m, 2H), 0.98 (t, J ¼ 6.9 Hz, 3H).
13C NMR (75 MHz, CDCl3); d 167.1, 161.6, 67.8, 30.5, 19.1, 13.8; ES-MS: m=z
382 [M þ Hþ].
2,4,6-Tris(isopropoxycarbonyl)-1,3,5-triazine (4)
1
Yield 45%; straw-yellow solid; mp 92–94ꢀC; H NMR (300 MHz, CDCl3): d
5.40–5.36 (m, 1H), 1.46 (d, J ¼ 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3): d 167.3,
161.3, 72.5, 21.8; ES-MS: m=z 340 [M þ Hþ].
Triallyl 1,3,5-Triazine-2,4,6-tricarboxylate (5)
1
Yield 49%; straw-yellow solid; mp 92–94ꢀC; H NMR (300 MHz, CDCl3): d
6.11–6.00 (m, 1H), 5.53–5.36 (m, 2H), 5.00–4.98 (m, 2H); 13C NMR (75 MHz,
CDCl3): d 166.8, 160.9, 130.6, 120.6, 68.3; ES-MS: m=z 334 [M þ Hþ].

ELECTRON-DEFICIENT 1,3,5-TRIAZINES
367
2,4,6-Tris(phenoxycarbonyl)-1,3,5-triazine (6)
Yield 50%; straw-yellow solid; mp 164–166ꢀC; 1H NMR (300 MHz, CDCl3): d
7.51–7.33 (m, 5H, PhH); 13C NMR (75 MHz, CDCl3): d 166.9, 159.5, 150.2, 129.7,
126.9, 121.0; ES-MS: m=z 442 [M þ Hþ].
2,4,6-Tris(benzyloxycarbonyl)-1,3,5-triazine (7)
Yield 48%; white solid; mp 102–104ꢀC; 1H NMR (300 MHz, CDCl3): d
7.49–7.36 (m, 5H, PhH), 5.51 (s, 2H); 13C NMR (75 MHz, CDCl3): d 167.1, 161.6,
67.8, 30.5, 19.1, 13.8; ES-MS: m=z 382 [M þ Hþ].
S,S,S-Triethyl 1,3,5-Triazine-2,4,6-tris(Carboxylothioate) (8)
1
Yield 45%; yellow solid; mp 84–86ꢀC; H NMR (300 MHz, CDCl3): d 3.18 (q,
J ¼ 7.5 Hz, 2H), 1.41 (t, J ¼ 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 188.7, 168.1,
24.5, 14.1, ES-MS: m=z 346 [M þ Hþ].
N2,N4,N6-Tribenzyl-1,3,5-triazine-2,4,6-tricarboxamide (9)
1
Yield 72%; white solid; mp 170–172ꢀC; H NMR (300 MHz, DMSO-d6): d
7.34–7.20 (m, 5H, PhH), 6.45 (t, J ¼ 6.0 Hz, 1H, NH), 4.24–4.22 (m, 2H). 13C
NMR (75 MHz, DMSO-d6): d 158.5, 141.0, 128.4, 127.3, 127.2, 126.8, 43.2; ES-MS:
m=z 240 [M þ 2Hþ].
N2,N4,N6-Trimethoxy-N2,N4,N6-
trimethyl-1,3,5-triazine-2,4,6-tricarboxamide (10)
Yield 59%; straw-yellow solid; mp 92–94ꢀC; 1H NMR (300 MHz, DMSO-d6): d
3.62 (s, 3H), 3.33 (s, 3H); 13C NMR (75 MHz, DMSO-d6): d 170.0, 162.5, 61.8, 31.5;
ES-MS: m=z 343 [M þ Hþ].
(1,3,5-Triazine-2,4,6-triyl)tris(Morpholinomethanone) (11)
1
Yield 51%; white solid; mp 241–243ꢀC; H NMR (300 MHz, DMSO-d6): d
3.68–3.67 (m, 2H), 3.58–3.53 (m, 1H), 3.48–3.44 (m, 1H); 13C NMR (75 MHz,
DMSO-d6): d 169.7, 161.6, 66.2, 65.8, 46.3, 41.6; ES-MS: m=z 421 [M þ Hþ].
ACKNOWLEDGMENTS
This work was supported by grants (90713008 and 20802024) from the
National Natural Science Foundation of China and Changchun Discovery
Sciences, Ltd.

368
G. XU ET AL.
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