Trizaine-based dehydrative condensation reagents bearing carbon-substituents

Journal Pre-proof Trizaine-based dehydrative condensation reagents bearing carbon-substituents Masanori Kitamura, Sayaka Komine, Kohei Yamada, Munetaka Kunishima PII:

S0040-4020(19)31316-X

DOI:

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

Reference:

TET 130900

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. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.

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: [email protected] (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 aqueousor 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 (R1 in 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 σm [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 (sp3 hybridization), and phenyl, o-tolyl, 2,6-dimethylphenyl (sp2 hybridization), 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 12h: R1 = Ph N N Cl 12i: R1 = o-tolyl N 12j: R1 = 2,6-Me2C6H3 R1 C6H13 12k: R1 = R1

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).

Amines 7 Carboxylic acids 5 + (1.1 eq.) (1.0 eq.)

entry

carboxylic acid 5

amine 7

Amides 8

+

N

9, 14, MeO

chlorotriazine 1 or 12

amide 8

N N N 15 H

i

Pr

or

N R1

N N N H 16

OH 5b

2

5b

7A

N H 8bA 8bA

time (h)

8b

yielda (%) side-products c

3

5b

7A

4

5b

5

Ph

1f: R1 =

Et

3

66

9f: 23

1h: R1 =

Ph

3

56

9h: 28

8bA

1i: R1 =

o-tolyl

3

68

9i: 25

7A

8bA

1j: R1 =

2,6-Me2C6H3

3

76

9j: 23

5b

7A

8bA

1k: R1 =

3

59

9k: 24

6

5b

7A

8bA O

9j: R1 =

2,6-Me2C6H3

3

81

14j: 20

7

5b

1a: R1 =

OMe

14

69

15a: 6

8

5b

7B

N H 8bB 8bB

1j: R1 =

2,6-Me2C6H3

14

80

15j: 7

9

5b

7B

8bB

1k: R1 =

14

77

15k: 9

10

5b

7B

8bB

9j: R1 =

14

85

16j: 5

20

69

d

14

52

d

O 11

iPr

OH 5c

iPr

O tBu

7A

tBu

R1

R1

THF, rt, time

O 1

Side-products

1 or 12 (1.1 eq.) NMM (1.2 eq.)

i Pr H2 N 7B

Et2NH 7C

tBu

iPr

O i

Pr NEt2 8cC 8cC

1a: R1 =

C6H13

C6H13 2,6-Me2C6H3 OMe

1h: R1 = Ph

12

5c

7C

13

5c

7C

8cC

1k: R1 =

C6H13

16

59

d

14

5c

7C

8cC

9j: R1 =

2,6-Me2C6H3

20

85

d

a

Based on 1H NMR. b The yields were calculated based on 5. c The yields were calculated based on 7. d Not 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

1h

1.5

Abs

1i 1j

1

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 (εmax = 5088 M–1·cm–1) was the smaller than that of 1h (εmax = 20506 M–1·cm–1) and 1i (εmax = 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 Chemical shifts for 1H 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

13

C 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 N2 atmosphere at – 30 °C. After stirring for 3 h, the reaction mixture was quenched with 1 M HClaq, and the mixture was extracted with AcOEt. The organic phase was washed with 1 M HClaq and 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 CHCl3 and 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 µL, 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 HClaq, 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), 2.85 (q, J = 7.6 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H); 13C 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): δ 4.09 (s, 3H), 1.37 (s, 9H); 13C 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 solid (2.86 g, 58% yield over 2 steps). M.p. 57.1–58.1 °C; 1H 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 solid (1.25 g, 76% yield over 2 steps). 1H 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); 13

C 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 CH2Cl2 solution (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 HClaq, 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 white solid. 1H 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), 1.29 (t, J = 7.4 Hz, 0.9H, minor), 1.25 (t, J = 7.6 Hz, 2.1H, major); 13C 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 preparative TLC (hexane/AcOEt = 9:1) to afford the title compound as a white solid (78 mg, 91% yield). 1H 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);

13

C 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 column chromatography (CHCl3) to afford the title compound as a white solid (87 mg, 94% yield). 1H 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), 2.96 (t, J = 7.2 Hz, 0.9H, minor), 2.92 (t, J = 6.9 Hz, 1.1H, major); 13C 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);

13

C 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, 1.8H, minor), 2.19 (s, 4.2H, major); 13C 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);

13

C 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 N2 atmosphere 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 yellow solid (63 mg, 94% yield). 1H 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);

13

C 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 C11H19N4O2 254.1060; 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 white solid (331 mg, 86% yield). 1H 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 C15H19N4O2 287.1508; 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 white solid (77 mg, 92% yield). 1H 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 C17H23N4O2 315.1821; 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 pale pink solid (260 mg, 85% yield). 1H 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 C17H27N4O2 319.2134; 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 N2 atmosphere at 0 °C. After stirring overnight at rt, the reaction mixture was quenched with 1 M HClaq, 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) and recrystallization from hexane to afford the title compound as colorless needles (2.78 g, 58% yield). 1H 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); 13

C 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 C15H11ClN3 268.0642; 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). 1

H 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 =

7.8 Hz, 2H), 7.34 (d, J = 7.3 Hz, 2H), 2.75 (s, 6H); 13C 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); 13

C 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 C19H19ClN3 324.1268; 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 C19H27ClzN3 332.1894; 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

white solid (418 mg, 85% yield). 1H 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 C24H29N4O1 389.2341; 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 (td, J = 7.6, 6.2 Hz, 2H), 2.91 (t, J = 7.6 Hz, 2H), 1.32 (s, 9H), 1.27 (s, 9H); 13C 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 C19H29N4 313.2392; 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); 13

C 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 C25H25N4 381.2079; 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 preparative TLC (hexane/AcOEt = 9:1) to afford the title compound as a colorless oil (41 mg, quant.). 1H 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 C27H29N4 409.2392; 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 extraction with CH2Cl2 to afford the title compound as a white solid (77 mg, 96%). 1H 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, 6H); 13C 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 C8H15N4O2 199.1195; 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);

13

C 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, 84% yield). 1H 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, major), 1.23 (d, J = 6.4 Hz, 2.7H), 1.20 (d, J = 6.4 Hz, 3.3H); 13C 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 extraction with CH2Cl2 to afford the title compound as a white solid (53 mg, 97%). 1H 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, 78% yield). 1H 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 = 6.6 Hz, 3H); 13C 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 C22H27N4 347.2236; 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 = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H); 13C 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 preparative TLC (hexane/AcOEt = 4:1) to afford the title compound as a white solid (16 mg, 60%). 1H 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 extraction with CH2Cl2 to afford the title compound as a white solid (84 mg, 98%). 1H 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, 3H), 3.95 (br s, 2H), 3.91 (br s, 2H), 3.76 (t, J = 4.8 Hz, 4H), 2.64 (s, 3H); 13C 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

extraction with CH2Cl2 to afford the title compound as a white solid (30 mg, quant.). 1H 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 C16H21N4O2 301.1665; 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 extraction with CH2Cl2 to afford the title compound as a white solid (30 mg, quant.). 1H 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%).

1

H

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); 13

C 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).

[1] M. Kunishima, C. Kawachi, F. Iwasaki, K. Terao, S. Tani, Tetrahedron Lett. 40 (1999) 5327–5330. [2] M. Kunishima, C. Kawachi, K. Hioki, K. Terao, S. Tani, Tetrahedron 57 (2001) 1551–1558. [3] M. Kunishima, T. Ujigawa, Y. Nagaoka, C. Kawachi, K. Hioki M. Shiro, Chem. Eur. J. 18 (2012) 15856– 15867. [4] M. Kunishima, D. Kato, N. Kimura, M. Kitamura, K. Yamada, K. Hioki, Beilstein J. Org. Chem. 12 (2016) 1897–1903. [5] M. Kitamura, S. Sasaki, R. Nishikawa, K. Yamada, M. Kunishima RSC Adv. 8 (2018) 22482–22489. [6] M. Kunishima, K. Yamamoto, K. Hioki, T. Kondo, M. Hasegawa, S. Tani Tetrahedron 63 (2007) 2604– 2612. [7]

C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 91 (1991) 165–195.

[8] K. Yamada, H. Fujita, M. Kunishima, Org. Lett. 14 (2012) 5026–5029. [9] For this kind of chlorotriazines, the reaction does not proceed smoothly without NMM [4,5]. [10] M. Kunishima, M. Kitamura, H. Tanaka, I. Nakakura, T. Moriya, K. Hioki, Chem. Pharm. Bull. 61 (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. [14] H. Suzuki, Bull. Chem. Soc. J. 27 (1954) 597–601. [15] H.B. Klevens, J.R. Platt, J. Am. Chem. Soc. 71 (1949) 1714–1720. [16] E.A. Braude, in: E.A. Braude, F.C. Nachod (Ed.), Determination of Organic Structures by Physical Methods, Vol. 1, Academic Press, New York, 1955, pp. 131–193. [17] J. Catalán, P. Pérez, R. M. Claramunt, D. S. María, V. Bobosik, Chem. Phys. 340, (2007) 32–42. [18] T. Bathini, V.S. Rawat, S. Bojja, Tetrahedron Lett. 56 (2015) 5656–5660. [19] M. Hayashi, H. Kawabata, K. Yoshimoto, T. Tanaka, Phosphorus, Sulfur Silicon Relat. Elem. 182 (2007) 433–445. [20] H.Yamada, H. Shizuka, S. Sekiguchi, K. Matsui, Bull. Chem. Soc. Japan 47 (1974) 238–239. 26

[21] J.W. Lee, J.T. Bork, H.-H. Ha, A. Samanta, Y.-T. Chang, Aust. J. Chem. 62 (2009) 1000–1006. [22] J. Kobe, B. Stanovnik, M. Tišler, Monatsh. Chem. 101 (1970) 724–735. [23] H. Bader, E.R. Ruckel, F.X. Markley, C.G. Santangelo, P. Schickedantz, J. Org. Chem. 30 (1965) 702– 707. [24] Y. Karuo, K. Yamada, M. Kunishima Chem. Pharm. Bull. 66 (2018) 303–308. [25] R. Braveenth, D.H. Ahn, J.-H. Han, J.S. Moon, S.W. Kim, H. Lee, W. Qiong, J.H. Kwon, K.Y. Chai, Dye Pig. 157 (2018) 377–384. [26] K. Abe, M. Kitamura, H. Fujita, M. Kunishima, Mol. Cat. 445 (2018) 87–93. [27] L. Hintermann, L. Xiao, A. Labonne, Angew. Chem. Int. Ed. 47 (2008) 8246–8250.

27

Legends Scheme 1. (a) Triazine-based dehydrative condensation reagents and (b) their use for amide-forming reactions. Table 1. (a) Inductive and resonance effects affecting the electrophilicity of triazines, (b) Carbon-substituents and their Hammett substituent constants. Table 2. Amide-forming reactions using chlorotriazines (1) bearing carbon-substituents. Table 3. Amide-forming reactions using ammonium salts (11). Table 4. Amide-forming reactions using chlorotriazines (12) or triazinylammonium salt (13j) bearing two carbon-substituents. Table 5. Amide-forming reactions using several carboxylic acids (5) and amines (7). Table 6. Kinetic study of model reactions of chlorotriazines 1 with various amines. Figure 1. Chlorotriazines that have methoxy and carbon-substituents. Figure 2. Chlorotriazines that have two carbon-substituents. Figure 3. ORTEP drawing (50% probability ellipsoids) of 1h. CCDC No. 1940180. Figure 4. ORTEP drawing (50% probability ellipsoids) of 1i. CCDC No. 1940181. Figure 5. ORTEP drawing (50% probability ellipsoids) of 1j. CCDC No. 1940182. Figure 6. UV spectra of 1h (Ph), 1i (o-tolyl), and 1j (2,6-dimethylphenyl) at 0.1 mM in acetonitrile.

28

Highlights

·

Amide-forming reactions with triazines bearing carbon-substituents proceed smoothly even in the absence of oxygen- or nitrogen-containing subsutituents.

·

Electrophilicity of these reagents is mainly dependent on the hybridization of the carbon-substituents.

·

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.

Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: