One-pot synthesis of 2-alkyl-4(5)-aryl-1H-imidazoles from 1-aryl-2-bromoethanones, ammonium carbonate and aliphatic carboxylic acids

Article abstract of DOI:10.3184/174751914X13932684206700

A simple and efficient protocol for the preparation of 2-alkyl-4(5)-aryl- 1H-imidazoles starting from α-bromo aryl methyl ketones and aliphatic carboxylic acids in the presence of ammonium carbonate has been developed.

Full text of DOI:10.3184/174751914X13932684206700

208 RESEARCH PAPER
VOL. 38 APRIL, 208–210
JOURNAL OF CHEMICAL RESEARCH 2014
One-pot synthesis of 2-alkyl-4(5)-aryl-1H-imidazoles from 1-aryl-2-
bromoethanones, ammonium carbonate and aliphatic carboxylic acids
Cong Liu, Yijiao Nie, Guowei Yao, Rongji Dai* and Yulin Deng
School of Life Science, Beijing Institute of Technology, Beijing 100081, P.R. China
A simple and efficient protocol for the preparation of 2‑alkyl‑4(5)‑aryl‑1H‑imidazoles starting from α‑bromo aryl methyl ketones
and aliphatic carboxylic acids in the presence of ammonium carbonate has been developed.
Keywords: heterocycles, imidazoles, aryl methyl ketones, aliphatic acids, ammonium carbonate
The imidazole nucleus is incorporated in a variety of molecules,
many of which are of biological interest, such as vitamin
B12,1 histidine,2 nucleosides and nucleotides.3 Imidazole
derivatives are widely employed as antinociceptive agents,4
anti–hypertensive drugs,5 and ionic liquids.6 The syntheses
of imidazole derivatives reported in the literature generally
require several steps.7–9 The large quantities of waste products,
coupled with difficult availability of starting materials limit the
application of these methods.
Here we describe an innovative method of synthesising
2-alkyl-4(5)-aryl-1H-imidazoles from α-bromo aryl methyl
ketones and aliphatic acids in the presence of ammonium
carbonate. Owing to mild reaction conditions, facile operation,
and low toxicity to the environment, this reaction provides a
promising procedure for imidazole synthesis.
Table 1 Optimisation of the reaction conditions
NH
O
(NH4)2CO3
100°C
Br
N
+
HCOOH
1
2
3
Entry
Amine
T/˚C
Time/min
Yield/%
1
2
3
4
5
6
7
8
9
NH4Cl
NH4F
(NH4)2SO4
CH3COONH4
HCOONH4
NH4HCO3
Hexamethylenetetramine
(NH4)2CO3
(NH4)2CO3
90
90
90
90
90
90
90
90
60
80
100
60
60
60
60
60
60
60
60
60
60
60
0
0
0
0
5
41
65
71
43
76
81
Results and discussion
4-(3-Pyridyl)-1-H-imidazole is the key intermediate to
synthesise telithromycin.10 When synthesising this compound
by the reported method,11 we discovered that treatment of
3-(bromoacetyl)pyridine with hexamethylenetetramine in
formic acid could also generate 4-(3-pyridyl)-1-H-imidazole.
As this route for the synthesis of the imidazole core has not been
reported before, our interest quickly focused on whether the
use of other ammonium salts such as ammonium bicarbonate
was also workable. In this case, 2-bromo-1-phenylethanone was
chosen as the substrate. The results under different conditions
were shown in Table 1.
10
11
(NH4)2CO3
(NH4)2CO3
12
(NH4)2CO3
110
60
78
13
14
15
16
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
100
100
100
100
5
15
30
67
87
84
80
120
Table 2 Reaction scope of 2‑bromo‑1‑phenylethanones
NH
O
No product was observed when strong acid salts (Table 1,
entries 1–3) and ammonium acetate (Table 1, entry 4) were
used. Among the feasible ammonium salts, ammonium
carbonate provided the best yield (Table 1, entries 5–8). A
higher conversion rate was observed when temperature was
100 °C and the time was 15 minutes (Table 1, entry 14).
Having the optimal reaction conditions established, we
explored the scope of this procedure. Thus, a series of 1-aryl-
2-bromoethanones were reacted with a variety of carboxylic
acids. The results are shown in Table 2.
(NH4)2CO3
+
Br
R
H
COO
R
100°C
Ar
Ar
N
3a-n
Entry
Ar
R
Product Yield/%
New
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
H
CH3
i‑Pr
3a
3b
3c
3d
3e
3f
87
89
71
74
85
81
78
65
63
67
57
70
80
78
N
N
N
Y
N
N
N
N
N
N
N
N
Y
Y
Ph
Ph
Ph
(CH2)6CH3
2-Bromo-1-phenylethanone reacted with different aliphatic
acids to produce the corresponding 2-alkyl-4(5)-phenyl-1H-
imidazoles in good yields (Table 2, entries 1–4). Various
4‑MeC6H4
3‑MeOC6H4
4‑MeOC6H4
4‑PhC6H4
3‑FC6H4
H
H
H
H
H
H
H
H
3g
3h
3i
3j
3k
3l
2-bromo-1-phenylethanones
bearing
electron-donating
substituents in the benzene ring reacted well to give good
yields of products (Table 2, entries 5–7), whereas the presence
of electron-withdrawing substituents gave somewhat lower
yields (Table 2, entries 8–11). Reaction of substituted 2-bromo-
1-phenylethanones with different aliphatic acids provided
the 2-alkyl-4(5)-aryl-1H-imidazoles (Table 2, entries 13 and
14). Of the 14 entries in Table 2, compounds 3d, 3m and 3n
4‑ClC6H4
4‑CF3C6H4
3‑Pyridyl
4‑MeC6H4
4‑MeOC6H4
(CH2)3CH3
CH2CH3
3m
3n
* Correspondent. E-mail: dairongji@bit.edu.cn
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JOURNAL OF CHEMICAL RESEARCH 2014 209
124.8, 115.0, 14.2. IR (KBr, νmax/cm–1): 3400, 2678, 1618, 1518, 1400,
1154, 907, 756, 618, 497. HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for
C10H10N2 +H+ 159.09167; found 159.09163.
2-Isopropyl-4-phenyl-1H-imidazole (3c): White solid. m.p. 184 °C,
(lit.15 181–182 °C). 1H NMR (500 MHz, CDCl3): δ 7.67 (d, J=6 Hz, 2H),
7.34 (t, J=6.5 Hz, 2H), 7.20 (m, 2H), 3.11 (m, 1H), 1.33 (d, J=6 Hz,
6H). 13C NMR (125 MHz, CDCl3): δ 154.3, 133.1, 128.8, 126.8, 124.9,
29.8, 28.6, 21.8. IR (KBr, νmax/cm–1): 3417, 2976, 1612, 1537, 1424, 1294,
1134, 997, 913, 761, 740, 697, 615. HRMS (ESI-Orbitrap) m/z: [M+H]+
calcd for C12H14N2 +H+ 187.1230; found 187.1229.
are novel (Table 2, entries 4, 13 and 14) while other products
have been reported previously. However, all of the known
compounds have been prepared by different means to that
reported here. Besides, the structure of 3h was also confirmed
by X-ray crystallography. The details of the crystal data have
been deposited with Cambridge Crystallographic Data Centre
as Supplementary Publication, CCDC 953712.
The yield was low when all substrates were added into the
reaction vessel at the beginning. It was necessary to heat organic
acids and ammonium carbonate for at least 30 minutes. Then
2-bromo-1-phenylethanone was added to the system to produce
the imidazoles in good yields. Besides, the yields of imidazoles
were very similar to those of obtained from the Bredereck
imidazole synthesis.12,13 On the basis of the results presented
above, we propose the possible mechanism in Scheme 1. Firstly
the organic acids and ammonium carbonate produced organic
amide at high temperature, then the amide reacted with the
added 2-bromo-1-phenylethanone to produce the imidazole by
a Bredereck reaction.
2-Heptyl-4-phenyl-1H-imidazole (3d): Yellow oil, 1H NMR
(500 MHz, CDCl3): δ 9.05 (s, 1H), 7.69 (d, J=6 Hz, 2H), 7.32 (t,
J=6.5 Hz, 2H), 7.20 (m, 2H), 2.69 (t, J=6.5 Hz, 2H), 1.66 (m, 2H), 1.21
(m, 8H), 0.83 (t, J=6 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 150.0,
137.4, 133.1, 128.7, 126.6, 124.8, 115.9, 31.8, 29.4, 29.1, 28.9, 28.7, 27.7,
14.1. IR (KBr, νmax/cm–1): 3424, 2927, 2855, 1609, 1515, 1457, 1134, 757,
693, 615. HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for C16H22N2 +H+
243.1856; found 243.1857.
4-(p-Tolyl)-1H-imidazole (3e): Yellow solid, m.p. 111–113 °C, (lit.14
1
112–114 °C). H NMR (400 MHz, (CD3)2CO): δ 10.57 (s, 1H), 7.76 (s,
1H), 7.71 (d, J=8.4 Hz, 2H), 7.49 (s, 1H), 7.17 (d, J=8 Hz, 2H), 2.31
(s, 3H). 13C NMR (100 MHz, (CD3)2CO): δ 139.9, 136.6, 136.4, 132.3,
129.9, 125.5, 114.9, 21.1. IR (KBr, cm–1): 3417, 3236, 1617, 1402, 1128,
956, 824, 619, 484. HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for
C10H10N2 +H+ 159.0917; found 159.0915.
4-(3-Methoxyphenyl)-1H-imidazole (3f): Yellow oil, 1H NMR
(500 MHz, CDCl3): δ 12.11 (s, 1H), 7.71 (s, 1H), 7.36 (s, 1H), 7.34 (t,
J=2 Hz, 1H), 7.31 (d, J=6.5 Hz, 1H), 7.24 (t, J=6.5 Hz, 1H), 6.77
(dd, J=7 Hz, J=2 Hz, 1H), 3.68 (s, 3H). 13C NMR (125 MHz, CDCl3):
δ 160.1, 138.3, 135.8, 134.3, 129.9, 117.6, 116.1, 112.9, 110.4, 55.2.
IR (KBr, νmax/cm–1): 3428, 1615, 1402, 1280, 1230, 1124, 828, 770,
615. HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for C10H10N2O+H+
175.0866; found 175.0864.
4-(4-Methoxyphenyl)-1H-imidazole (3g): White solid, m.p. 136–
137 °C, (lit.12 137 °C). 1H NMR (500 MHz, CDCl3): δ 8.13 (s, 1H), 7.66
(s, 1H), 7.63 (d, J=7 Hz, 2H), 7.24 (s, 1H), 6.90 (d, J=7.5 Hz, 2H),
3.81 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 159.0, 138.3, 135.4, 126.4,
125.6, 114.7, 114.4, 55.4. IR (KBr, νmax/cm–1): 3466, 3117, 3001, 2833,
1611, 1500, 1400, 1282, 1252, 1174, 1105, 1062, 1029, 953, 839, 771,
618, 536. HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for C10H10N2O+H+
175.0866; found 175.0864.
O
RCOOH + (NH4)2CO3
RCOONH4
R
NH2
NH
O
+
r
O
r
B
R
r
A
R
NH2
A
N
Scheme 1 Proposed reaction sequence.
Conclusion
In conclusion, a new method has been developed for the
synthesis of 2-alkyl-4(5)-aryl-1H-imidazoles from 1-aryl-
2-bromoethanones, ammonium carbonate and aliphatic
carboxylic acids. Accessible substrates, simple operations
and short reaction times make it a promising procedure for
imidazole synthesis.
Experimental
All reagents and solvents were purchased from J&K Chemical Co. and
used without further purification. Melting points were determined on
a SGW X-4 micro melting point instrument. 1H and 13C NMR spectra
were recorded on Bruker 400 or 500 MHz spectrometer. IR spectra
were obtained on a PerkinElmer FT-IR system. HRMS spectra were
obtained by a LTQ Orbitrap Discovery spectrometer from Thermo.
4-[(1,1′-Biphenyl)-4-yl]-1H-imidazole (3h): Yellow solid, m.p.
1
221 °C, (lit.17 222–223 °C). H NMR (400 MHz, (CD3)2CO): δ 7.93 (d,
J=10.5 Hz, 2H), 7.73 (s, 1H), 7.67 (m, 4H), 7.60 (d, J=1 Hz, 1H), 7.46
(t, J=10 Hz, 2H), 7.34 (t, J=9 Hz, 1H). 13C NMR (100 MHz, (CD3)2CO):
δ 141.7, 139.5, 136.7, 134.7, 129.7, 127.9, 127.8, 127.4, 125.9, 114.9. IR
(KBr, νmax/cm–1): 3427, 3112, 2835, 1618, 1484, 1405, 1122, 953, 831,
764, 728, 695, 617, 495. HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for
C15H12N2 +H+ 221.1073; found 221.1075.
4-(3-Fluorophenyl)-1H-imidazole (3i): Yellow oil, 1H NMR
(500 MHz, CDCl3): δ 7.80 (s, 1H), 7.72 (d, J=0.5 Hz, 1H), 7.50 (d,
J=6.5 Hz, 1H), 7.43 (ddd, J=8.5 Hz, J=2 Hz, J=1.5 Hz, 1H), 7.35
(d, J=1 Hz, 1H), 7.32 (td, J=6.5 Hz, J=5 Hz, 1H), 6.94 (tdd, J=7 Hz,
J=2.5 Hz, J=0.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 164.2, 138.4,
135.8, 135.3, 130.5, 120.7, 115.1, 114.1, 112.1. IR (KBr, νmax/cm–1): 3410,
1617, 1401, 1266, 1197, 1125, 854, 772, 622, 478. HRMS (ESI-Orbitrap)
m/z: [M+H]+ calcd for C9H7FN2 +H+ 163.0666; found 163.0665.
4-(4-Chlorophenyl)-1H-imidazole (3j): Yellow solid, m.p. 135–
136 °C, (lit.14 140–143 °C). 1H NMR (500 MHz, CDCl3): δ 9.61 (s, 1H),
7.69 (s, 1H), 7.63 (d, J=7 Hz, 2H), 7.31 (m, 3H). 13C NMR (125 MHz,
Synthesis of compounds 3a–n; general procedure
Ammonium carbonate (0.29 g, 3 mmol) was added to the appropriate
aliphatic carboxylic acid (1 mL) and the mixture was stirred at 100 °C
for 30 minutes. The appropriate 1-aryl-2-bromoethanone (1 mmol) was
added to the solution. Then the mixture was stirred for 15 minutes. The
reaction was extracted with CH2Cl2, and the combined organic extracts
were dried, filtered and concentrated under reduced pressure to give
2-alkyl-4(5)-aryl-1H-imidazoles.
4-Phenyl-1H-imidazole (3a): Yellow solid, m.p. 126–128 °C, (lit.18
131–132 °C). H NMR (400 MHz, (CD3)2CO): δ 9.45 (s, 1H), 7.84 (d,
1
J=7.6 Hz, 2H), 7.77 (s, 1H), 7.56 (s, 1H), 7.35 (t, J=7.6 Hz, 2H), 7.20 (t,
J=7.6 Hz, 1H). 13C NMR (100 MHz, (CD3)2CO): δ 140.1, 136.6, 135.3,
129.3, 127.1, 125.5, 115.0. IR (KBr, νmax/cm–1): 3452, 3113, 2820, 2616,
1604, 1520, 1466, 1400, 1314, 1070, 957, 828, 757, 699, 620. HRMS
(ESI-Orbitrap) m/z: [M+H]+ calcd for C9H8N2 +H+ 145.07602; found
145.07591.
2-Methyl-4-phenyl-1H-imidazole (3b): White solid, m.p. 161–162 °C,
(lit.19 161 °C). H NMR (500 MHz, CDCl3): δ 7.67 (d, J=6.5 Hz, 2H),
7.34 (t, J=6.5 Hz, 2H), 7.22 (t, J=6 Hz, 1H), 7.20 (s, 1H), 2.42 (s,
3H). 13C NMR (125 MHz, CDCl3): δ 145.3, 138.4, 133.1, 128.8, 126.9,
CDCl3): δ 138.4, 135.8, 132.9, 131.6, 129.0, 126.4, 114.9. IR (KBr, νmax
/
cm–1): 3414, 3233, 2976, 2925, 2611, 1617, 1506, 1402, 1315, 1092, 1061,
950, 832, 772, 621, 507. HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for
C9H7ClN2 +H+ 179.0371; found 179.0371.
1
4-[4-(Trifluoromethyl)phenyl]-1H-imidazole (3k): White solid,
1
m.p. 147–149 °C, (lit.16 151–151.5 °C). H NMR (500 MHz, CDCl3): δ
7.85 (d, J=7 Hz, 2H), 7.76 (s, 1H), 7.62 (d, J=7 Hz, 2H), 7.43 (s, 1H),
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210 JOURNAL OF CHEMICAL RESEARCH 2014
6.85 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 136.8, 136.0, 129.2, 128.9,
125.9, 125.3, 125.2 114.6. IR (KBr, νmax/cm–1): 3420, 3232, 2834, 1618,
1462, 1411, 1324, 1171, 1121, 846, 624, 488. HRMS (ESI-Orbitrap) m/z:
[M+H]+ calcd for C10H7F3N2 +H+ 213.0634; found 213.0632.
Received 25 November 2013; accepted 6 February 2014
Paper 1302303 doi: 10.3184/174751914X13932684206700
Published online: 2 April 2014
4-(3-Pyridyl)-1H-imidazole (3l): Yellow solid, m.p. 117–118 °C, (lit.11
References
1
117–118 °C). H NMR (400 MHz, (CD3)2CO): δ 10.51 (s, 1H), 9.09 (d,
1
K. Bernhauer, O. Mueller and F. Wagner, Angew. Chem. Int. Ed. Engl.,
1964, 3, 200.
J=2 Hz, 1H), 8.43 (dd, J=4.8 Hz, J=1.6 Hz, 1H), 8.17 (dt, J=8 Hz,
J=2 Hz, 1H), 7.83 (s, 1H), 7.73 (d, J=0.8 Hz, 1H), 7.35 (dd, J=8 Hz,
J=3.2 Hz, 1H). 13C NMR (100 MHz, (CD3)2CO): δ 148.2, 147.1, 137.2,
132.3, 131.5, 124.3, 114.9. IR (KBr, νmax/cm–1): 3464, 3115, 3062, 2878,
2637, 1626, 1568, 1533, 1233, 944, 779. HRMS (ESI-Orbitrap) m/z:
[M+H]+ calcd for C8H7N3 +H+ 146.07127; found 146.07123.
2
3
4
5
6
S.W. Fox, Chem. Rev., 1943, 32, 47.
L.B. Townsend, Chem. Rev., 1967, 67, 533.
A. Puratchikody and M. Doble, Bioorg. Med. Chem., 2007, 15, 1083.
J.R. Kumar, J.L. Jat and D.P. Pathak, E-J. Chem., 2006, 3, 278.
H. Mehdi, A. Bodor, D. Lantos, I.T. Horvath, D.E. De Vos and K.
Binnemans, J. Org. Chem., 2007, 72, 517.
7
8
9
R. Di Santo, R. Costi, M. Artico, S. Massa, C. Musiu, F. Scintu, M. Putzolu
and P. La Colla, Eur. J. Med. Chem., 1997, 32, 143.
X.-C. Wang, F. Wang, Z.-J. Quan, M.-G. Wang and Z. Li, J. Chem. Res.,
2005, 11, 689.
2-Butyl-4-(p-tolyl)-1H-imidazole (3m): Yellow solid, m.p. 111–
113 °C. 1H NMR (400 MHz, CDCl3): δ 9.65 (s, 1H), 7.57 (d, J=6.5 Hz,
2H), 7.17 (s, 1H), 7.13 (d, J=6.5 Hz, 2H), 2.68 (t, J=6.5 Hz, 2H), 2.32
(s, 3H), 1.63 (m, 2H), 1.27 (m, 2H), 0.82 (t, J=6 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 149.7, 137.2, 136.4, 130.1, 129.5, 124.8, 115.5,
30.9, 28.3, 22.5, 21.2, 13.8. IR (KBr, νmax/cm–1): 3416, 2957, 1617, 1401,
1131, 822, 618, 478. HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for
C14H18N2 +H+ 215.1543; found 215.1542.
2-Ethyl-4-(3-methoxyphenyl)-1H-imidazole (3n): Yellow oil, 1H
NMR (500 MHz, CDCl3): δ 7.25 (m, 3H), 7.21 (s, 1H), 6.77 (m, 1H),
3.77 (s, 3H), 2.78 (q, J=1.5 Hz, 2H), 1.29 (t, J=6.5 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 160.1, 150.6, 137.6, 134.2, 129.9, 117.4, 115.5,
112.9, 110.2, 55.4, 21.9, 12.9. IR (KBr, νmax/cm–1): 3416, 1616, 1489,
1401, 1284, 1229, 1131, 840, 773, 689, 615, 484. HRMS (ESI-Orbitrap)
m/z: [M+H]+ calcd for C12H14N2O+H+ 203.1179; found 203.1177.
L. Yet, Prog. Heterocycl. Chem., 2004, 16, 198.
10 A. Denis, C. Agouridas, J.-M. Auger, Y. Benedetti, A. Bonnefoy, F. Bretin,
J.-F. Chantot, A. Dussarat, C. Fromentin, S.G. D’Ambrieres, S. Lachaud,
P. Laurin, O. Le Martret, V. Loyau, N. Tessot, J.-M. Pejac and S. Perron,
Bioorg. Med. Chem. Lett., 1999, 9, 3075.
11 Z. Cao, B. Liu, W. Liu, G. Yao, H. Li and T. Zou, J. Chem. Res., 2011, 35,
600.
12 H. Bredereck and G. Theilig, Chem. Ber., 1953, 86, 88.
13 S. Kumar, D. Jaller, B. Patel, J.M. LaLonde, J.B. DuHadaway, W.P.
Malachowski, G.C. Prendergast and A.J. Muller, J. Med. Chem., 2008, 51,
4968.
14 R. ten Have, M. Huisman, A. Meetsma and A.M. van Leusen, Tetrahedron,
1997, 53, 11355.
15 F. Marquez, An. R. Soc. Esp. Fis. Quim., Ser. B, 1961, 57, 723.
16 N.P. Jensen, S.M. Schmitt, T.B. Windholz, T.Y. Shen, L.R. Mandel, B.
Lopez-Ramos and C.C. Porter, J. Med. Chem., 1972, 15, 341.
17 G.P. Ellis, C. Epstein, C. Fitzmaurice, L. Golberg and G.H. Lord, J. Pharm.
Pharmacol., 1964, 16, 400.
Electronic Supplementary Information
1
13
Copies of the H and C NMR spectra for the compounds are
available through:
18 F. Bellina, S. Cauteruccio, A. Di Fiore, C. Marchetti and R. Rossi,
Tetrahedron, 2008, 64, 6060.
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
19 G. Theilig, Chem. Ber., 1953, 86, 96.
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