Trizaine-based dehydrative condensation reagents bearing carbon-substituents

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Masanori Kitamura, Sayaka Komine, Kohei Yamada, Munetaka Kunishima

PII:

S0040-4020(19)31316-X

https://doi.org/10.1016/j.tet.2019.130900

TET 130900

DOI:

Reference:

To appear in: Tetrahedron

Received Date: 18 November 2019

Revised Date: 12 December 2019

Accepted Date: 19 December 2019

Please cite this article as: Kitamura M, Komine S, Yamada K, Kunishima M, Trizaine-based dehydrative

condensation reagents bearing carbon-substituents, Tetrahedron (2020), doi: https://doi.org/10.1016/

j.tet.2019.130900.

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Graphical abstract

Trizaine-Based

Dehydrative

Condensation

Reagents

Bearing

Carbon-Substituents

Masanori Kitamura, Sayaka Komine, Kohei Yamada, Munetaka Kunishima*

Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa

University, Kakuma-machi, Kanazawa 920-1192, Japan.

* Corresponding author.

E-mail address: kunisima@p.kanazawa-u.ac.jp (M. Kunishima).

ABSTRACT

Herein, we report on the synthesis of alkyl-, aryl-, and alkynyl-substituted chlorotriazines and their

ammonium salts, and demonstrate their utility in dehydrative condensation reactions. Although the

electrophilicity of these reagents is mainly dependent on the hybridization of the carbon-substituents, it was

found that bulky 2,6-dimethylphenyl group-substituted reagents resulted in the highest product yields because

of a slight increase in reagent electrophilicity and/or steric hindrance favorable for desired dehydrative

condensation reactions.

Keywords

Condensation reactions, Triazine, Carbon-substituents, Amides, Carboxylic acids, Amines

1. Introduction

Chlorotriazines (1 shown in Scheme 1), and their ammonium salts (2 or 4) that are prepared from 1 and

N-methylmorpholine (NMM) or tertiary amines 3, have been developed as dehydrative condensation reagents

[1–5]. Using these reagents (1 + NMM, 2, or 4), carboxylic acids (5) are converted to activated esters (6),

which then react with amines (7) to give amides (8), even in the presence of hydroxy-groups, and in aqueous-

or alcoholic solvents.

1

Scheme 1. (a) Triazine-based dehydrative condensation reagents and (b) their use for amide-forming

reactions.

It was determined that substituents on the triazine ring (R¹in the Scheme 1) are important in terms of reagent

reactivity. For example, amido- and imido-substituents, which are more electron-withdrawing than methoxy

groups

of

2-chloro-4,6-dimethoxy-1,3,5-triazine

(1a:

CDMT)

or

4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (2a: DMT-MM), have been examined

based on the idea that the π-electron deficiency of the triazine ring is the driving force of the condensation

reactions [4,5]. Indeed, amido- and imido-substituted triazines (1b–1c and 2b–2c, respectively) achieved

better yields or shorter reaction times than previously reported triazine-based reagents in some cases. For the

introduction of such substituents on the triazine ring, oxygen (e.g. methoxy group) or nitrogen (e.g. amino-,

amido- and imido-substituents) atoms were used previously. It is unambiguous that significant triazine

reactivity is affected by competing electron-withdrawing inductive effects and electron-donating resonance

effects of such oxygen and nitrogen atoms (Table 1a). Hence, the large resonance effect of amino groups

decreases their reactivity (1d) [6], while the weakly electron-withdrawing methoxy substituent furnishes

suitable electrophilicity in the triazines (1a). Therefore, we were interested in carbon-substituents that bring

small inductive and resonance effects, as they would presumably lead to comparable electron-withdrawing

effects in the triazines, based on the Hammett substituent constant σ_m[7] (Table 1).

2

Table 1. (a) Inductive and resonance effects affecting the electrophilicity of triazines, (b) Carbon-substituents

and their Hammett substituent constants.

Furthermore, in contrast to oxygen and nitrogen atoms there are no electron lone pairs on carbon, allowing

for facile introduction of bulky substituents on the triazine ring for selective reactions. Specifically,

α-substituted aryl groups, such as 2,6-di-substituted phenyls might be effective as they are close to the

reaction site of the triazine ring.

In addition, triazine containing oxygen- or nitrogen-substituents would be involved in decompositions or

side-reactions under acidic or basic conditions, e.g. dealkylation of alkoxy-substituents on triazines under

acidic conditions [8] and aromatic nucleophilic substitution reactions of an alkoxy-group on the triazine ring

under basic conditions [4] have been reported. In this context, carbon-substituents would presumably be more

stable under such reaction conditions.

Herein, we present chlorotriazines and their ammonium salts bearing carbon-substituents for dehydrative

condensation reactions.

2. Results and Discussion

Owing to a simplified comparison of reactivity, replacement of only one methoxy group of CDMT (1a) by

corresponding carbon-substituents was considered (1e–1k in Figure 1). They were prepared by reactions of

cyanuric chloride with Grignard reagents or organolithium reagents, followed by sodium methoxide.

Carbon-substituents utilized were methyl, ethyl, tert-butyl (sp³hybridization), and phenyl, o-tolyl,

2,6-dimethylphenyl (sp²hybridization), and 1-octyn-1-yl groups (sp hybridization).

3

Figure 1. Chlorotriazines that have methoxy and carbon-substituents.

Dehydrative condensation reactions with 3-phenylpropionic acid (5a) and phenetylamine (7A) in MeOH

or THF were performed using condensation reagents generated in situ from chlorotriazines (1e–1k) and NMM

[9] (Table 2, entries 2–8). Amide (8aA) yields were determined by quantitative NMR with an internal standard

after three hours of reaction time. The NMR spectra were consistent with previously reported values (8aA, 9a,

10) [3], or with those of authentic samples prepared in this study (9e–9k). The yields (82–95% in MeOH and

64–82% in THF) were comparable and, in some cases, superior to reactions with CDMT (Table 2, entry 1). It

was revealed that the amide-forming reactions with triazines bearing carbon-substituents proceed smoothly

even in the absence of oxygen- or nitrogen-containing subsutituents. It is noteworthy 1j, containing a

2,6-dimethylphenyl group, afforded the highest yields of amide product as well as decreased formation of

side-product 10 (Table 2, entry 7).

4

Table 2. Amide-forming reactions using chlorotriazines (1) bearing carbon-substituents.

The formation of the side-product 9 was more prevalent in THF (Table 2), probably because in less polar

THF, the amine 7A exists predominantly in the unionized form, thus its lone pair of electrons can react with 1

[10]. As we know that chlorotriazines are generally more susceptible to attack by amines than

triazinylammonium salts, we first prepared triazinylammonium salts with perchlorate anion (11) [11] (Yields

for the preparation of 11 are indicated in Table 3a).

Using ammonium salts (11), amide-forming reactions between carboxylic acid 5a and amine 7A in a

mixture of polar solvents MeOH and CH₃CN (1:1) proceeded smoothly (Table 3b, entries 1, 3, 5, 7, and 9). In

THF as a representative solvent of less polarity, longer reaction times were necessary for ammonium salts 11a

and 11j because of problematic solubilities (Table 3b, entries 2 and 8). However, in all the cases, formation of

the side-product 10 was decreased as expected. The results demonstrate the practical utility of these

ammonium salts.

5

Table 3. Amide-forming reactions using ammonium salts (11).

Moreover, in order to probe the effect of carbon-substituents further, chlorotriazines bearing two

carbon-substituents (12g–12k shown in Figure 2) were prepared from cyanuric chloride and Grignard reagents

or organolithium reagents, and were tested for in situ amidation (Table 4b, entries 1–5). Although low yields

were observed due to poor solubility in two cases (Table 4b, MeOH of entry 1 and THF of entry 2), good

yields of the amide 8aA were generally obtained. Interestingly, in the case of the triazine 12j disubstituted

with 2,6-dimethylphenyl, the amide was once more the highest among the triazine derivatives utilized (Table

4b, entry 4).

12g: R¹= ^tBu

R¹

12h: R¹=

Ph

N

12i: R¹=

12j: R¹=

N

Cl

oꢀtolyl

N

2,6ꢀMe₂C₆H₃

R¹

12k: R¹=

C₆H₁₃

Figure 2. Chlorotriazines that have two carbon-substituents.

6

Table 4. Amide-forming reactions using chlorotriazines (12) or triazinylammonium salt (13j) bearing two

carbon-substituents.

Next, we explored amide-forming reactions with several sterically-hindered carboxylic acids (5b–5c) and

amines (7B–7C) (Table 5). When a combination of pivalic acid (5b) and phenethylamine (7A) was utilized as

starting materials (Table 5, entries 1–6), we found a significant improvement in the yield of the amide (8bA)

for 1j and 9j along with the decrease in the formation of side-products 9 or 14 (Table 5, entries 4 and 6 vs.

entries 1–3 and 5). A similar trend was observed for amide 8bB (Table 5, entries 8 and 10 vs. 7 and 9) and

8cC (Table 5, entries 14 vs. 11–13).

7

Table 5. Amide-forming reactions using several carboxylic acids (5) and amines (7).

Sideꢀproducts

R¹

1 or 12 (1.1 eq.)

NMM (1.2 eq.)

Amines 7

(1.1 eq.)

N

R¹

N

Carboxylic acids 5

N

or

ⁱPr

Amides 8

9, 14,

+

ⁱPr

(1.0 eq.)

THF, rt, time

N

MeO

N

15

N

H

16

yield^a(%)

sideꢀproducts^c

carboxylic

acid 5

time

(h)

entry

1

amine 7

amide 8

chlorotriazine 1 or 12

8^b

O

Ph

1f: R¹=

^tBu

N

H

8bA

9f: 23

7A

3

66

^tBu OH

Et

5b

1h: R¹= Ph

9h: 28

9i: 25

9j: 23

9k: 24

14j: 20

2

3

4

5

6

5b

7A

8bA

3

56

68

76

59

81

1i: R¹=

oꢀtolyl

1j: R¹=

2,6ꢀMe₂C₆H₃

C₆H₁₃

1k: R¹=

8bA

9j: R¹= 2,6ꢀMe₂C₆H₃

O

ⁱPr

^tBu

N

7

5b

1a: R¹=

14

69

15a: 6

OMe

H₂N

H

7B

8bB

8

9

5b

7B

8bB

1j: R¹=

14

80

77

85

15j: 7

15k: 9

16j: 5

d

2,6ꢀMe₂C₆H₃

1k: R¹=

C₆H₁₃

7B

10

5b

8bB

9j: R¹=

2,6ꢀMe₂C₆H₃

O

1a: R¹=

20

69

Et₂NH

7C

11

OMe

ⁱPr NEt₂

8cC

ⁱPr OH

5c

1h: R¹=

d

Ph

12

13

14

5c

7C

8cC

14

16

20

52

59

85

1k: R¹=

C₆H₁₃

9j: R¹=

2,6ꢀMe₂C₆H₃

^aBased on ¹H NMR. ^bThe yields were calculated based on 5. ^cThe yields were calculated based on 7.

^dNot determined.

In order to elucidate the significant effect of the 2,6-dimethylphenyl group, we obtained X-ray single

crystal structures of 1h–1j (Figures 3–5). Although the phenyl group of 1h is almost planar to the triazine ring

(average dihedral angle 0.37°), the o-tolyl group of 1i (average dihedral angle 9.37°) and 2,6-dimethylphenyl

group of 1j (average dihedral angle 49.44°) are twisted in relation to the triazine ring. One would expect that

this distortion electronically and/or sterically affects the reactivity of the triazines. From the view point of

electronic effect, it could be assumed that the resonance between the triazine and the 2,6-dimethylphenyl

group is inhibited by the non-aligned orientation between the two groups. This would lead to a reduction in

8

the electron-donating resonance effect, whilst the electron-withdrawing inductive effect by the sp²-hybridized

carbon would be retained, resulting in enhanced triazine electrophilicity. Therefore, as a means of ascertaining

the electrophilicities, we investigated the kinetics of model reactions of chlorotriazines 1 with various amines,

by using UV absorption spectroscopy.

(a) Top view

(b) Side view

Figure 3. ORTEP drawing (50% probability ellipsoids) of 1h. CCDC No. 1940180.

(a) Top view

(b) Side view

Figure 4. ORTEP drawing (50% probability ellipsoids) of 1i. CCDC No. 1940181.

9

(a) Top view

(b) Side view

Figure 5. ORTEP drawing (50% probability ellipsoids) of 1j. CCDC No. 1940182.

10

Table 6. Kinetic study of model reactions of chlorotriazines 1 with various amines.

The UV spectra of chlorotriazine (1) were changed to that of amino-substituted triazines (17) upon the

addition of morpholine as a nucleophile at 10 °C (Figures S1–S5 in the Supporting Information). Although a

slight increase in the reactivity of the 2,6-dimethylphenyl group was observed, the second-order rate constants

were chiefly dependent on the hybridization of carbon substituents (Table 6, entries 1–5) [12]. Using other

amines such as isopropylamine and n-butylamine, similar results were obtained (Table 6, entries 6–11).

11

2

1.5

1

1h

1i

1j

0.5

0

200

220

240

260

280

300

320

340

Wavelength (nm)

Figure 6. UV spectra of 1h (Ph), 1i (o-tolyl), and 1j (2,6-dimethylphenyl) at 0.1 mM in acetonitrile.

Owing to the torsion of 2,6-dimethylphenyl group of 1j even in solution, maximum absorption wavelength of

1j (259 nm) was blue-shifted compared to 1h (265 nm) and 1i (263 nm) (Figure 6), and the molar absorption

coefficient of 1j (ε_max= 5088 M^–1·cm^–1) was the smaller than that of 1h (ε_max= 20506 M^–1·cm^–1) and 1i (ε_max

=

14890 M^–1·cm^–1), as can be expected [13–17]. Therefore, presumably the better efficiency associated with the

2,6-dimethylphenyl group is attributed to the slight increase in electrophilicity and/or steric effects that enable

selective reactions.

3. Conclusion

Chlorotriazines bearing alkyl, aryl, or alkynyl substituents, as well as their ammonium salts were

developed for amide-forming reactions. The electrophilicity of triazines was mainly dependent on the

hybridization of carbon-substituents. It was found that 2,6-dimethylphenyl-substituted triazines afforded the

highest yields of amides among the alkyl, aryl, and alkynyl substituted triazines. It was concluded that this

efficiency of the 2,6-dimethylphenyl group was due to a slight increase in electrophilicity and/or steric effects

for the desired reactions.

4. Experimental

4.1 General

1

Chemical shifts for H NMR spectra are reported as δ values relative to tetramethylsilane as an internal

standard for chloroform-d and acetonitrile-d3. Coupling constants are in hertz (Hz). The following

abbreviations are used for spin multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and

br = broad. NMR yields were determined by quantitative NMR spectroscopy using coumarin,

12

6-methylcoumarin, or 1,3,5-trimethoxybenzene as internal standards. Chemical shifts for ¹³C NMR are

reported as δ values relative to the center lines of the signals at 77.16 ppm corresponding to chloroform-d, or

118.26 ppm corresponding to acetonitrile-d3. Flash chromatography separations were performed on KANTO

CHEMICAL Silica Gel 60 N (spherical, neutral, 40–100 mesh). All reactions sensitive to oxygen or moisture

were conducted under a nitrogen atmosphere. The NMR spectra of 8aA [3], 8bA [5], 8bB [5], 8cC [18], 9a

[3], 10 [19] were consistent with reported data. The CCDC 1940180–1940182 contains the supplementary

crystallographic data for 1h, 1i, and 1j. These data can be obtained free of charge from The Cambridge

Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.

4.2.1. Typical procedure for synthesis of chlorotriazines (1): 2-chloro-4-methoxy-6-phenyl-1,3,5-triazine

(1h) [20]

To a benzene solution (250 mL) of cyanuric chloride (4.057 g, 22.0 mmol), a THF/ether (1:1) solution of

phenylmagnesium bromide (30.6 mL, 22.0 mmol, 0.72 M) was added dropwise under a N₂atmosphere at –

30 °C. After stirring for 3 h, the reaction mixture was quenched with 1 M HCl_aq, and the mixture was

extracted with AcOEt. The organic phase was washed with 1 M HCl_aqand water, dried over anhydrous sodium

sulfate, filtered, and concentrated under reduced pressure. 2,4-Dichloro-6-phenyl-1,3,5-triazine [21] was

obtained by recrystallization from CHCl₃and hexane as pale yellow needles (4.038 g, 81% yield).

To a THF solution (20 mL) of 2,4-dichloro-6-phenyl-1,3,5-triazine (791 mg, 3.75 mmol), a THF solution

(1.0 mL) of sodium methoxide generated from MeOH (142 ꢁL, 3.75 mmol) and sodium hydride (60%, 140

mg, 3.75 mmol) was added dropwise at –30 °C. After stirring for 10 h, the reaction mixture was quenched

with 1 M HCl_aq, and extracted with CH₂Cl₂. The organic phase was washed with water, dried over anhydrous

sodium sulfate, filtered, and concentrated under reduced pressure. The title compound (575 mg, 74% yield)

was obtained by flash column chromatography (hexane/AcOEt = 9:1) as a white solid. M.p. 72.8–73.6 °C; ¹H

NMR (400 MHz, CDCl₃/TMS): δ 8.50 (dd, J = 7.8, 1.5 Hz, 2H), 7.62 (tt, J = 7.8, 1.5 Hz, 1H), 7.51 (td, J = 7.8,

1.5 Hz, 2H), 4.17 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 175.06, 172.62, 171.82, 133.97, 133.84, 129.54,

128.89, 56.09; IR (KBr): 3008, 2949, 1558, 1541, 1516, 1487, 1406, 1363, 1313, 1269, 1045, 1022, 914, 837,

822, 781, 712, 690, 665 cm^–1; Anal. Calcd for C₁₀H₈ClN₃O: C, 54.19; H, 3.64; N, 18.96. Found: C, 53.96; H,

3.74; N, 18.90. Crystals suitable for X-ray single crystal structure analysis were obtained from a hexane

solution.

4.2.2. 2-Chloro-4-methoxy-6-methyl-1,3,5-triazine (1e) [22]

The title compound was synthesized in a similar manner to 1h using THF as a solvent. The crude product

was purified by flash column chromatography (hexane/AcOEt = 50:1 to 9:1) to afford the title compound as a

white solid (530 mg, 33% yield over 2 steps). M.p. 62.0–62.9 °C; ¹H NMR (400 MHz, CDCl₃/TMS): δ 4.09 (s,

3H), 2.60 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 180.69, 172.04, 171.36, 56.06, 25.50; IR (KBr): 3016, 2951,

1570, 1529, 1487, 1381, 1281, 1201, 1169, 1072, 960, 874, 808, 580 cm^–1; HRMS (DART) m/z: [M + H]⁺

13

Calcd for C₅H₇ClN₃O 160.0278; Found: 160.0255; Anal. Calcd for C₅H₆ClN₃O: C, 37.63; H, 3.79; N, 26.33.

Found: C, 37.33; H, 3.80; N, 26.16.

4.2.3. 2-Chloro-4-ethyl-6-methoxy-1,3,5-triazine (1f) [23]

The title compound was synthesized in a similar manner to 1h using THF as a solvent. The crude product

was purified by flash column chromatography (hexane/AcOEt = 20:1) to afford the title compound as a white

solid (994 mg, 38% yield over 2 steps). M.p. 34.9–36.1 °C; ¹H NMR (400 MHz, CDCl₃/TMS): δ 4.09 (s, 3H),

13

2.85 (q, J = 7.6 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H); C NMR (100 MHz, CDCl₃): δ 184.78, 172.10, 171.50,

56.03, 32.08, 11.43; IR (film): 2981, 2943, 2883, 1558, 1525, 1489, 1377, 1317, 1284, 1194, 1167, 1084, 1059,

995, 924, 872, 823 cm^–1; HRMS (DART) m/z: [M + H]⁺Calcd for C₆H₉ClN₃O 174.0434; Found: 174.0457;

Anal. Calcd for C₆H₈ClN₃O: C, 41.51; H, 4.65; N, 24.21. Found: C, 41.34; H, 4.66; N, 24.00.

4.2.4. 2-tert-Butyl-4-chloro-6-methoxy-1,3,5-triazine (1g) [24]

The title compound was synthesized in a similar manner to 1h using THF as a solvent and copper iodide

as a catalyst. The crude product was purified by flash column chromatography (hexane/AcOEt = 50:1) to

afford the title compound as a white solid (2.43 g, 71% yield over 2 steps). ¹H NMR (400 MHz, CDCl₃/TMS):

13

δ 4.09 (s, 3H), 1.37 (s, 9H); C NMR (100 MHz, CDCl₃): δ 190.28, 172.15, 171.44, 55.89, 39.92, 28.72; IR

(CHCl₃): 2966, 2937, 2904, 2870, 1558, 1550, 1518, 1475, 1385, 1369, 1356, 1286, 1188, 1163, 1066, 937,

924, 889, 875, 829 cm^–1; HRMS (DART) m/z: [M + H]⁺Calcd for C₈H₁₃ClN₃O 202.0747; Found: 202.0767;

Anal. Calcd for C₈H₁₂ClN₃O: C, 47.65; H, 6.00; N, 20.84. Found: C, 47.79; H, 6.07; N, 20.75.

4.2.5. 2-Chloro-4-methoxy-6-(o-tolyl)-1,3,5-triazine (1i)

The title compound was synthesized in a similar manner to 1h using THF as a solvent. The crude product

was purified by flash column chromatography (hexane/AcOEt = 9:1) to afford the title compound as a white

solid (753 mg, 45% yield over 2 steps). M.p. 69.0–70.7 °C; ¹H NMR (400 MHz, CDCl₃/TMS): δ 8.15 (dd, J =

8.0, 1.3 Hz, 1H), 7.44 (td, J = 7.6, 1.3 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.3 Hz, 1H), 4.15 (s, 3H),

2.70 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 177.44, 172.08, 171.43, 139.81, 133.75, 132.23, 131.62, 126.30,

56.15, 22.46; IR (KBr): 2974, 2931, 1545, 1508, 1489, 1362, 1306, 1254, 1184, 1045, 854, 785, 648 cm^–1;

HRMS (DART) m/z: [M + H]⁺Calcd for C₁₁H₁₁ClN₃O 236.0591; Found: 236.0597; Anal. Calcd for

C₁₁H₁₀ClN₃O: C, 56.06; H, 4.28; N, 17.83. Found: C, 56.04; H, 4.27; N, 17.77. Crystals suitable for X-ray

single crystal structure analysis were obtained from a hexane solution.

4.2.6. 2-Chloro-4-(2,6-dimethylphenyl)-6-methoxy-1,3,5-triazine (1j)

The title compound was synthesized in a similar manner to 1h using THF as a solvent. The crude product

14

was purified by flash column chromatography (hexane/AcOEt = 20:1) to afford the title compound as a white

1

solid (2.86 g, 58% yield over 2 steps). M.p. 57.1–58.1 °C; H NMR (400 MHz, CDCl₃/TMS): δ 7.25 (t, J =

7.8 Hz, 1H), 7.11 (d, J = 7.8 Hz, 2H), 4.14 (s, 3H), 2.20 (s, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 179.69,

172.49, 171.64, 135.82, 135.59, 129.74, 128.14, 56.36, 20.13; IR (CHCl₃): 3025, 2954, 2927, 1539, 1516,

1444, 1387, 1363, 1269, 1047, 847, 827, 773 cm^–1; HRMS (DART) m/z: [M + H]⁺Calcd for C₁₂H₁₃ClN₃O

250.0747; Found: 250.0731; Anal. Calcd for C₁₂H₁₂ClN₃O: C, 57.72; H, 4.84; N, 16.83. Found: C, 57.34; H,

4.82; N, 16.70. Crystals suitable for X-ray single crystal structure analysis were obtained from a hexane

solution.

4.2.7. 2-Chloro-4-methoxy-6-(1-octyn-1-yl)-1,3,5-triazine (1k)

The title compound was synthesized in a similar manner to 1h using THF as a solvent. The crude product

was purified by flash column chromatography (hexane/AcOEt = 50:1) to afford the title compound as a white

1

solid (1.25 g, 76% yield over 2 steps). H NMR (400 MHz, CDCl₃/TMS): δ 4.09 (s, 3H), 2.48 (t, J = 7.3 Hz,

2H), 1.65 (quintet, J = 7.3 Hz, 2H), 1.44 (quintet, J = 7.4 Hz, 2H), 1.37–1.25 (m, 4H), 0.90 (t, J = 6.9 Hz, 3H);

¹³C NMR (100 MHz, CDCl₃): δ 172.25, 171.34, 162.60, 98.20, 78.44, 56.38, 31.37, 28.79, 27.75, 22.61, 19.65,

14.17; IR (film): 2954, 2931, 2870, 2860, 2241, 1533, 1508, 1477, 1456, 1408, 1367, 1273, 1169, 1038, 922,

816 cm^–1; HRMS (DART) m/z: [M + H]⁺Calcd for C₁₂H₁₇ClN₃O 254.1060; Found: 254.1087; Anal. Calcd for

C₁₂H₁₆ClN₃O: C, 56.81; H, 6.36; N, 16.56. Found: C, 56.68; H, 6.42; N, 16.58.

4.3.1.

Typical

procedure

for

synthesis

of

amino-substituted

triazines

(9):

2-methoxy-4-methyl-6-(phenetylamino)-1,3,5-triazine (9e)

To a CH₂Cl₂solution (1.5 mL) of 1e (48 mg, 0.30 mmol), phenethylamine (78 µL, 0.63 mmol) was added

at rt. After stirring overnight, the reaction mixture was quenched with 0.5 M HCl_aq, extracted with CH₂Cl₂,

dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was

purified using preparative TLC (hexane/AcOEt = 4:1) to afford the title compound (56 mg, 77% yield) as a

1

white solid. H NMR (400 MHz, CDCl₃/TMS): δ 7.30 (t, J = 7.1 Hz, 2H), 7.24–7.20 (m, 3H), 5.64 (s, 0.7H,

major), 5.41 (s, 0.3H, minor), 3.97 (s, 2.1H, major), 3.88 (s, 0.9H, minor), 3.71 (q, J = 6.9 Hz, 2H), 2.90 (t, J =

6.9 Hz, 2H), 2.41 (s, 0.9H, minor), 2.32 (s, 2.1H, major); ¹³C NMR (100 MHz, CDCl₃): δ 178.39, 177.48,

171.29, 170.84, 167.26, 167.19, 138.74, 128.89, 128.81, 126.72, 54.43, 54.32, 42.26, 42.11, 35.83, 35.68,

25.75, 25.32; IR (film): 3263, 3141, 3026, 2945, 1576, 1473, 1369, 1346, 1228, 1201, 1149, 1103, 816, 748,

700 cm^–1; HRMS (DART) m/z: [M + H]⁺Calcd for C₁₃H₁₇N₄O 245.1402; Found: 245.1392.

4.3.2. 2-Ethyl-4-methoxy-6-(phenetylamino)-1,3,5-triazine (9f)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by flash

column chromatography (CHCl₃) and preparative TLC (hexane/AcOEt = 4:1) to afford the title compound as

15

a white solid (56 mg, 72% yield). ¹H NMR (400 MHz, CDCl₃/TMS): δ 7.31 (t, J = 7.3 Hz, 2H), 7.25–7.21 (m,

3H), 5.43 (br s, 0.7H, major), 5.28 (br s, 0.3H, minor), 3.98 (s, 2.1H, major), 3.89 (s, 0.9H, minor), 3.72 (q, J

= 6.8 Hz, 2H), 2.91 (t, J = 6.8 Hz, 2H), 2.66 (q, J = 7.4 Hz, 0.6H, minor), 2.57 (q, J = 7.6 Hz, 1.4H, major),

13

1.29 (t, J = 7.4 Hz, 0.9H, minor), 1.25 (t, J = 7.6 Hz, 2.1H, major); C NMR (100 MHz, CDCl₃): δ 181.60,

171.40, 167.37, 138.93, 138.78, 128.95, 128.90, 128.81, 126.72, 126.67, 54.40, 54.28, 42.36, 42.16, 35.88,

35.69, 32.15, 31.93, 11.71, 11.59; IR (film): 3261, 3141, 3026, 2939, 1576, 1473, 1369, 1352, 1308, 1220,

1201, 1066, 825, 748, 700 cm^–1; Anal. Calcd for C₁₄H₁₈N₄O: C, 65.09; H, 7.02; N, 21.69. Found: C, 65.03; H,

6.98; N, 21.62.

4.3.3. 2-tert-Butyl-4-methoxy-6-(phenetylamino)-1,3,5-triazine (9g)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

1

preparative TLC (hexane/AcOEt = 9:1) to afford the title compound as a white solid (78 mg, 91% yield). H

NMR (400 MHz, CDCl₃/TMS): δ 7.34–7.30 (m, 2H), 7.25–7.22 (m, 3H), 5.40 (br s, 0.55H, major), 5.35 (br s,

0.45H, minor), 3.97 (s, 1.65H), 3.89 (s, 1.35H), 3.74–3.68 (m, 2H), 2.91 (t, J = 7.1 Hz, 2H), 1.33 (s, 4.05H),

1.27 (s, 4.95H); ¹³C NMR (100 MHz, CDCl₃): δ 187.59, 186.94, 171.42, 171.10, 167.62, 167.36, 139.11,

138.95, 128.95, 128.91, 128.76, 126.65, 126.60, 54.25, 54.17, 42.57, 42.23, 39.22, 38.87, 35.97, 35.77, 28.86,

28.81; IR (film): 3263, 3145, 2978, 1618, 1577, 1531, 1458, 1369, 1348, 1250, 1196, 1147, 831, 752, 700 cm^–

¹; Anal. Calcd for C₁₆H₂₂N₄O: C, 67.11; H, 7.74; N, 19.56. Found: C, 67.08; H, 7.54; N, 19.58.

4.3.4. 2-Methoxy-4-(phenetylamino)-6-phenyl-1,3,5-triazine (9h)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by flash

1

column chromatography (CHCl₃) to afford the title compound as a white solid (87 mg, 94% yield). H NMR

(400 MHz, CDCl₃/TMS): δ 8.49 (d, J = 7.3 Hz, 0.9H, minor), 8.36 (d, J = 6.9 Hz, 1.1H, major), 7.54–7.43 (m,

3H), 7.34–7.29 (m, 2H), 7.25–7.20 (m, 3H), 5.80 (br s, 0.55H, major), 5.60 (br s, 0.45H, minor), 4.07 (s,

1.65H, major), 4.00 (s, 1.35H, minor), 3.84 (q, J = 7.2 Hz, 0.9H, minor), 3.74 (q, J = 6.9 Hz, 1.1H, major),

13

2.96 (t, J = 7.2 Hz, 0.9H, minor), 2.92 (t, J = 6.9 Hz, 1.1H, major); C NMR (100 MHz, CDCl₃): δ 173.14,

172.76, 171.82, 171.42, 167.77, 167.58, 138.95, 138.85, 136.32, 136.13, 132.16, 132.03, 128.95, 128.91,

128.85, 128.78, 128.62, 128.45, 128.42, 126.66, 54.57, 54.48, 42.56, 42.26, 35.90, 35.69; Anal. Calcd for

C₁₈H₁₈N₄O: C, 70.57; H, 5.92; N, 18.29. Found: C, 70.52; H, 5.99; N, 18.26.

4.3.5. 2-Methoxy-4-(phenetylamino)-6-o-tolyl-1,3,5-triazine (9i)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by flash

column chromatography (CHCl₃) to afford the title compound as a white solid (98 mg, quant.). ¹H NMR (400

MHz, CDCl₃/TMS): δ 8.05 (d, J = 7.8 Hz, 0.45H, minor), 7.79 (d, J = 7.8 Hz, 0.55H, major), 7.39–7.19 (m,

8H), 5.91 (t, J = 6.0 Hz, 0.55H, major), 5.61 (t, J = 6.6 Hz, 0.45H, minor), 4.04 (s, 1.65H, major), 3.98 (s,

1.35H, minor), 3.76 (q, J = 6.9 Hz, 0.9H), 3.71 (q, J = 6.7 Hz, 1.1H), 2.92–2.88 (m, 2H), 2.69 (s, 1.35H,

16

minor), 2.57 (s, 1.65H, major); ¹³C NMR (100 MHz, CDCl₃): δ 175.99, 175.82, 171.38, 170.99, 167.36,

167.28, 138.89, 138.85, 138.57, 137.75, 136.63, 136.40, 131.72, 131.49, 130.79, 130.59, 130.30, 130.08,

128.93, 128.77, 128.74, 126.65, 125.92, 54.67, 54.53, 42.47, 42.19, 36.03, 35.64, 22.32, 21.38; Anal. Calcd

for C₁₉H₂₀N₄O: C, 71.23; H, 6.29; N, 17.49. Found: C, 71.20; H, 6.33; N, 17.31.

4.3.6. 2-(2,6-Dimethylphenyl)-4-methoxy-6-(phenetylamino)-1,3,5-triazine (9j)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by flash

column chromatography (CHCl₃) and preparative TLC (hexane/AcOEt = 9:1) to afford the title compound as

a white solid (81 mg, 81% yield). ¹H NMR (400 MHz, CDCl₃/TMS): δ 7.30–7.25 (m, 2H), 7.23–7.13 (m, 4H),

7.09–7.04 (m, 2H), 6.63 (br s, 0.7H, major), 5.90 (br s, 0.3H, minor), 3.99 (s, 2.1H, major), 3.93 (s, 0.9H,

minor), 3.61 (q, J = 6.9 Hz, 0.6H, minor), 3.51 (q, J = 6.9 Hz, 1.4H, major), 2.80 (t, J = 6.9 Hz, 2H), 2.23 (s,

13

1.8H, minor), 2.19 (s, 4.2H, major); C NMR (100 MHz, CDCl₃): δ 177.53, 176.82, 171.44, 170.91, 167.34,

138.83, 138.79, 138.19, 137.78, 135.26, 134.97, 128.92, 128.69, 128.66, 128.58, 127.82, 126.60, 54.72, 54.64,

42.17, 41.93, 35.91, 35.58, 20.07, 19.77; IR (film): 3253, 3126, 3062, 3026, 2937, 2862, 1610, 1599, 1558,

1473, 1456, 1412, 1367, 1348, 1230, 1207, 1124, 1032, 831, 771, 750, 700 cm^–1; HRMS (DART) m/z: [M +

H]⁺Calcd for C₂₀H₂₃N₄O 335.1872; Found: 335.1886.

4.3.7. 2-Methoxy-4-(1-octyn-1-yl)-6-(phenetylamino)-1,3,5-triazine (9k)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by flash

column chromatography (CHCl₃) and preparative TLC (hexane/AcOEt = 9:1) to afford the title compound as

a white solid (90 mg, 88% yield). ¹H NMR (400 MHz, CDCl₃/TMS): δ 7.33–7.28 (m, 2H), 7.24–7.19 (m, 3H),

5.64 (br s, 0.7H, major), 5.42 (br s, 0.3H, minor), 3.98 (s, 2.1H, major), 3.90 (s, 0.9H, minor), 3.76 (q, J = 6.6

Hz, 0.6H, minor), 3.72 (q, J = 6.6 Hz, 1.4H, major), 2.89 (t, J = 6.9 Hz, 2H), 2.44 (t, J = 7.3 Hz, 0.6H, minor),

2.40 (t, J = 7.1 Hz, 1.4H, major), 1.67–1.57 (m, 2H), 1.48–1.37 (m, 2H), 1.32–1.25 (m, 4H), 0.88 (t, J = 6.9

Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 171.21, 166.84, 160.96, 138.61, 138.51, 128.94, 128.89, 128.85,

128.82, 126.80, 126.75, 92.27, 78.92, 54.84, 54.71, 42.25, 42.08, 35.68, 35.49, 31.41, 28.82, 27.99, 22.61,

19.58, 19.42, 14.17; IR (film): 3255, 3128, 3025, 2952, 2931, 2240, 1614, 1541, 1473, 1363, 1348, 1234, 820,

700 cm^–1; Anal. Calcd for C₂₀H₂₆N₄O: C, 70.98; H, 7.74; N, 16.55. Found: C, 70.71; H, 7.74; N, 16.39.

4.4.1.

Representative

procedure

for

synthesis

of

ammonium

salts

11:

4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium perchlorate (11a)

To a THF solution (20 mL) of CDMT (878 mg, 5.0 mmol) and LiClO₄(585 mg, 5.5 mmol), NMM (605

µL, 5.5 mmol) was added dropwise under a N₂atmosphere at rt. After stirring for 30 min, the solvent was

removed by decantation and the residue was washed with THF. Repetition of this washing process afforded

the title compound (1.57 g, 92% yield) as a white solid. ¹H NMR (400 MHz, CD₃CN/TMS): δ 4.46 (d, J = 9.6

17

Hz, 2H), 4.13 (s, 6H), 4.04–3.98 (m, 2H), 3.79–3.70 (m, 4H), 3.41 (s, 3H); ¹³C NMR (100 MHz, CD₃CN):

– +

174.99, 171.20, 62.76, 61.09, 57.82, 56.94; HRMS (DART) m/z: [M – ClO₄] Calcd for C₁₀H₁₇N₄O₃

241.1301; Found: 241.1246.

4.4.2. 4-(4-Ethyl-6-methoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium perchlorate (11f)

The title compound was synthesized in a similar manner to 11a except reaction time (1.5 h), and it was a

1

yellow solid (63 mg, 94% yield). H NMR (400 MHz, CD₃CN/TMS): δ 4.51 (dd, J = 11.2, 1.6 Hz, 2H), 4.14

(s, 3H), 4.01 (dd, J = 10.3, 2.5 Hz, 2H), 3.79–3.69 (m, 4H), 3.40 (s, 3H), 2.95 (q, J = 7.6 Hz, 2H), 1.34 (t, J =

7.6 Hz, 3H); ¹³C NMR (100 MHz, CD₃CN): δ 187.77, 173.67, 169.96, 62.65, 60.94, 57.58, 56.91, 32.72,

– +

10.96; HRMS (ESI) m/z: [M – ClO₄] Calcd for C₁₁H₁₉N₄O₂254.1060; Found: 254.1087.

4.4.3. 4-(4-Methoxy-6-phenyl-1,3,5-triazin-2-yl)-4-methylmorpholinium perchlorate (11h)

The title compound was synthesized in a similar manner to 11a except reaction time (1 h), and it was a

1

white solid (331 mg, 86% yield). H NMR (400 MHz, CD₃CN/TMS): δ 8.56 (d, J = 7.6 Hz, 2H), 7.76 (t, J =

7.8 Hz, 1H), 7.63 (t, J = 7.8 Hz, 2H), 4.64 (d, J = 12.8 Hz, 2H), 4.25 (s, 3H), 4.07 (d, J = 9.6 Hz, 2H), 3.86 (t,

J = 11.0 Hz, 2H), 3.80 (t, J = 11.0 Hz, 2H), 3.50 (s, 3H); ¹³C NMR (100 MHz, CD₃CN): δ 177.52, 174.13,

– +

170.66, 135.73, 134.29, 130.55, 130.11, 62.73, 61.06, 57.80, 56.94; HRMS (ESI) m/z: [M – ClO₄] Calcd for

C₁₅H₁₉N₄O₂287.1508; Found: 287.1485.

4.4.4. 4-[4-(2,6-Dimethylphenyl)-6-methoxy-1,3,5-triazin-2-yl]-4-methylmorpholinium perchlorate (11j)

The title compound was synthesized in a similar manner to 11a except reaction time (1 h), and it was a

1

white solid (77 mg, 92% yield). H NMR (400 MHz, CD₃CN/TMS): δ 7.35 (t, J = 7.6 Hz, 1H), 7.21 (d, J =

7.8 Hz, 2H), 4.51 (dd, J = 9.6, 3.2 Hz, 2H), 4.21 (s, 3H), 4.06 (dd, J = 9.4, 4.0 Hz, 2H), 3.82 (t, J = 9.8 Hz,

2H), 3.79 (t, J = 9.6 Hz, 2H), 3.47 (s, 3H), 2.26 (s, 6H); ¹³C NMR (100 MHz, CD₃CN): δ 181.62, 173.86,

– +

170.56, 137.55, 135.87, 131.37, 129.29, 62.66, 61.07, 58.01, 56.52, 20.49; HRMS (ESI) m/z: [M – ClO₄]

Calcd for C₁₇H₂₃N₄O₂315.1821; Found: 315.1803; Anal. Calcd for C₁₇H₂₃ClN₄O₆: C, 49.22; H, 5.59; N, 13.51.

Found: C, 49.13; H, 5.53; N, 13.61.

4.4.5. 4-[4-Methoxy-6-(1-octyn-1-yl)-1,3,5-triazin-2-yl]-4-methylmorpholinium perchlorate (11k)

The title compound was synthesized in a similar manner to 11a except reaction time (1.5 h), and it was a

1

pale pink solid (260 mg, 85% yield). H NMR (400 MHz, CD₃CN/TMS): δ 4.46–4.42 (m, 2H), 4.42 (s, 3H),

4.05–4.01 (m, 2H), 3.84–3.72 (m, 4H), 3.44 (s, 3H), 2.58 (t, J = 7.1 Hz, 2H), 1.69–1.62 (m, 2H), 1.50–1.42 (m,

2H), 1.38–1.30 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, CD₃CN): δ 173.69, 170.46, 164.48,

100.91, 79.20, 62.59, 61.11, 58.08, 56.75, 31.86, 29.24, 28.25, 23.15, 19.83, 14.30; HRMS (ESI) m/z: [M –

18

– +

ClO₄] Calcd for C₁₇H₂₇N₄O₂319.2134; Found: 319.2092.

4.5.1. Representative procedure for synthesis of chlorotriazines (12): 2-chloro-4,6-diphenyl-1,3,5-triazine

(12h) [25, 26]

To a THF solution (36 mL) of cyanuric chloride (3.32 g, 18.0 mmol), a THF solution of phenylmagnesium

bromide (29.6 mL, 37 mmol, 0.80 M) was added dropwise under a N₂atmosphere at 0 °C. After stirring

overnight at rt, the reaction mixture was quenched with 1 M HCl_aq, and extracted with Et₂O. The combined

organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under

reduced pressure. The crude product was purified by flash column chromatography (hexane/AcOEt = 50:1)

1

and recrystallization from hexane to afford the title compound as colorless needles (2.78 g, 58% yield). H

NMR (400 MHz, CDCl₃/TMS): δ 8.51 (d, J = 8.2 Hz, 4H), 7.67 (t, J = 7.3 Hz, 2H), 7.54 (t, J = 7.6 Hz, 4H);

¹³C NMR (100 MHz, CDCl₃): δ 174.98, 172.20, 134.89, 132.77, 130.08, 129.22: HRMS (DART) m/z: [M +

H]⁺Calcd for C₁₅H₁₁ClN₃268.0642; Found: 268.0661.

4.5.2. 2,4-Di-tert-butyl-6-chloro-1,3,5-triazine (12g) [24, 27]

The title compound was synthesized in a similar manner to 12h using copper iodide as a catalyst. The

crude product was purified by flash column chromatography (hexane) to afford the title compound as a white

solid (2.53 g, 74% yield). ¹H NMR (400 MHz, CDCl₃/TMS): δ 1.37 (s, 18H); ¹³C NMR (100 MHz, CDCl₃): δ

187.82, 171.25, 39.95, 28.89.

4.5.3. 2-Chloro-4,6-di-o-tolyl-1,3,5-triazine (12i)

The title compound was synthesized in a similar manner to 12h. The crude product was purified by

recrystallization from CH₂Cl₂/hexane to afford the title compound as colorless crystals (941 mg, 40% yield).

¹H NMR (400 MHz, CDCl₃/TMS): δ 8.20 (dd, J = 7.8, 1.4 Hz, 2H), 7.46 (td, J = 7.4, 1.5 Hz, 2H), 7.36 (t, J =

13

7.8 Hz, 2H), 7.34 (d, J = 7.3 Hz, 2H), 2.75 (s, 6H); C NMR (100 MHz, CDCl₃): δ 175.68, 171.13, 139.79,

134.33, 132.23, 132.04, 131.74, 126.36, 22.42: HRMS (DART) m/z: [M + H]⁺Calcd for C₁₇H₁₅ClN₃

296.0955; Found: 296.0972.

4.5.4 2-Chloro-4,6-bis(2,6-dimethylphenyl)-1,3,5-triazine (12j)

The title compound was synthesized in a similar manner to 12h. The crude product was purified by flash

column chromatography (hexane/AcOEt = 100 : 1) to afford the title compound as a white solid (1.92 g, 78%

yield). ¹H NMR (400 MHz, CDCl₃/TMS): δ 7.26 (t, J = 7.7 Hz, 2H), 7.12 (d, J = 7.7 Hz, 4H), 2.21 (s, 12H);

¹³C NMR (100 MHz, CDCl₃): δ 178.69, 172.00, 135.95, 135.36, 129.83, 128.11, 20.12: HRMS (DART) m/z:

[M + H]⁺Calcd for C₁₉H₁₉ClN₃324.1268; Found: 324.1239.

19

4.5.5. 2-Chloro-4,6-di(1-octyn-1-yl)-1,3,5-triazine (12k)

The title compound was synthesized in a similar manner to 12h. The crude product was purified by flash

column chromatography (hexane/AcOEt = 200:1 to 100:1) to afford the title compound as a pale orange oil

(229 mg, 15% yield). ¹H NMR (400 MHz, CDCl₃/TMS): δ 2.49 (t, J = 7.1 Hz, 2H), 1.65 (quintet, J = 7.3 Hz,

2H), 1.44 (quintet, J = 7.4 Hz, 2H), 1.37–1.25 (m, 4H), 0.89 (t, J = 7.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃):

δ: 171.27, 161.35, 99.60, 78.38, 31.34, 28.75, 27.68, 22.56, 19.67, 14.11; HRMS (DART) m/z: [M + H]⁺

Calcd for C₁₉H₂₇Cl_zN₃332.1894; Found: 332.1891.

4.6. 4-[4,6-Bis(2,6-dimethylphenyl)-1,3,5-triazin-2-yl]-4-methylmorpholinium perchlorate (13j)

The title compound was synthesized in a similar manner to 11a except reaction time (1 h), and it was a

1

white solid (418 mg, 85% yield). H NMR (400 MHz, CD₃CN/TMS): δ 7.39 (t, J = 7.8 Hz, 2H), 7.25 (d, J =

7.8 Hz, 4H), 4.51–4.45 (m, 2H), 4.17–4.10 (m, 2H), 3.97–3.86 (m, 4H), 3.61 (s, 3H), 2.30 (s, 12H); ¹³C NMR

(100 MHz, CD₃CN): δ 180.53, 170.40, 137.82, 135.68, 131.73, 129.48, 62.43, 61.03, 54.93, 20.78: HRMS

– +

(ESI) m/z: [M – ClO₄] Calcd for C₂₄H₂₉N₄O₁389.2341; Found: 389.2368.

4.7.1. 2,4-Di-tert-butyl-6-(phenetylamino)-1,3,5-triazine (14g)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

preparative TLC (hexane/AcOEt = 9:1) to afford the title compound as a colorless oil (26 mg, 84% yield). ¹H

NMR (400 MHz, CDCl₃/TMS): δ 7.32 (t, J = 7.3 Hz, 2H), 7.25–7.21 (m, 3H), 5.27 (t, J = 6.2 Hz, 1H), 3.69

13

(td, J = 7.6, 6.2 Hz, 2H), 2.91 (t, J = 7.6 Hz, 2H), 1.32 (s, 9H), 1.27 (s, 9H); C NMR (100 MHz, CDCl₃): δ

184.81, 184.49, 166.07, 139.36, 128.97, 128.71, 126.52, 42.46, 39.25, 38.93, 35.99, 28.96; HRMS (DART)

m/z: [M + H]⁺Calcd for C₁₉H₂₉N₄313.2392; Found: 313.2356.

4.7.2. 2-(Phenetylamino)-4,6-diphenyl-1,3,5-triazine (14h)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

preparative TLC (hexane/AcOEt = 20:1) to afford the title compound as a colorless oil (27 mg, 76% yield). ¹H

NMR (400 MHz, CDCl₃/TMS): δ 8.63 (d, J = 7.3 Hz, 2H), 8.51 (d, J = 7.3 Hz, 2H), 7.56–7.47 (m, 6H), 7.34–

7.31 (m, 2H), 7.26–7.21 (m, 3H), 5.73 (t, J = 6.7 Hz, 1H), 3.87 (q, J = 6.7 Hz, 2H), 2.99 (t, J = 6.7 Hz, 2H);

¹³C NMR (100 MHz, CDCl₃): δ 171.56, 171.34, 166.58, 139.04, 136.94, 136.77, 132.04, 131.93, 128.97,

128.86, 128.80, 128.67, 128.51, 126.66, 42.46, 35.85; HRMS (ESI) m/z: [M + H]⁺Calcd for C₂₃H₂₁N₄

353.1766; Found: 353.1746.

4.7.3. 2-(Phenetylamino)-4,6-di-o-tolyl-1,3,5-triazine (14i)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

20

preparative TLC (hexane/AcOEt = 9:1) to afford the title compound as a colorless oil (33 mg, 86% yield). ¹H

NMR (400 MHz, CDCl₃/TMS): δ 8.10 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.39–7.18 (m, 11H), 6.06

(t, J = 6.0 Hz, 1H), 3.71 (q, J = 6.9 Hz, 2H), 2.88 (t, J = 7.1 Hz, 2H), 2.74 (s, 3H), 2.63 (s, 3H); ¹³C NMR (100

MHz, CDCl₃): δ 174.29, 174.22, 165.75, 138.92, 138.53, 137.73, 137.18, 136.86, 131.70, 131.47, 130.95,

130.48, 130.29, 130.18, 128.93, 128.70, 126.61, 125.97, 42.31, 35.87, 22.36, 21.41; HRMS (ESI) m/z: [M +

H]⁺Calcd for C₂₅H₂₅N₄381.2079; Found: 381.2099.

4.7.4. 2,4-Bis(2,6-dimethylphenyl)-6-(phenetylamino)-1,3,5-triazine (14j)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

1

preparative TLC (hexane/AcOEt = 9:1) to afford the title compound as a colorless oil (41 mg, quant.). H

NMR (400 MHz, CDCl₃/TMS): δ 7.24 (t, J = 7.3 Hz, 2H), 7.19–7.03 (m, 10H), 3.37 (q, J = 6.7 Hz, 2H), 2.69

(t, J = 7.1 Hz, 2H), 2.21 (s, 6H), 2.21 (s, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 176.47, 175.49, 165.87, 138.72,

138.31, 137.90, 134.74, 134.66, 128.89, 128.73, 128.48, 128.46, 127.73, 127.62, 126.43, 41.64, 35.50, 19.86,

19.70; HRMS (ESI) m/z: [M + H]⁺Calcd for C₂₇H₂₉N₄409.2392; Found: 409.2343.

4.8.1. 2-(Isopropylamino)-4,6-dimethoxy-1,3,5-triazine (15a)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

1

extraction with CH₂Cl₂to afford the title compound as a white solid (77 mg, 96%). H NMR (600 MHz,

CDCl₃/TMS): δ 5.64 (d, J = 7.2 Hz, 1H), 4.27–4.21 (m, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 1.23 (d, J = 6.5 Hz,

13

6H); C NMR (150 MHz, CDCl₃): δ 172.52, 171.97, 167.30, 54.52, 54.35, 42.82, 22.60; HRMS (ESI) m/z:

[M + H]⁺Calcd for C₈H₁₅N₄O₂199.1195; Found: 199.1201.

4.8.2. 2-(Isopropylamino)-4-methoxy-6-phenyl-1,3,5-triazine (15h)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

preparative TLC (hexane/AcOEt = 95:5) to afford the title compound as a colorless oil (65 mg, 89% yield). ¹H

NMR (400 MHz, CDCl₃/TMS): δ 8.47 (d, J = 7.3 Hz, 0.8H, minor), 8.38 (d, J = 7.3 Hz, 1.2H, major), 7.53–

7.43 (m, 3H), 5.41 (d, J = 6.8 Hz, 0.6H, major), 5.22 (d, J = 6.7 Hz, 0.4H, minor), 4.42 (octet, J = 6.7 Hz,

0.4H, minor), 4.28 (octet, J = 6.8 Hz, 0.6H, major), 4.06 (s, 1.8H, major), 4.00 (s, 1.2H, minor), 1.30 (d, J =

6.7 Hz, 2.4H, minor), 1.27 (d, J = 6.8 Hz, 3.6H, major); ¹³C NMR (100 MHz, CDCl₃): δ 173.11, 172.66,

171.84, 171.46, 167.00, 166.85, 136.40, 136.17, 132.05, 131.99, 128.82, 128.55, 128.44, 128.37, 54.52, 54.40,

43.15, 42.86, 22.90, 22.82; IR (film): 3269, 2972, 1591, 1558, 1533, 1473, 1385, 1362, 1232, 1174, 1022, 827,

785, 704 cm^–1; Anal. Calcd for C₁₃H₁₆N₄O: C, 63.91; H, 6.60; N, 22.93. Found: C, 64.02; H, 6.58; N, 22.94.

4.8.3. 2-(Isopropylamino)-4-methoxy-6-o-tolyl-1,3,5-triazine (15i)

21

The title compound was synthesized in a similar manner to 9e using THF as a solvent. The crude product

was purified by preparative TLC (hexane/AcOEt = 4:1) to afford the title compound as a colorless oil (21 mg,

1

84% yield). H NMR (400 MHz, CDCl₃/TMS): δ 8.03 (d, J = 7.3 Hz, 0.45H, minor), 7.83 (d, J = 7.8 Hz,

0.55H, major), 7.39–7.24 (m, 3H), 5.69 (d, J = 7.3 Hz, 0.55H, major), 5.38 (d, J = 6.9 Hz, 0.45H, minor),

4.37–4.20 (m, 1H), 4.02 (s, 1.65H, major), 3.98 (s, 1.35H, minor), 2.67 (s, 1.35H, minor), 2.60 (s, 1.65H,

13

major), 1.23 (d, J = 6.4 Hz, 2.7H), 1.20 (d, J = 6.4 Hz, 3.3H); C NMR (100 MHz, CDCl₃): 175.96, 175.67,

171.33, 170.99, 166.57, 166.52, 138.46, 137.80, 136.59, 136.47, 131.61, 131.45, 130.69, 130.43, 130.21,

130.12, 125.84, 54.54, 54.37, 42.99, 42.74, 22.90, 22.62, 22.16, 21.46; IR (film): 3255, 3141, 3059, 2972,

2929, 2873, 1558, 1473, 1458, 1360, 1232, 1178, 1024, 829, 779, 733 cm^–1; HRMS (DART) m/z: [M + H]⁺

Calcd for C₁₄H₁₉N₄O 259.1559; Found: 259.1564.

4.8.4. 2-(2,6-Dimethylphenyl)-4-(isopropylamino)-6-methoxy-1,3,5-triazine (15j)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

1

extraction with CH₂Cl₂to afford the title compound as a white solid (53 mg, 97%). H NMR (600 MHz,

CDCl₃/TMS): δ 7.17 (t, J = 7.7 Hz, 1H), 7.06 (t, J = 7.7 Hz, 2H), 5.56 (d, J = 7.2 Hz, 0.7H, major), 5.38 (d, J

= 6.9 Hz, 0.3H, minor), 4.25 (ttt, J = 6.6, Hz, 1H), 4.00 (s, 2.1H), 3.94 (s, 0.9H), 2.23 (s, 4.2H), 2.21 (s, 1.8H),

1.24 (d, J = 6.6 Hz, 4.2H), 1.20 (d, J = 6.6 Hz, 1.8H); ¹³C NMR (150 MHz, CDCl₃): δ 177.53, 176.89, 171.50,

170.98, 166.63, 166.52, 138.28, 137.74, 135.15, 134.95, 128.54, 128.48, 127.74, 54.68, 54.50, 42.89, 42.84,

22.86, 22.60, 19.93, 19.80; IR (film): 3261, 3132, 2972, 2929, 2873, 1593, 1558, 1541, 1475, 1458, 1410,

1360, 1338, 1227, 1211, 1178, 1026, 829, 771, 754 cm^–1; HRMS (DART) m/z: [M + H]⁺Calcd for C₁₅H₂₁N₄O

273.1715; Found: 273.1706.

4.8.5. 2-(Isopropylamino)-4-methoxy-6-(1-octyn-1-yl)-1,3,5-triazine (15k)

The title compound was synthesized in a similar manner to 9e using THF as a solvent. The crude product

was purified by preparative TLC (hexane/AcOEt = 4:1) to afford the title compound as a colorless oil (20 mg,

1

78% yield). H NMR (400 MHz, CDCl₃/TMS): δ 5.31 (d, J = 6.9 Hz, 0.7H, m), 5.16 (d, J = 8.7 Hz, 0.3H),

4.35–4.25 (m, 0.3H), 4.23–4.13 (m, 0.7H), 3.97 (s, 2.1H), 3.91 (s, 0.9H), 2.41 (t, J = 7.3 Hz, 2H), 1.62

(quintet, J = 7.3 Hz, 2H), 1.42 (quintet, J = 7.2 Hz, 2H), 1.34–1.25 (m, 4H), 1.22 (d, J = 6.9 Hz, 6H), 0.89 (t, J

13

= 6.6 Hz, 3H); C NMR (100 MHz, CDCl₃): 171.17, 170.61, 166.22, 166.05, 161.65, 160.91, 92.06, 91.95,

79.54, 78.93, 54.76, 54.55, 42.90, 42.83, 31.39, 31.39, 28.79, 27.96, 22.94, 22.61, 22.59, 19.55, 19.38. HRMS

(ESI) m/z: [M + H]⁺Calcd for C₁₅H₂₅N₄O 277.2028; Found: 277.1993.

4.9.1. 2,4-Bis(2,6-dimethylphenyl)-6-(isopropylamino)-1,3,5-triazine (16j)

The title compound was synthesized in a similar manner to 9e using THF as a solvent. The crude product

was purified by preparative TLC (hexane/AcOEt = 9:1) and reprecipitation from hexane to afford the title

22

compound as a white solid (32 mg, qunat.). ¹H NMR (400 MHz, CDCl₃/TMS): δ 7.18 (t, J = 7.4 Hz, 1H), 7.16

(t, J = 7.4 Hz, 1H), 7.08 (d, J = 7.4 Hz, 2H), 7.06 (d, J = 7.4 Hz, 2H), 5.47 (d, J = 8.7 Hz, 1H), 4.35–4.23 (m,

1H), 2.24 (s, 6H), 2.22 (s, 6H), 1.27 (d, J = 6.8 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 175.41, 174.74,

163.99, 137.30, 136.74, 133.67, 133.46, 127.40, 126.52, 41.74, 21.60, 18.72, 18.60; HRMS (DART) m/z: [M

+ H]⁺Calcd for C₂₂H₂₇N₄347.2236; Found: 347.2213.

4.10.1. 2-Ethyl-4-methoxy-6-morpholino-1,3,5-triazine (17f)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

preparative TLC (hexane/AcOEt = 4:1) to afford the title compound as a white solid (22 mg, qunat.). ¹H NMR

(400 MHz, CDCl₃/TMS): δ 3.94 (s, 3H), 3.89 (br s, 2H), 3.86 (br s, 2H), 3.74 (t, J = 4.8 Hz, 4H), 2.63 (q, J =

13

7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H); C NMR (100 MHz, CDCl₃): δ 181.78, 171.18, 166.09, 66.84, 54.28,

43.94, 43.79, 32.12, 11.58; IR (film): 2974, 2939, 2910, 2870, 1585, 1577, 1541, 1466, 1448, 1373, 1113,

1012, 991, 866, 822 cm^–1; Anal. Calcd for C₁₀H₁₆N₄O₂: C, 53.56; H, 7.19; N, 24.98. Found: C, 53.22; H, 7.19;

N, 24.88.

4.10.2. 2-Methoxy-4-morpholino-6-phenyl-1,3,5-triazine (17h)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

1

preparative TLC (hexane/AcOEt = 4:1) to afford the title compound as a white solid (16 mg, 60%). H NMR

(400 MHz, CDCl₃/TMS): δ 8.43 (dt, J = 7.0, 1.6 Hz, 2H), 7.52 (tt, J = 7.0, 1.6 Hz, 1H), 7.46 (tt, J = 7.0, 1.6

Hz, 2H), 4.04 (s, 3H), 4.04 (br s, 2H), 3.91 (br s, 2H), 3.78 (br s, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 172.72,

171.68, 166.36, 136.30, 132.11, 128.72, 128.39, 66.86, 54.50, 44.12, 43.80; Anal. Calcd for C₁₄H₁₆N₄O₂: C,

61.75; H, 5.92; N, 20.58. Found: C, 61.52; H, 5.91; N, 20.49.

4.10.3. 2-Methoxy-4-morpholino-6-o-tolyl-1,3,5-triazine (17i)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

1

extraction with CH₂Cl₂to afford the title compound as a white solid (84 mg, 98%). H NMR (400 MHz,

CDCl₃/TMS): δ 7.99 (dd, J = 7.6, 1.6 Hz, 1H), 7.36 (td, J = 7.6, 1.6 Hz, 1H), 7.27 (t, J = 7.6 Hz, 2H), 4.02 (s,

13

3H), 3.95 (br s, 2H), 3.91 (br s, 2H), 3.76 (t, J = 4.8 Hz, 4H), 2.64 (s, 3H); C NMR (100 MHz, CDCl₃): δ

175.56, 171.29, 166.10, 138.29, 136.47, 131.67, 130.63, 130.52, 125.90, 66.83, 54.56, 44.20, 43.83, 22.11; IR

(KBr): 3020, 2962, 2902, 2850, 1585, 1567, 1522, 1458, 1383, 1363, 1265, 1221, 1113, 1034, 995, 822, 779,

735 cm^–1; Anal. Calcd for C₁₅H₁₈N₄O₂: C, 62.92; H, 6.34; N, 19.57. Found: C, 62.73; H, 6.31; N, 19.45.

4.10.4. 2-(2,6-Dimethylphenyl)-4-methoxy-6-morpholino-1,3,5-triazine (17j)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

23

1

extraction with CH₂Cl₂to afford the title compound as a white solid (30 mg, quant.). H NMR (400 MHz,

CDCl₃/TMS): δ 7.18 (t, J = 7.7 Hz, 1H), 7.07 (d, J = 7.7 Hz, 2H), 3.99 (s, 3H), 3.90 (br s, 4H), 3.78 (br s, 2H),

3.71 (br s, 2H), 2.22 (s, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 176.96, 171.28, 166.07, 138.09, 135.24, 128.58,

127.84, 66.79, 66.68, 54.63, 44.11, 43.72, 20.05; IR (film): 2960, 2920, 2858, 1560, 1516, 1460, 1446, 1363,

1302, 1281, 1267, 1228, 1213, 1115, 1041, 1001, 829, 773 cm^–1; HRMS (DART) m/z: [M + H]⁺Calcd for

C₁₆H₂₁N₄O₂301.1665; Found: 301.1676.

4.10.5. 2-Methoxy-4-morpholino-6-(1-octyn-1-yl)-1,3,5-triazine (17k)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

1

extraction with CH₂Cl₂to afford the title compound as a white solid (30 mg, quant.). H NMR (400 MHz,

CDCl₃/TMS): δ 3.95 (s, 3H), 3.89 (br s, 2H), 3.84 (br s, 2H), 3.72 (t, J = 4.8 Hz, 4H), 2.43 (t, J = 7.1 Hz, 2H),

1.63 (quintet, J = 7.4 Hz, 2H), 1.43 (quintet, J = 7.4 Hz, 2H), 1.35–1.25 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H); ¹³C

NMR (100 MHz, CDCl₃): δ 170.90, 165.59, 161.19, 92.04, 79.38, 66.81, 66.67, 54.69, 44.18, 43.71, 31.39,

28.80, 27.96, 22.59, 19.49, 14.15; IR (film): 2927, 2854, 2239, 1558, 1541, 1508, 1458, 1396, 1363, 1115,

816, 418 cm^–1; Anal. Calcd for C₁₆H₂₄N₄O₂: C, 63.13; H, 7.95; N, 18.41. Found: C, 62.94; H, 7.97; N, 18.35.

4.11.1. 2-(n-Butylamino)-4-methoxy-6-phenyl-1,3,5-triazine (18h)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

preparative TLC (hexane/AcOEt = 95:5) to afford the title compound as a white solid (77 mg, 99%). ¹H NMR

(400 MHz, CDCl₃/TMS): δ 8.47 (d, J = 7.3 Hz, 0.8H, minor), 8.38 (d, J = 7.3 Hz, 1.2H, major), 7.52–7.43 (m,

3H), 5.68 (br s, 0.6H, major), 5.53 (br s, 0.4H, minor), 4.06 (s, 1.8H, major), 4.01 (s, 1.2H, minor), 3.58 (q, J

= 6.6 Hz, 0.8H, minor), 3.48 (q, J = 6.7 Hz, 1.2H, major), 1.66–1.56 (m, 2H), 1.47–1.36 (m, 2H), 0.96 (t, J =

7.3 Hz, 1.2H), 0.94 (t, J = 7.3 Hz, 1.8H); ¹³C NMR (100 MHz, CDCl₃): δ 173.09, 172.63, 171.83, 171.40,

167.84, 167.68, 136.40, 136.20, 132.05, 131.96, 128.81, 128.57, 128.42, 128.36, 54.50, 54.39, 40.96, 40.78,

31.82, 31.62, 20.12, 13.89; IR (film): 3257, 3132, 3022, 2954, 1570, 1533, 1448, 1437, 1387, 1373, 823, 783,

702 cm^–1; Anal. Calcd for C₁₄H₁₈N₄O: C, 65.09; H, 7.02; N, 21.69. Found: C, 65.00; H, 6.97; N, 21.64.

4.11.2. 2-(n-Butylamino)-4-methoxy-6-o-tolyl-1,3,5-triazine (18i)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

preparative TLC (hexane/AcOEt = 95:5) to afford the title compound as a white solid (80 mg, 98%). ¹H NMR

(600 MHz, CDCl₃/TMS): δ 8.04 (d, J = 7.6 Hz, 0.4H, minor), 7.79 (d, J = 7.6 Hz, 0.6H, major), 7.36–7.24 (m,

3H), 6.36 (br s, 0.6H, major), 5.90 (br s, 0.4H, minor), 4.02 (s, 1.8H, major), 3.99 (s, 1.2H, minor), 3.42 (q, J

= 6.8 Hz, 0.8H, minor), 3.34 (q, J = 6.8 Hz, 1.2H, major), 2.67 (s, 1.2H, minor), 2.58 (s, 1.8H, major), 1.54–

1.46 (m, 2H), 1.38–1.29 (m, 2H), 0.93–0.89 (m, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 175.86, 175.67, 171.32,

170.91, 167.35, 167.31, 138.52, 137.62, 136.78, 136.45, 131.64, 131.38, 130.69, 130.45, 130.16, 129.97,

24

125.86, 125.81, 54.53, 54.38, 40.93, 40.65, 31.84, 31.46, 22.17, 21.25, 20.09, 13.85; IR (film): 3267, 3149,

2958, 2931, 2871, 1608, 1581, 1558, 1533, 1473, 1458, 1412, 1379, 1358, 1236, 829, 779, 733 cm^–1; HRMS

(DART) m/z: [M + H]⁺Calcd for C₁₅H₂₁N₄O 273.1715; Found: 273.1730.

4.11.3. 2-(n-Butylamino)-4-(2,6-dimethylphenyl)-6-methoxy-1,3,5-triazine (18j)

The title compound was synthesized in a similar manner to 9e. The crude product was purified by

preparative TLC (hexane/AcOEt = 95:5) to afford the title compound as a white solid (78 mg, 91%). ¹H

NMR (400 MHz, CDCl₃/TMS): δ 7.22 (br s, 0.75H, major), 7.18 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.8 Hz, 0.5H,

minor), 7.06 (d, J = 7.8 Hz, 1.5H, major), 6.15 (br s, 0.25H, minor), 3.97 (s, 2.25H, major), 3.94 (s, 0.75H,

minor), 3.25 (q, J = 6.7 Hz, 0.5H, minor), 3.05 (q, J = 6.9 Hz, 1.5H, major), 2.22 (s, 1.5H), 2.21 (s, 4.5H),

1.42–1.35 (m, 2H), 1.33–1.19 (m, 2H), 0.90 (t, J = 7.1 Hz, 2.25H, major), 0.88 (t, J = 6.9 Hz, 0.75H, minor);

¹³C NMR (100 MHz, CDCl₃): δ 177.40, 176.47, 171.36, 170.81, 167.33, 167.23, 138.25, 137.89, 135.23,

135.03, 128.62, 128.49, 127.78, 127.74, 54.60, 54.52, 40.77, 40.42, 31.97, 31.53, 20.12, 19.97, 19.77, 13.92;

IR (film): 3259, 3128, 2958, 2931, 2871, 1612, 1558, 1473, 1410, 1352, 1227, 1211, 831, 771 cm^–1; Anal.

Calcd for C₁₆H₂₂N₄O: C, 67.11; H, 7.74; N, 19.56. Found: C, 67.11; H, 7.69; N, 19.46.

4.12. Typical Procedure for in situ amidation with chlorotriazines (1 or 12)

To a mixture of 3-phenylpropionic acid 5a (60 mg, 0.4 mmol), phenetylamine 7A (56 µL, 0.44 mmol), and

NMM (52 µL, 0.48 mmol) in an appropriate solvent (2 mL), chlorotriazine 1 or 12 (0.44 mmol) was added at

rt. After stirring for 3 h, the mixture was quenched with 1 M KHSO₄(4 mL) and the solvent was evaporated in

vacuo, and then the mixture was extracted with CHCl₃(10 mL × 3). The combined organic fractions were

washed with 1 M HCl, sat. NaHCO₃, and brine, and was dried over Na₂SO₄. Following filtration, the solvent

was evaporated, and quantitative NMR was conducted by using interal standards (coumarin, 6-methylcourarin,

or 1,3,5-trimethoxybenzene).

4.13. Typical Procedure for amidation with triazinylammonium salts (11 or 13)

To a mixture of 3-phenylpropionic acid 5a (60 mg, 0.4 mmol) and phenetylamine 7A (56 µL, 0.44 mmol) in

an appropriate solvent (2 mL), ammonium salts 11 or 13 (0.44 mmol) was added at rt. After stirring for 3 h,

the mixture was quenched with 1 M KHSO₄(4 mL) and the solvent was evaporated in vacuo, and then the

mixture was extracted with CHCl₃(10 mL × 3). The combined organic fractions were washed with 1 M HCl,

sat. NaHCO₃, and brine, and was dried over Na₂SO₄. Following filtration, the solvent was evaporated, and

quantitative NMR was conducted by using interal standards (coumarin, 6-methylcourarin, or

1,3,5-trimethoxybenzene).

4.14. Kinetic study by using UV spectroscopy (Table 6)

25

A CH₃CN solution (300 µL) of chlorotriazines 1 (1.00 mM) was added to a CH₃CN solution (2400 µL) of

EtNⁱPr₂(10 mM) in a quartz cell. To this mixture, a CN₃CN solution (300 µL) of amines (1.0 mM) was added.

UV absorption spectra were recorded on a SHIMADZU UV-2400PC spectrophotometer at a controlled

temperature.

Acknowledgments

This work was supported by JSPS KAKENHI Grant (No. 26293003, 17H03970, 19K06994).

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[9] For this kind of chlorotriazines, the reaction does not proceed smoothly without NMM [4,5].

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(2013) 882–886.

[11] Because demethylation by the chloride anion was expected [1–3].

[12] Due to the high reactivity of 1k (Table 6, entry 5), the unidentified side products were indeed observed

during the amide-forming reactions.

[13] E.A. Braude, F. Sondheimer, W.F. Forbes, Nature 173 (1954) 117–119.

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Legends