Silver-Catalyzed [3+2+1] Annulation of Aryl Amidines with Benzyl lsocyanide

Xiaodong Lua,b, Xiaoyi Xina,*, Boshun Wana,*

a Dalian Institute of Chemical Physics, Chinese Academy of Sciences,

457 Zhongshan Road, Dalian 116023, China

b University of Chinese Academy of Sciences, Beijing 100049, China

E-mail: xyxin@dicp.ac.cn; bswan@dicp.ac.cn 

 

 

 

Supplementary data

 

 

Table of Contents

1. General .................................................................................................................... S1 

2. General procedure for the synthesis of 2,4‐diaryl‐1,3,5‐triazines 3 ...................... S1 

3. Mechanistic studies ................................................................................................. S2 

4. Characterization data of the obtained compounds ............................................... S4 

5. References ............................................................................................................... S9 

6. NMR spectra of the obtained compounds ........................................................... S11 

 

S1  

1. General 

All reactions were carried out under an atmosphere of argon using standard Schlenk

techniques. Solvents were treated prior to use according to the standard methods.

Column chromatography was carried out on silica gel (300–400 mesh) using a forced

flow of eluent at 0.3–0.5 bar pressure. NMR spectra were recorded at room

temperature in CDCl3 on a 400 MHz NMR spectrometer. The chemical shifts for 1H

NMR were recorded in ppm downfield from tetramethylsilane (TMS) with TMS

resonance (0.00 ppm) as the internal standard. The chemical shifts for 13C NMR were

recorded in ppm downfield using the central peak of CDCl3 (77.16 ppm) as the

internal standard. Coupling constants (J) are reported in Hz and refer to apparent peak

multiplications. The abbreviations s, d, t, q, and m stand for singlet, doublet, triplet,

quartet, and multiplet in that order. HRMS data were obtained with Micromass

HPLC-Q-TOF mass spectrometer.

2.  General  procedure  for  the  synthesis  of 

2,4‐diaryl‐1,3,5‐triazines 3 

 

Scheme S1. Synthesis of 2,4-diaryl-1,3,5-triazines

General procedure for synthesis of symmetrical 2,4-diaryl-1,3,5-triazines:

In a Schlenk tube, the mixture of aryl amidine 1 (0.4 mmol), AgSbF6 (0.015 mmol)

and benzyl isocyanide 2 (0.3 mmol) were stirred in toluene (2 mL) at 140 oC for 10 h.

The solvent was removed under vacuum. The residue was directly purified by flash

chromatography (eluent: 10:1 petroleum ether/ethyl acetate) to give the desired

symmetrical 2,4-diaryl-1,3,5-triazine.

General procedure for synthesis of unsymmetrical

2,4‐diaryl‐1,3,5‐triazines:

In a Schlenk tube, the mixture of aryl amidine 1 (0.2 mmol), amidine 1’ (0.2 mmol),

AgSbF6 (0.015 mmol) and benzyl isocyanide 2 (0.3 mmol) were stirred in toluene (2

S2  

mL) at 140 oC for 10 h. The solvent was removed under vacuum. The residue was

directly purified by flash chromatography (eluent: 10:1 petroleum ether/ethyl acetate)

to give the desired unsymmetrical 2,4-diaryl-1,3,5-triazine.

Generalprocedureforsynthesisofarylamidines1:

Scheme S2. Synthesis of aryl amidinesAmidines 1 were prepared according to literature procedures, except benzamidine

which is commercial available. A 100 mL flask was charged with 30 mL of anhydrous MeOH, 10 mmol of the aryl nitrile, and 1.0 mmol of sodium methoxide. The complex was protected from moisture and stirred for 48 h. Then, 10 mmol of NH4Cl was added and stirring was continued for 24 h. Unreacted NH4Cl was filtered, and methanol was stripped from the filtrate to afford the productaryl amidine hydrochlorides, which was dissolved in 2.5 mL 8M sodium hydroxide aqueous solution and stirred for 1 h. Then chloroform (20 ml x 3) and H2O (20 ml x 3) were added successively to extract the product, and the combined organic layer was dried with anhydrous MgSO4 and then evaporated under vacuum to remove the organic solvent to give the desired aryl amidine.

Generalprocedureforsynthesisofisocyanides2:

R NHCHO

POCl3(1.25 eq) / NEt3(3.75 eq)

DCM, -5 - 0 oCR NC

 

Scheme S3. Synthesis of isocyanides 

A stirred suspension of substituted formamide (40 mmol), 50 mL dry dichloromethane, and 20.8 mL NEt3 (15.2 g, 150mmol) was cooled in ice-salt to -5 oC. A solution of POCl3 (4.7 mL, 50 mmol) in 10 mL dichloromethane was added dropwise, while keeping the temperature beween -5 and 0 oC until the reaction completed. Then saturated Na2CO3 solution was added slowly until no gas released to quench the reaction. Subsquently dichloromethane (30 ml x 3) and H2O (30 ml x 3) were added successively to extract the product, and the combined organic layer was dried with anhydrous MgSO4 and then evaporated under vacuum to remove the organic solvent. The residue was directly purified by flash chromatography to give the desired isocyanide.

3. Mechanistic studies 

S3  

Scheme S4. Control experiments

By Micromass HPLC-Q-TOF mass spectrometer, we detected the mass of

benzylamine in the reaction mixture under the standard conditions. HRMS (Q-TOF,

m/z) calcd for C7H10N+ [M+H]+ 108.0808, found 108.0809.

In a Schlenk tube, the mixture of aryl amidine 1f (0.4 mmol), AgSbF6 (0.015 mmol)

and benzyl isocyanide 2 (0.3 mmol) were stirred in toluene (2 mL) at 50 oC for 1 h.

After cooled down, the reaction mixture was detected by Micromass HPLC-Q-TOF

mass spectrometer, and the peak corresponding to intermediate E can be observed.

HRMS (Q-TOF, m/z) calcd for C15H15BrN3+ [M+H]+ 316.0444, found 316.0450.

Scheme S5 a

S4  

 

Scheme S5 b 

4. Characterization data of the obtained compounds   

2,4-Diphenyl-1,3,5-triazine (3a)3

Yield: 38.5 mg (82%), white solid. 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.64

(d, J = 7.1 Hz, 4H), 7.60 (m, J = 7.2 Hz, 2H), 7.54 (m, J = 7.3 Hz, 4H); 13C NMR

(100 MHz, CDCl3) δ 171.5, 166.9, 135.7, 132.9, 129.0, 128.9.

2,4-Di-p-tolyl-1,3,5-triazine (3b)3

Yield: 46.0 mg (88%). 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.49 (d, J = 8.1

Hz, 4H), 7.31 (d, J = 8.0 Hz, 4H), 2.43 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 171.2,

166.6, 143.5, 133.1, 129.6, 129.0, 21.8.

N N

N

Cl Cl

2,4-Bis(4-chlorophenyl)-1,3,5-triazine (3c)3

Yield: 48.0 mg (80%), white solid. 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.55

S5  

(d, J = 8.6 Hz, 4H), 7.51 (d, J = 8.6 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 170.6,

166.9, 139.5, 134.0, 130.4, 129.2.

2,4-Bis(4-bromophenyl)-1,3,5-triazine (3d)3

Yield: 59.6 mg (76%), white solid, m.p. 144-145 oC. 1H NMR (400 MHz, CDCl3) δ

9.22 (s, 1H), 8.47 (d, J = 8.2 Hz, 4H), 7.67 (d, J = 8.2 Hz, 4H); 13C NMR (100 MHz,

CDCl3) δ 170.8, 167.0, 134.4, 132.2, 130.5, 128.2.

2,4-Bis(4-methoxyphenyl)-1,3,5-triazine (3e) 3

Yield: 46.3 mg (82%), white solid. 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.54

(d, J = 7.4 Hz, 4H), 6.99 (d, J = 7.4 Hz, 4H), 3.86 (s, 6H); 13C NMR (100 MHz,

CDCl3) δ 170.6, 166.4, 163.5, 128.3, 114.3, 114.1, 55.5.

2,4-Bis(4-(trifluoromethyl)phenyl)-1,3,5-triazine (3f) 3

Yield: 29.3 mg (49%), white solid. 1H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.74

(d, J = 8.2 Hz, 4H), 7.81 (d, J = 8.3 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 170.6,

167.3, 138.6, 134.6 (q, J = 32.6 Hz), 129.4, 125.9 (q, J = 3.8 Hz), 123.59 (q, J = 272.6

Hz); 19F NMR (375 MHz, CDCl3) δ -63.04.

2,4-Bis(3-bromophenyl)-1,3,5-triazine (3g)

Yield: 55.2 mg (70%), white solid, m.p. 185-187 oC. 1H NMR (400 MHz, CDCl3) δ

9.27 (s, 1H), 8.76 (s, 2H), 8.57 (d, J = 7.9 Hz, 2H), 7.74 (d, J = 8.6 Hz, 2H), 7.44 (m,

2H); 13C NMR (100 MHz, CDCl3) δ 170.5, 167.0, 137.5, 136.0, 132.0, 130.5, 127.7,

S6  

123.2. HRMS (Q-TOF, m/z) calcd for C15H10Br2N3 [M+H]+ 389.9236, found

389.9238.

2,4-Di(thiophen-2-yl)-1,3,5-triazine (3h)

Yield: 46.3 mg (94%), white solid, m.p. 128-130 oC. 1H NMR (400 MHz, CDCl3) δ

8.99 (s, 1H), 8.21 (d, J = 3.6 Hz, 2H), 7.62 (d, J = 4.9 Hz, 2H), 7.21 – 7.15 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 167.5, 166.5, 141.0, 132.9, 132.1, 128.7. HRMS

(Q-TOF, m/z) calcd for C11H8N3S2 [M+H]+ 246.0154, found 246.0167.

2-(4-Methoxyphenyl)-4-phenyl-1,3,5-triazine (3i)

Yield: 20.0 mg (38%), white solid, m.p. 114-116 oC. 1H NMR (400 MHz, CDCl3) δ

9.18 (s, 1H), 8.61 (m, J = 7.4 Hz, 4H), 7.60 (m, J = 7.3 Hz, 1H), 7.54 (m, J = 7.2 Hz,

2H), 7.03 (d, J = 8.9 Hz, 2H), 3.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.2,

171.0, 166.7, 163.7, 135.9, 132.8, 131.0, 129.0, 128.8, 128.2, 114.2, 55.6. HRMS

(Q-TOF, m/z) calcd for C16H14N3O [M+H]+ 264.1131, found 264.1132.

2-(4-Bromophenyl)-4-(4-methoxyphenyl)-1,3,5-triazine (3j)

Yield: 25.8 mg (38%), white solid, m.p. 149-151 oC. 1H NMR (400 MHz, CDCl3) δ

9.16 (s, 1H), 8.57 (d, J = 9.0 Hz, 2H), 8.47 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.7 Hz,

2H), 7.03 (d, J = 9.0 Hz, 2H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.1,

170.4, 166.7, 163.8, 134.8, 132.1, 131.0, 130.4, 128.0, 127.8, 114.3, 55.6. HRMS

(Q-TOF, m/z) calcd for C16H13BrN3O [M+H]+ 342.0237, found 342.0242.

S7  

2-(3-Bromophenyl)-4-(4-methoxyphenyl)-1,3,5-triazine (3k)

Yield: 20.6 mg (30%), white solid, m.p. 135-137 oC. 1H NMR (400 MHz, CDCl3) δ

9.16 (s, 1H), 8.74 (s, 1H), 8.57 (d, J = 9.0 Hz, 2H), 8.53 (d, J = 7.9 Hz, 1H), 7.70 (d, J

= 9.9 Hz, 1H), 7.40 (m, J = 7.9 Hz, 1H), 7.03 (d, J = 9.0 Hz, 2H), 3.90 (s, 3H); 13C

NMR (100 MHz, CDCl3) δ 171.1, 169.9, 166.7, 163.9, 138.0, 135.6, 131.9, 131.1,

130.3, 127.9, 127.5, 123.1, 114.3, 55.6. HRMS (Q-TOF, m/z) calcd for C16H13BrN3O

[M+H]+ 342.0237, found 342.0242.

2-(4-Chlorophenyl)-4-(4-methoxyphenyl)-1,3,5-triazine (3l)

Yield: 23.0 mg (39%), white solid, m.p. 143-145 oC.  1H NMR (400 MHz, CDCl3) δ

9.15 (s, 1H), 8.55 (m, 4H), 7.49 (d, J = 8.6 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 3.90 (s,

3H); 13C NMR (100 MHz, CDCl3) δ 171.1, 170.3, 166.7, 163.8, 139.1, 134.4, 131.0,

130.3, 129.1, 128.0, 114.3, 55.6. HRMS (Q-TOF, m/z) calcd for C16H13ClN3O

[M+H]+ 298.0742, found 298.0747. 

N N

N

O

2-(4-Methoxyphenyl)-4-(p-tolyl)-1,3,5-triazine (3m)

Yield: 17.0 mg (33%), white solid, m.p. 134-136 oC.  1H NMR (400 MHz, CDCl3) δ

9.14 (s, 1H), 8.59 (d, J = 8.8 Hz, 2H), 8.50 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.0 Hz,

2H), 7.03 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3)

δ 171.2, 170.9, 166.6, 163.6, 143.4, 133.2, 130.9, 129.6, 129.0, 128.3, 114.2, 55.6,

21.8. HRMS (Q-TOF, m/z) calcd for C17H16N3O [M+H]+ 278.1288, found 278.1296. 

2-(4-Methoxyphenyl)-4-(thiophen-2-yl)-1,3,5-triazine (3n)

Yield: 30.0 mg (56%), white solid, m.p. 106-108 oC. 1H NMR (400 MHz, CDCl3) δ

9.05 (s, 1H), 8.53 (d, J = 9.0 Hz, 2H), 8.23 (dd, J = 3.7, 1.2 Hz, 1H), 7.61 (dd, J = 5.0,

1.1 Hz, 1H), 7.20 (dd, J = 4.9, 3.8 Hz, 1H), 7.01 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H); 13C

S8  

NMR (101 MHz, CDCl3) δ 170.8, 167.5, 166.5, 163.7, 141.6, 132.5, 131.7, 131.0,

128.7, 127.8, 114.2, 55.6. HRMS (Q-TOF, m/z) calcd for C14H12N3OS [M+H]+

270.0696, found 270.0699.

2-(4-Chlorophenyl)-4-(thiophen-2-yl)-1,3,5-triazine (3o)

Yield: 24.3 mg (44%), white solid, m.p. 153-155 oC.  1H NMR (400 MHz, CDCl3) δ

9.10 (s, 1H), 8.50 (d, J = 8.6 Hz, 2H), 8.25 (dd, J = 3.7, 1.1 Hz, 1H), 7.64 (dd, J = 5.0,

1.1 Hz, 1H), 7.49 (d, J = 8.6 Hz, 2H), 7.21 (dd, J = 4.9, 3.9 Hz, 1H); 13C NMR (100

MHz, CDCl3) δ 170.4, 167.9, 166.8, 141.2, 139.4, 133.9, 133.1, 132.2, 130.3, 129.2,

128.9. HRMS (Q-TOF, m/z) calcd for C13H9ClN3S [M+H]+ 274.0200, found

274.0204. 

2-(4-Bromophenyl)-4-(thiophen-2-yl)-1,3,5-triazine (3p)

Yield: 21.4 mg (34%), white solid, m.p. 153-155 oC.  1H NMR (400 MHz, CDCl3) δ

9.11 (s, 1H), 8.44 (d, J = 8.6 Hz, 2H), 8.26 (m, 1H), 7.67 (m, 1H), 7.65 (d, 2H), 7.24 –

7.19 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 170.6, 167.9, 166.8, 141.2, 134.3, 133.1,

132.2, 132.2, 130.5, 128.9, 128.1. HRMS (Q-TOF, m/z) calcd for C13H9BrN3S

[M+H]+ 317.9696, found 317.9697. 

2-(3-Bromophenyl)-4-(thiophen-2-yl)-1,3,5-triazine (3q)

Yield: 27.5 mg (43%), white solid, m.p. 107-109 oC.  1H NMR (400 MHz, CDCl3) δ

9.11 (s, 1H), 8.69 (s, 1H), 8.49 (d, J = 7.9 Hz, 1H), 8.26 (d, J = 4.9 Hz, 1H), 7.70 (d, J

= 8.9 Hz, 1H), 7.65 (d, J = 6.1 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.24 – 7.19 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 170.1, 167.9, 166.8, 141.1, 137.4, 135.8, 133.2, 132.3,

131.9, 130.3, 128.9, 127.5, 123.1. HRMS (Q-TOF, m/z) calcd for C13H9N3S [M+H]+

317.9696, found 317.9700. 

S9  

2-(Thiophen-2-yl)-4-(p-tolyl)-1,3,5-triazine (3r)

Yield: 18.0 mg (36%), white solid, m.p. 93-95 oC. 1H NMR (400 MHz, CDCl3) δ 9.09

(s, 1H), 8.46 (d, J = 8.2 Hz, 2H), 8.25 (dd, J = 3.7, 1.2 Hz, 1H), 7.62 (dd, J = 5.0, 1.1

Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.20 (dd, J = 4.9, 3.8 Hz, 1H), 2.44 (s, 3H); 13C

NMR (100 MHz, CDCl3) δ 171.3, 167.7, 166.6, 143.7, 141.5, 132.7, 131.9, 129.6,

129.0, 128.7, 21.9. HRMS (Q-TOF, m/z) calcd for C14H12N3S [M+H]+ 254.0746,

found 254.0748. 

2-Phenyl-4-(thiophen-2-yl)-1,3,5-triazine (3s)

Yield: 24.1 mg (50%), white solid, m.p. 100-102 oC. 1H NMR (400 MHz, CDCl3) δ

9.13 (s, 1H), 8.62 – 8.55 (m, 2H), 8.27 (d, J = 3.7 Hz, 1H), 7.64 (d, J = 4.9 Hz, 1H),

7.59 (d, J = 7.1 Hz, 1H), 7.53 (t, J = 7.4 Hz, 2H), 7.24 – 7.19 (m, 1H); 13C NMR (100

MHz, CDCl3) δ 171.4, 167.8, 166.7, 141.4, 135.4, 133.0, 132.9, 132.0, 129.0, 128.9,

128.8. HRMS (Q-TOF, m/z) calcd for C13H10N3S [M+H]+ 240.0590, found 240.0590.

2-(Thiophen-2-yl)-4-(4-(trifluoromethyl)phenyl)-1,3,5-triazine (3t)

Yield: 20.1 mg (33%), white solid, m.p. 131-133 oC. 1H NMR (400 MHz, CDCl3) δ

9.16 (s, 1H), 8.68 (d, J = 8.2 Hz, 2H), 8.28 (dd, J = 3.7, 1.1 Hz, 1H), 7.79 (d, J = 8.3

Hz, 2H), 7.67 (dd, J = 4.9, 1.1 Hz, 1H), 7.23 (dd, J = 4.9, 3.9 Hz, 1H); 13C NMR (100

MHz, CDCl3) δ 170.0, 167.9, 166.9, 140.9, 138.6, 134.3(q, J = 32.6 Hz), 133.3, 132.4,

129.2, 128.9, 125.7 (q, J = 272.5 Hz), 124.0 (q, J = 3.7 Hz); 19F NMR (375 MHz,

CDCl3) δ -62.98. HRMS (Q-TOF, m/z) calcd for C14H9N3F3S [M+H]+ 308.0464,

found 308.0467.

5. References 

S10  

1. Jung, K.-Y.; Kim, S.-K.; Gao Z.-G.; Gross, A.- S.; Melman, N.; Jacobsonb, K.- A.;

Kim, Y.-C. Bioorg. Med. Chem. 2004, 12, 613.

2. Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J. Org. Chem. 1977, 42, 1153

3. Xu, X.-W.; Zhang, M.; Jiang, H.-F.; Zheng, J.; L, Y.-Q. Org. Lett. 2014, 16, 3540.

S11  

6. NMR spectra of the obtained compounds   

S12  

 

S13  

 

N N

N

3b1H NMR (400 MHz, CDCl3)

S14  

 

N N

N

3b13C NMR (100 MHz, CDCl3)

S15  

 

N N

N

Cl Cl

3c1H NMR (400 MHz, CDCl3)

S16  

 

N N

N

Cl Cl

3c13C NMR (100 MHz, CDCl3)

S17  

 

N N

N

Br Br

3d1H NMR (400 MHz, CDCl3)

S18  

   

N N

N

Br Br

3d13C NMR (100 MHz, CDCl3)

S19  

 

N N

N

O O

3e1H NMR (400 MHz, CDCl3)

S20  

 

N N

N

O O

3e13C NMR (100 MHz, CDCl3)

S21  

 

N N

N

F3C CF3

3f1H NMR (400 MHz, CDCl3)

S22  

   

N N

N

F3C CF3

3f13C NMR (100 MHz, CDCl3)

S23  

   

N N

N

F3C CF3

3f19F NMR (375 MHz, CDCl3)

S24  

   

N N

NBr Br

3g1H NMR (400 MHz, CDCl3)

S25  

 

N N

NBr Br

3g13C NMR (100 MHz, CDCl3)

S26  

   

S27  

   

S28  

 

N N

N

O

3i1H NMR (400 MHz, CDCl3)

S29  

 

S30  

 

S31  

 

S32  

 

S33  

 

S34  

 

N N

N

Cl O

3l1H NMR (400 MHz, CDCl3)

S35  

 

S36  

 

N N

N

OH3C

3m1H NMR (400 MHz, CDCl3)

S37  

 

S38  

 

S39  

 

S40  

   

S41  

     

S42  

 

S43  

 

N N

NS

Br

3p13C NMR (100 MHz, CDCl3)

S44  

 

N N

NS Br

3q1H NMR (400 MHz, CDCl3)

S45  

 

S46  

 

S47  

 

S48  

   

S49  

 

S50  

 

S51  

 

S52