Simple Synthesized Mannich Bases as Ligands in Cu-Catalyzed
N-Arylation of Imidazoles in Water
Yefeng Zhu ● Yixing Shi ● Yunyang Wei
General Conditions:
All reagents unless otherwise stated were purchased from commercial suppliers and
used without further purification. Column chromatography was carried out with silica gel
(200-300 mesh). Thin layer chromatography was carried out using silica gel GF254 plates.
1
H NMR spectra were recorded on Bruker DPX (300 MHz or 400 MHz ) with CDCl3 as
solvent. Chemical shifts are reported in ppm using TMS as internal standard. Gas
chromatography mass spectra (GC/MS) were recorded on an Agilent Technologies 6890
N instrument with an Agilent 5973 N mass detector (EI) and an HP5-MS 30 m × 0.25 mm
capillary apolar column (Stationary phase: 5% diphenyldimethylpolysiloxane
film,
0.25μm). GC/MS metod: Initial temperature: 100 oC; Initial time: 2 min; Ramp: 10 oC
/min until 250 oC then held for 20 min.
All the compounds have been reported previously and characterized by comparison
with their reported data.
1
The characterization data of compounds 3a-h and 4-7
1-phenyl-1H-imidazole[1] ( 3a )
Following the general produce, using 1H-imidazole (163 mg, 2.4 mmol) and
iodobenzene (408 mg, 2 mmol) provided 260 mg ( 90% yield) of the coupling product as
a yellow oil after purification by flash chromatography (eluent: petrol ether/ethyl acetate
= 3/1).
N
N
1
H NMR ( 400 MHz, CDCl3): δ = 7.86 (s, 1H), 7.46-7.50 (m, 2H), 7.35-7.40 (m, 3H),
7.29 (br s, 1H), 7.21 (br s, 1H) ppm.
MS ( EI , M/Z): 144 [M+], 117, 90, 77.
1-(4-tolyl)-1H-imidazole[3] ( 3b )
Following the general produce, using 1H-imidazole(163 mg, 2.4 mmol) and 4–
methyliodobenzene(436 mg, 2 mmol) provided 246 mg(78% yield) of the coupling
product as a white solid after purification by flash chromatography (eluent: petrol
ether/ethyl acetate = 3/1).
N
H3C
N
Mp: 38-40 oC (lit 38-40 oC)[9]
1
H NMR ( 400 MHz, CDCl3): δ = 7.82 (s, 1H), 7.25-7.27 (m, 5H), 7.19 (br s, 1H), 2.40
(s, 3H) ppm.
MS ( EI , M/Z): 158 [M+], 131, 104, 91, 77.
2
1-(4-nitrophenyl)-1H-imidazole[4] ( 3c )
Following the general produce, using 1H-imidazole(163 mg, 2.4 mmol) and 4 –
nitroiodobenzene(498 mg, 2 mmol) provided 350 mg(93% yield) of the coupling product
as a pale yellow solid after purification by flash chromatography (eluent: petrol
ether/ethyl acetate = 1/1).
N
O2N
N
Mp: 203-205 oC (lit 204.4-205.2 oC)[9]
1
H NMR ( 300 MHz, CDCl3): δ = 8.36-8.43 (m, 2H), 8.03 (s, 1H), 7.58-7.67 (m, 2H),
7.41 (br s, 1H), 7.28 (br s, 1H) ppm.
MS ( EI , M/Z): 189 [M+], 143, 116, 89, 76.
1-(4-chlorophenyl)-1H-imidazole[2] ( 3d )
Following the general produce, using 1H-imidazole(163 mg, 2.4 mmol) and 4 –
chlorobromobenzene(383 mg, 2 mmol) provided 296 mg(83% yield) of the coupling
product as a yellow solid after purification by flash chromatography (eluent: petrol
ether/ethyl acetate = 3/1).
N
Cl
N
Mp: 84-86 oC (lit 85-87 oC)[10]
1
H NMR ( 400 MHz, CDCl3): δ = 7.82 (s, 1H), 7.43-7.46 (m, 4H), 7.32-7.34 (m, 2H),
7.24 (br s, 1H), 7.21 (br s, 1H) ppm.
MS ( EI , M/Z): 178 [M+], 151, 124, 111, 75.
3
1-(2-pyridyl)-1H-imidazole[5] ( 3e )
Following the general produce, using 1H-imidazole(163 mg, 2.4 mmol) and 2bromopyridine (316 mg, 2 mmol) provided 246 mg(85% yield) of the coupling product as
a yellow oil after purification by flash chromatography (eluent: petrol ether/ethyl acetate
= 1/1).
N
N
N
1
H NMR ( 400 MHz, CDCl3): δ = 8.51-8.53 (m, 1H), 8.38 (s, 1H), 7.84-7.88 (m, 1H),
7.68 (br s, 1H), 7.38-7.40 (m, 1H), 7.23-7.29 (m, 2H) ppm.
MS ( EI , M/Z): 145 [M+], 118, 91, 78, 51.
1-imidazol-1-yl-phenylamine[6] ( 3f )
Following the general produce, using 1H-imidazole(163 mg, 2.4 mmol) and 4aminobromobenzene (344 mg, 2 mmol) provided 197 mg(62% yield) of the coupling
product as a yellow solid after purification by flash chromatography(eluent: petrol
ether/ethyl acetate = 1/1).
N
H2N
N
Mp: 137-138 oC (lit 138-139 oC)[13].
1
H NMR ( 400 MHz, CDCl3): δ = 7.72 (s, 1H), 7.13-7.16 (m, 4H), 6.71-6.75 (m, 2H),
3.73(s, 2H) ppm.
MS ( EI , M/Z): 159 [M+], 131, 118, 92, 75.
4
4-imidazol-1-yl-phenol[3] ( 3g )
Following the general produce, using 1H-imidazole(163 mg, 2.4 mmol) and 4hydroxylbromobenzene (346 mg, 2 mmol) provided 192 mg(60% yield) of the coupling
product as a yellow solid after purification by flash chromatography(eluent: petrol
ether/ethyl acetate = 1/1).
N
HO
N
Mp: 202-205 oC (lit 203-205 oC)[14].
MS ( EI , M/Z): 160 [M+], 159, 118, 93, 75.
1-(4-methoxyphenyl)-1H-imidazole[4] ( 3h )
Following the general produce, using 1H-imidazole(163 mg, 2.4 mmol) and 4 –
methoxybromobenzene(374 mg, 2 mmol) provided 222 mg(64% yield) of the coupling
product as a yellow oil after purification by flash chromatography (eluent: petrol
ether/ethyl acetate = 3/1).
N
H3CO
1
N
H NMR ( 400 MHz, CDCl3): δ = 7.76 (s, 1H), 7.30(d, J = 8.8 Hz, 2H), 7.19(d, J = 8.8
Hz, 2H), 6.97-6.99(m, 2H), 3.85(s, 3H) ppm.
MS ( EI , M/Z): 174 [M+], 159, 147, 132, 120, 104, 92, 77.
5
1-phenyl-1H- pyrrole[7] ( 4 )
Following the general produce, using 1H- pyrrole (161 mg, 2.4 mmol) and
4-
iodobenzene (408 mg, 2 mmol) provided 257 mg(90% yield) of the coupling product as a
pale brown solid after purification by flash chromatography (eluent: petrol ether).
N
Mp: 61-63 oC (lit 62 oC)[11]
1
H NMR ( 300 MHz, CDCl3): δ = 7.36-7.43 (m, 4H), 7.20-7.25 (m, 1H), 7.07-7.09 (m,
2H), 6.33-6.35 (m, 2H) ppm.
MS ( EI , M/Z): 143 [M+], 116, 77, 65, 51.
1-phenyl-1H-indole[1] ( 5 )
Following the general produce, using 1H-indole(286 mg, 2.4 mmol) and
4-
iodobenzene (408 mg, 2 mmol) provided 355 mg(92% yield) of the coupling product as a
light green oil after purification by flash chromatography (eluent: petrol ether).
N
1
H NMR ( 300 MHz, CDCl3): δ = 7.66-7.69 (m, 1H), 7.52-7.56 (m, 1H), 7.45-7.47 (m,
4H), 7.27-7.33 (m, 2H), 7.12-7.22 (m, 2H), 6.65-6.66 (m, 1H) ppm.
MS ( EI , M/Z): 193 [M+], 192, 165, 90, 89, 77.
6
1-(2-pyridyl)-1H-benzimidazole[4] ( 6 )
Following the general produce, using 1H-benzimidazole(284 mg, 2.4 mmol) and 2bromopyridine (316 mg, 2 mmol) provided 350 mg(90% yield) of the coupling product as
a white solid after purification by flash chromatography (eluent: petrol ether/ethyl acetate
= 3/1).
N
N
N
Mp:59-60 oC ( lit 59-60 oC)[12]
1
H NMR ( 400 MHz, CDCl3): δ = 8.60-8.62 (m, 1H), 8.57 (s, 1H), 7.92-8.07 (m, 1H),
7.86-7.92 (m, 2H), 7.56-7.58 (m, 1H), 7.28-7.31 (m, 1H), 7.33-7.40 (m, 2H) ppm.
MS ( EI , M/Z): 195 [M+], 194, 170, 169, 84, 78.
1-(2-pyridyl)-2-methyl-imidazole[8] ( 7 )
Following the general produce, using 2-methylimidazole (197 mg, 2.4 mmol) and 2bromopyridine (316 mg, 2 mmol) provided 257 mg(81% yield) of the coupling product as
a light yellow oil after purification by flash chromatography(eluent: petrol ether/ethyl
acetate = 1/1).
H3C
N
N
N
1
H NMR ( 300 MHz, CDCl3): δ = 7.81-7.87 (m, 1H), 7.81-7.87 (m, 1H), 7.27-7.38 (m,
3H), 7.01-7.02 (m, 1H), 2.59 (s, 3H) ppm.
MS ( EI , M/Z): 159 [M+], 118, 105, 78, 65, 51.
7
Reference
[1] Taillefer M, Xia N, Ouali A (2007) Angew Chem Int Ed 46:934
[2] Sreedhar B, Arundhathi R, LingaReddy P, LakshmiKantam M (2009) J Org Chem
74:7951
[3] Altman RA, Koval ED, Buchwald SL (2007) J Org Chem 72:6190
[4] Ma HC, Jiang XZ (2007) J Org Chem. 72:8943
[5] Suresh P, Pitchumani K (2008) J Org Chem. 73:9121
[6] Zhu L, Guo P, Li G, Lan J, Xie R, You J (2007) J Org Chem. 72:8535
[7] Cristau HJ, Cellier PP, Spindler JF, Taillefer M (2004) Eur Chem J 10:5607
[8] Lei Liang, Zhengkai Li, Xiangge Zhou (2009) Org Lett 11:3294
[9] Tonhnson AL, Kaner JC, Sharma DC, Donfman RL (1969) J Med Chem 12:1024.
[10] Franchetti P, Grifantini M, Marteui S, Slein ML (1974) J Med Chem 17:18.
[11] Dumoulin H, Raulkt S, Robba M (1995) J Heterocyel Chem 32:1703.
[12] Palmer BD, Smaill JB, Boyd M (1998) 41:5457.
[13] Zhangjin Z, Jincheng M, Zhu D, Fan W, Huilin C, Boshun W (2006) Tetrahedron
62:4435.
[14] Spencer J (2008) Tetrahedron 64:10195.
8
The NMR spectra of compounds 3a-h and 4-7
1-phenyl-1H-imidazole ( 3a )
N
N
9
1-(4-tolyl)-1H-imidazole ( 3b )
N
H3C
N
1-(4-nitrophenyl)-1H-imidazole ( 3c )
N
O2N
N
10
1-(2-pyridyl)-1H-imidazole ( 3e )
N
N
N
11
1-(4-chlorophenyl)-1H-imidazole ( 3d )
N
Cl
N
1-imidazol-1-yl-phenylamine ( 3f )
N
H2N
N
12
1-(4-methoxyphenyl)-1H-imidazole ( 3h )
N
H3CO
N
1-(2-pyridyl)-1H-benzimidazole ( 6 )
N
N
N
13
7.70
7.60
7.50
7.40
7.0
6.5
7.30
6.0
7.20
5.5
7.10
6.3484
6.3411
6.3337
7.5
2.0000
8.0
7.0878
7.0805
7.0732
8.5
2.0646
9.0
7.2518
7.2439
7.2329
7.2231
7.2140
7.2024
7.4341
7.4048
7.3920
7.3841
7.3621
9.5
1.1735
4.1588
Integral
2.0000
2.0646
1.1735
4.1588
Integral
5.0
7.00
4.5
6.90
4.0
3.5
6.80
3.0
6.70
2.5
6.60
2.0
1.5
6.50
-0.0006
1.2564
6.3484
6.3411
6.3337
7.4341
7.4048
7.3920
7.3841
7.3621
7.2518
7.2439
7.2329
7.2231
7.2140
7.2024
7.0878
7.0805
7.0732
1-phenyl-1H- pyrrole ( 4 )
N
2# 1H-NMR CDCL3 300K AV-300
(ppm)
1.0
6.40
0.5
0.0
2# 1H-NMR CDCL3 300K AV-300
(ppm)
6.30
14
7.90
7.80
7.70
7.60
7.50
7.40
4.5
7.30
7.20
4.0
7.10
6.6629
6.6519
5.0
1.0000
5.5
2.2325
6.0
7.2219
7.2030
7.1982
7.1756
7.1701
7.1494
7.1451
7.1262
6.5
7.3317
7.3170
7.3024
7.2914
7.2744
7.0
2.0782
7.5
4.1820
8.0
7.4700
7.4554
8.5
7.5286
9.0
7.5560
7.6852
7.6614
9.5
1.0832
1.0517
Integral
1.0000
2.2325
2.0782
4.1820
1.0832
1.0517
Integral
3.5
3.0
7.00
2.5
6.90
2.0
1.5
6.80
0.0000
1.2576
7.6852
7.6614
7.5560
7.5286
7.4700
7.4554
7.3317
7.3170
7.3024
7.2914
7.2744
7.2219
7.2030
7.1982
7.1756
7.1701
7.1494
7.1451
7.1262
6.6629
6.6519
1-phenyl-1H-indole ( 5 )
N
3# 1H-NMR CDCL3 300K AV-300
(ppm)
1.0
6.70
0.5
3# 1H-NMR CDCL3 300K AV-300
(ppm)
6.60
15
8.8
8.7
8.6
8.5
8.4
8.3
8.2
8.1
8.0
5.0
7.9
7.8
4.0
7.7
7.6
3.0
7.5
7.4
7.3
7.2
7.0159
7.0110
6.0
1.0774
7.0
3.1689
8.0
3.3155
1.0774
3.1689
1.0626
1.0000
Integral
2.0
7.1
-0.0000
1.2625
2.3720
2.3494
2.3226
2.0294
2.0025
1.9757
2.8273
2.8029
2.5890
3.3894
3.3662
3.3424
5.2919
8.5533
8.5502
8.5374
8.5338
7.8718
7.8657
7.8449
7.8407
7.8199
7.8138
7.3762
7.3310
7.3152
7.3121
7.3042
7.3006
7.2957
7.2847
7.2798
7.2744
7.0159
7.0110
N
7.3310
7.3152
7.3121
7.3042
7.3006
7.2957
7.2847
7.2798
7.2744
9.0
7.3762
7.8718
7.8657
7.8449
7.8407
7.8199
7.8138
8.5533
8.5502
8.5374
8.5338
10.0
1.0626
1.0000
Integral
1-(2-pyridyl)-2-methyl-imidazole ( 7 )
H3C
N
N
1# 1H-NMR CDCL3 300K AV-300
(ppm)
1.0
7.0
0.0
1# 1H-NMR CDCL3 300K AV-300
(ppm)
6.9
16