Synthesis of 1,2,4,5-tetrasubstituted imidazoles by a sequential aza-Wittig/Michael/isomerization reaction

Article abstract of DOI:10.1021/jo201846w

Carbodiimides 4, obtained from aza-Wittig reactions of iminophosphorane 3 with aryl isocyanates, reacted with secondary amines in the presence of a catalytic amount of sodium alkoxide to give 1,2,4,5-tetrasubstituted imidazoles 7 in good yields. However,

Full text of DOI:10.1021/jo201846w

Note
pubs.acs.org/joc
Synthesis of 1,2,4,5-Tetrasubstituted Imidazoles by a Sequential Aza-
Wittig/Michael/Isomerization Reaction
Yi-Bo Nie, Long Wang, and Ming-Wu Ding*
Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, Central China Normal University, Wuhan 430079,
People’s Republic of China
S
* Supporting Information
ABSTRACT: Carbodiimides 4, obtained from aza-Wittig reactions of
iminophosphorane 3 with aryl isocyanates, reacted with secondary
amines in the presence of a catalytic amount of sodium alkoxide to give
1,2,4,5-tetrasubstituted imidazoles 7 in good yields. However, 4-
acylimidazoles 11 were obtained, as phenols were used in the presence
of a catalytic amount of potassium carbonate due to further air oxidation
of the expected products 10.
ultisubstituted imidazoles are a class of pharmaceutically
important heterocyclic compounds and have been found
imidazolones were obtained efficiently via the tandem processes
involving aza-Wittig/intermolecular nucleophilic addition/
intramolecular cyclizations.25 Here, we wish to report a new
approach to the synthesis of 1,2,4,5-tetrasubstituted imidazoles
by a new sequential aza-Wittig/Michael/isomerization reaction.
The α-azidocinnamaldehyde 1, obtained from the reaction of
α,β-dibromocinnamaldehyde with sodium azide,26 reacted with
alkoxycarbonylmethylidenetriphenylphosphorane to give the
azide 2 in 88−92% yields. Further Staudinger reaction of azide
2 with triphenylphosphine at room temperature produced
iminophosphorane 3 in high yields (Scheme 1).
M
to show widespread biological activities. A wide variety of
derivatives of this ring system have been used as heme
oxygenase-1 inhibitors,1 HMG-CoA reductase inhibitors,2 heme
oxygenase inhibitors,3 fatty acid amide hydrolase inhibitors,4 γ-
aminobutyric acid receptor agonists,5 and P2X7 receptor
agonists.6 Some of them have also been incorporated in
marketed drugs such as cimetidine and losartan.7 There are
many known methods for the synthesis of imidazoles. For
example, some imidazoles have been prepared by Ugi reaction
and Davidson cyclization8−10 or by reaction of imidazolium
ylids and lithiated imidazoles,11,12 and other imidazoles can be
obtained starting from amino acids or p-toluenesulfonylmethyl
isocyanide (TosMIC).13−17 However, there is no general
method for the synthesis of different functionalized imidazole
derivatives, and 2-amino- or 2-aryloxy-substituted imidazoles
were not easily accessible by currently existing routes.
Consequently, new methodologies for the preparation of
multisubstituted imidazoles are still desirable in synthetic
organic and pharmaceutical chemistry.
Scheme 1
The aza-Wittig reactions of iminophosphoranes have
received increased attention in view of their utility in the
synthesis of nitrogen heterocyclic compounds.18 The carbodii-
mides, obtained efficiently by aza-Wittig reaction of imino-
phosphoranes with isocyanates under mild neutral conditions,
can be used as synthetic intermediates of heterocycles by
tandem processes involving aza-Wittig/intermolecular nucleo-
philic addition/intramolecular cyclizations. These tandem
processes have been utilized previously in synthesis of
imidazolones,19 quinazolinones,20 pteridin-4(3H)-ones,21 pyr-
azinothienopyrimidinone,22 and quinazolines.23 We have also
been interested in the synthesis of N-heterocycles through aza-
Wittig reactions, with the aim of evaluating their biological
activities.24 Among them, indoles, fused pyrimidinones, and
Reaction of iminophosphorane 3 with aromatic isocyanates
at room temperature furnished the required carbodiimides 4
(Scheme 2), which were allowed to react with secondary
amines to provide the guanidine intermediates 5. Even in
refluxing acetonitrile, 5 did not cyclize; however, in the
presence of a catalytic amount of sodium ethoxide, 5 was
converted directly to 1,2,4,5-tetrasubstituted imidazoles 7a−k
in satisfactory yields at room temperature. The results are listed
in Table 1. The formation of 7 can be rationalized in terms of
Received: September 13, 2011
Published: November 18, 2011
© 2011 American Chemical Society
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The Journal of Organic Chemistry
Note
Scheme 2
Scheme 3
Table 1. Yields of Compounds 7a−k and 11a−g
entry
NR1R2/OAr2
Ar1
R
yield (%)
The structures of imidazoles 7 and 11 were confirmed by
their spectral data. Furthermore, a single crystal of 11b was
obtained from a CH2Cl2 solution of 11b. X-ray structure
analysis verified the proposed structure (Figure S1 in the
Supporting Information).
In summary, we have developed an efficient synthesis of
1,2,4,5-substituted imidazoles via base-catalyzed reaction of
functionalized carbodiimides with various amines or phenols.
Because of the mild reaction conditions, good yields, and easily
accessible starting material, we think that this new synthetic
approach discussed here has potential in the synthesis of
various 1,2,4,5-substituted imidazoles, which are of considerable
interest as potential biologically active compounds or
pharmaceuticals.
7a
morpholin-4-yl
morpholin-4-yl
morpholin-4-yl
morpholin-4-yl
morpholin-4-yl
N(Et)2
4-Cl-C6H5
4-F-C6H5
3-Me-C6H5
4-Me-C6H5
4-Cl-C6H5
4-Cl-C6H5
4-Cl-C6H5
4-Cl-C6H5
4-Cl-C6H5
4-Cl-C6H5
4-Cl-C6H5
C6H5
Et
86
82
84
83
87
84
79
80
81
82
83
67
73
75
69
73
72
62
7b
Et
7c
Et
7d
Et
7e
Me
Et
7f
7g
N(n-Bu)2
Et
7h
piperidin-1-yl
piperidin-1-yl
pyrrolidin-1-yl
pyrrolidin-1-yl
4-Cl-C6H5O
C6H5O
Et
7i
Me
Et
7j
7k
Me
Et
11a
11b
11c
11d
11e
11f
11g
4-Cl-C6H5
4-Cl-C6H5
4-Cl-C6H5
4-Me-C6H5
4-Cl-C6H5
4-Me-C6H5
Et
4-Me-C6H5O
2,4-2Cl-C6H5O
4-Cl-C6H5O
4-Cl-C6H5O
4-Cl-C6H5O
Et
Et
EXPERIMENTAL SECTION
■
Et
Preparation of Azides 2. To a solution of alkoxycarbonylme-
thylidenetriphenylphosphorane (3 mmol) in dry methylene chloride
(15 mL) was added 2-azido-cinnamaldehyde 1 (0.52 g, 3 mmol) at
room temperature. After the reaction mixture was stirred for 2 h at
ambient temperature, the solvent was removed under reduced
pressure, and the residue was purified by chromatography eluting
with Et2O/petroleum ether 1:2 to give azides 2.
Et
Me
an initial intramolecular Michael addition of the guanidine
intermediates 5 under the catalysis of sodium ethoxide to give
the dihydroimidazoles 6, which isomerize through 1,3-H shift
Ethyl 4-Azido-5-phenylpenta-2,4-dienoate (2a). Light yellow oil
to give 7.
(yield 88%): IR (KBr, cm−1) 2112, 1716, 1624, 1447, 1368, 1306,
The reactions of carbodiimides 4 with phenols were further
examined in MeCN at 40−50 °C for 2−3 days, in the presence
of a catalytic amount of potassium carbonate. To our surprise,
the final products 4-phenacylimidazoles 11 were obtained
directly from the reaction mixture instead of imidazoles 10
(Scheme 3). The results are listed in Table 1. As indicated in
Table 1, the reaction is relatively insensitive to the presence or
absence of substituents on the phenols, and the 2-aryloxy-4-
phenacylimidazoles 11 can be obtained in 62−75% yields. The
unexpected formation of 11 can be rationalized in terms of an
initial nucleophilic addition of phenoxides to the carbodiimides
4 to give the intermediates 8, which undertake intramolecular
Michael addition to create the dihydroimidazoles 9 by the
catalysis of potassium carbonate. Further isomerization of 9
through 1,3-H shift produces imidazoles 10, which might be
oxidized by air to give 4-phenacylimidazoles 11 under the
reaction conditions. Although the reason for the above
oxidixation is not yet very clear, it is deduced that 2-
aryloxyimidazoles 10 are more easily oxidized than 2-amino-
imidazoles 7.
1
1264, 1156, 1036, 972, 693; H NMR (CDCl3, 600 MHz) δ (ppm)
7.64−7.26 (m, 6H), 6.38 (s, 1H), 6.27 (d, J = 15.6 Hz, 1H), 4.26 (q, J
= 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz)
δ (ppm) 166.2, 140.6, 133.6, 132.4, 129.6, 128.8, 128.5, 127.5, 119.3,
60.7, 14.2.
Methyl 4-Azido-5-phenylpenta-2,4-dienoate (2b). Light yellow
oil (yield 92%): IR (KBr, cm−1) 2105, 1716, 1625, 1434, 1384, 1309,
1
1266, 1197, 1163, 982, 916, 852, 748, 690; H NMR (CDCl3, 600
MHz) δ (ppm) 7.64−7.26 (m, 6H), 6.38 (s, 1H), 6.28 (d, J = 15.6 Hz,
1H), 3.81 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 166.7,
140.9, 133.5, 132.3, 129.6, 128.8, 128.5, 127.7, 118.7, 51.8.
Preparation of Iminophosphosphorane 3. To a stirred
solution of 2a (5 mmol) in methylene dichloride (10 mL) was
added dropwise triphenylphosphine (1.31 g, 5 mmol) in methylene
dichloride (10 mL) at room temperature. After the reaction mixture
was stirred for 2 h at ambient temperature, the solvent was removed
under reduced pressure, and the residual was purified by
chromatography eluting with Et2O/petroleum ether 1:2 to give
iminophosphosphorane 3 as yellow solid.
Ethyl 5-Phenyl-4-((triphenylphosphoranylidene)amino)penta-
2,4-dienoate (3a). Yellow solid (yield 90%): mp 96−98 °C; 1H
NMR (CDCl3, 600 MHz) δ (ppm) 7.82−7.02 (m, 21H), 6.08 (s, 1H),
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Note
5.73 (d, J = 15.6 Hz, 1H), 4.02 (q, J = 7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.2, 149.2, 132.5,
132.0, 131.7, 131.4, 128.9, 128.7, 128.4, 127.8, 127.6, 125.3, 117.5,
59.6, 14.2; MS (EI, 70 eV) m/z (%) 477 (M+, 2), 407 (34), 378 (14),
277 (44), 262 (87), 239 (75), 183 (100), 133 (48). Anal. Calcd for
C31H28NO2P: C, 77.97; H, 5.91; N, 2.93. Found: C, 77.83; H, 6.04; N,
3.08.
Methyl 2-(4-Benzyl-1-(4-chlorophenyl)-2-morpholino-1H-imida-
1
zol-5-yl)acetate (7e). White solid (yield 87%): mp 94−96 °C; H
NMR (CDCl3, 600 MHz) δ (ppm) 7.69−7.18 (m, 9H), 3.91 (s, 2H),
3.58−3.54 (m, 4H), 3.47 (s, 3H), 3.27 (s, 2H), 2.99−2.95 (m, 4H);
13C NMR (CDCl3, 150 MHz) δ (ppm) 170.2, 151.0, 139.8, 135.2,
134.8, 134.1, 132.0, 131.9, 131.8, 129.6, 128.8, 128.5, 128.4, 128.3,
128.1, 125.8, 118.5, 66.3, 51.8, 49.7, 33.6, 29.3; MS (EI, 70 eV) m/z
(%) 425 (M+, 50), 366 (100), 277 (14), 138 (12), 128 (11), 117 (18),
91 (14). Anal. Calcd for C23H24ClN3O3: C, 64.86; H, 5.68; N, 9.87.
Found: C, 64.98; H, 5.81; N, 10.06.
Methyl 5-Phenyl-4-((triphenylphosphoranylidene)amino)penta-
1
2,4-dienoate (3b). Yellow solid (yield 92%): mp 124−125 °C; H
NMR (CDCl3, 600 MHz) δ (ppm) 7.82−7.02 (m, 21H), 6.08 (s, 1H),
5.76 (d, J = 15.6 Hz, 1H), 3.57 (s, 3H); 13C NMR (CDCl3, 150 MHz)
δ (ppm) 167.8, 149.8, 143.7, 138.4, 132.6, 132.2, 131.5, 128.8, 128.5,
127.7, 127.4, 120.4, 117.0, 51.1; MS (EI, 70 eV) m/z (%) 463 (M+, 2),
404 (38), 378 (13), 277 (26), 262 (56), 185 (100), 108 (35). Anal.
Calcd for C30H26NO2P: C, 77.74; H, 5.65; N, 3.02. Found: C, 77.97;
H, 5.84; N, 2.98.
Ethyl 2-(4-Benzyl-1-(4-chlorophenyl)-2-(diethylamino)-1H-imida-
1
zol-5-yl)acetate (7f). White solid (yield 84%): mp 56−57 °C; H
NMR (CDCl3, 600 MHz) δ (ppm) 7.42−7.16 (m, 9H), 3.93−3.89
(m, 4H), 3.24 (s, 2H), 2.94 (q, J = 7.2 Hz, 4H), 1.09 (t, J = 7.2 Hz,
3H), 0.92 (t, J = 7.2 Hz, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm)
169.9, 151.0, 140.2, 135.2, 135.1, 133.9, 129.5, 129.3, 129.2, 128.5,
128.3, 128.2, 127.9, 125.8, 125.6, 118.3, 60.7, 46.1, 33.5, 29.7, 13.6,
13.2, 12.3; MS (EI, 70 eV) m/z (%) 425 (M+, 37), 352 (100), 286
(17), 138 (10), 128 (7), 117 (14), 91 (14). Anal. Calcd for
C24H28ClN3O2: C, 67.67; H, 6.63; N, 9.87. Found: C, 67.83; H, 6.49;
N, 10.11.
General Procedure for Preparation of 1,2,4,5-Tetrasubsti-
tuted Imidazoles 7a−k. To a solution of iminophosphorane 3 (3
mmol) in dry methylene dichloride (15 mL) was added aromatic
isocyanate (3 mmol) at room temperature. After the reaction mixture
was left to stand for 20 min at room temperature, the secondary amine
R1R2NH (3 mmol) was added. The reaction mixture was allowed to be
stirred for 0.5−1 h, and then the solvent was removed, and anhydrous
ethanol (10 mL) with EtONa (0.3 mmol, 10% equiv) in EtOH was
added. The mixture was stirred for 2−4 h at room temperature. The
solution was concentrated under reduced pressure, and the residue was
subjected to chromatography on silica gel eluting with Et2O/
petroleum ether 1:3 to give 7a−k.
Ethyl 2-(4-Benzyl-1-(4-chlorophenyl)-2-(dibutylamino)-1H-imida-
1
zol-5-yl)acetate (7g). White solid (yield 79%): mp 45−47 °C; H
NMR (CDCl3, 600 MHz) δ (ppm) 7.42−7.15 (m, 9H), 3.92−3.88
(m, 4H), 3.23 (s, 2H), 2.87 (t, J = 7.2 Hz, 4H), 1.32−1.12 (m, 8H),
1.08 (t, J = 7.2 Hz, 3H), 0.81 (t, J = 7.2 Hz, 6H); 13C NMR (CDCl3,
150 MHz) δ (ppm) 170.0, 151.7, 140.3, 135.4, 135.1, 134.0, 129.6,
129.4, 128.6, 128.4, 128.2, 128.0, 125.8, 118.1, 60.8, 51.8, 33.5, 29.7,
20.1, 14.1, 13.7; MS (EI, 70 eV) m/z (%) 481 (M+, 44), 408 (77), 382
(100), 272 (20), 138 (23), 125 (16), 117 (24), 91 (29). Anal. Calcd
for C28H36ClN3O2: C, 69.76; H, 7.53; N, 8.72. Found: C, 69.89; H,
7.72; N, 8.96.
Ethyl 2-(4-Benzyl-1-(4-chlorophenyl)-2-morpholino-1H-imidazol-
1
5-yl)acetate (7a). White solid (yield 86%): mp 93−94 °C; H NMR
(CDCl3, 600 MHz) δ (ppm) 7.44−7.43 (m, 2H), 7.30−7.25 (m,, 6H),
7.18−7.16 (m, 1H), 3.93−3.90 (m, 4H), 3.57−3.55 (m, 4H), 3.26 (s,
2H), 2.98−2.96 (m, 4H), 1.10 (t, J = 14.4 Hz, 3H); 13C NMR
(CDCl3, 150 MHz) δ (ppm) 169.7, 151.0, 139.9, 135.2, 134.9, 134.1,
129.6, 128.9, 128.7, 128.6, 128.4, 128.2, 128.0, 125.8, 125.6, 118.7,
66.3, 60.8, 49.7, 33.5, 29.5, 14.0, 13.6; MS (EI, 70 eV) m/z (%) 439
(M+, 40), 382 (10), 366 (100), 218 (7), 138 (11), 128 (11), 117 (16).
Anal. Calcd for C24H26ClN3O3: C, 65.52; H, 5.96; N, 9.55. Found: C,
65.79; H, 6.03; N, 9.78.
Ethyl 2-(4-Benzyl-1-(4-chlorophenyl)-2-(piperidin-1-yl)-1H-imida-
1
zol-5-yl)acetate (7h). White solid, (yield 80%): mp 50−51 °C; H
NMR (CDCl3, 600 MHz) δ (ppm) 7.42−7.16 (m, 9H), 3.92−3.89
(m, 4H), 3.26 (s, 2H), 2.92 (t, J = 4.8 Hz, 4H), 1.43−1.40 (m, 6H),
1.09 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 170.0,
152.4, 140.1, 135.4, 135.0, 133.7, 129.4, 128.8, 128.6, 128.1, 125.8,
118.1, 60.8, 50.8, 33.6, 29.8, 25.5, 24.0, 13.9; MS (EI, 70 eV) m/z (%)
437 (M+, 40), 408 (4), 366 (37), 364 (100), 218 (6), 138 (10), 128
(9), 117 (13), 91 (10). Anal. Calcd for C25H28ClN3O2: C, 68.56; H,
6.44; N, 9.59. Found: C, 68.62; H, 6.56; N, 9.78.
Ethyl 2-(4-Benzyl-1-(4-fluorophenyl)-2-morpholino-1H-imidazol-
5-yl)acetate (7b). White solid (yield 82%): mp 104−106 °C; 1H
NMR (CDCl3, 600 MHz) δ (ppm) 7.33−7.15 (m, 9H), 3.93−3.90
(m, 4H), 3.57−3.53 (m, 4H), 3.26 (s, 2H), 2.99−2.95 (m, 4H), 1.10
(t, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 169.8,
161.9, 151.1, 139.9, 135.0, 132.4, 129.4, 129.3, 128.6, 128.4, 128.2,
128.0, 125.8, 125.6, 118.9, 116.4, 116.3, 116.1, 66.4, 60.8, 49.8, 33.6,
29.6, 14.1; MS (EI, 70 eV) m/z (%) 423 (M+, 32), 366 (100), 218
(15), 138 (27), 128 (46), 117 (58). Anal. Calcd for C24H26FN3O3: C,
68.07; H, 6.19; N, 9.92. Found: C, 68.16; H, 6.08; N, 9.68.
Ethyl 2-(4-Benzyl-2-morpholino-1-(m-tolyl)-1H-imidazol-5-yl)-
acetate (7c). White solid (yield 84%): mp 61−63 °C; 1H NMR
(CDCl3, 600 MHz) δ (ppm) 7.34−7.12 (m, 9H), 3.92−3.89 (m, 4H),
3.55−3.52 (m, 4H), 3.27 (s, 2H), 2.99−2.96 (m, 4H), 2.38 (s, 3H),
1.09 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 169.9,
150.9, 140.1, 139.3, 136.3, 134.6, 129.1, 128.9, 128.6, 128.4, 128.1,
128.0, 127.8, 125.8, 125.6, 124.5, 118.8, 66.4, 60.6, 49.6, 33.5, 29.7,
21.1, 14.1, 13.7; MS (EI, 70 eV) m/z (%) 419 (M+, 39), 362 (9), 346
(100), 277 (21), 199 (5), 128 (5), 118 (9), 106 (6), 91 (24). Anal.
Calcd for C25H29N3O3: C, 71.57; H, 6.97; N, 10.02. Found: C, 71.69;
H, 7.20; N, 10.25.
Ethyl 2-(4-Benzyl-2-morpholino-1-(p-tolyl)-1H-imidazol-5-yl)-
acetate (7d). White solid (yield 83%): mp 64−65 °C; 1H NMR
(CDCl3, 600 MHz) δ (ppm) 7.29−7.17 (m, 9H), 3.92−3.90 (m, 4H),
3.56−3.53 (m, 4H), 3.25 (s, 2H), 2.99−1.97 (m, 4H), 2.40 (s, 3H),
1.09 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 170.0,
151.0, 140.1, 138.2, 134.5, 133.7, 130.0, 129.8, 128.6, 128.5, 128.2,
128.0, 127.4, 127.2, 125.8, 119.0, 66.4, 60.7, 49.6, 33.5, 29.7, 21.1, 14.1,
13.7; MS (EI, 70 eV) m/z (%) 419 (M+, 38), 362 (8), 346 (100), 144
(3), 118 (7), 91 (16). Anal. Calcd for C25H29N3O3: C, 71.57; H, 6.97;
N, 10.02. Found: C, 71.82; H, 7.23; N, 10.28.
Methyl 2-(4-Benzyl-1-(4-chlorophenyl)-2-(piperidin-1-yl)-1H-imi-
1
dazol-5-yl)acetate (7i). White solid (yield 81%): mp 62−63 °C; H
NMR (CDCl3, 600 MHz) δ (ppm) 7.43−7.16 (m, 9H), 3.91 (s, 2H),
3.45 (s, 3H), 3.26 (s, 2H), 2.92 (t, J = 4.8 Hz, 4H), 1.48−1.32 (m,
6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 170.3, 152.4, 140.0,
135.3, 135.0, 133.7, 129.4, 128.7, 128.6, 128.1, 125.7, 117.9, 51.8, 50.7,
33.6, 29.4, 25.4; MS (EI, 70 eV) m/z (%) 423 (M+, 47), 366 (30), 364
(100), 218 (4), 138 (10), 128 (6), 117 (15), 111 (13), 91 (11). Anal.
Calcd for C24H26ClN3O2: C, 68.00; H, 6.18; N, 9.91. Found: C, 68.27;
H, 6.46; N, 10.12.
Ethyl 2-(4-Benzyl-1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)-1H-imi-
1
dazol-5-yl)acetate (7j). White solid (yield 82%): mp 53−55 °C; H
NMR (CDCl3, 600 MHz) δ (ppm) 7.40−7.15 (m, 9H), 3.92−3.90
(m, 4H), 3.18 (s, 2H), 3.06 (t, J = 6.6 Hz, 4H), 1.76−1.73 (m, 4H),
1.10 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 170.2,
151.3, 140.2, 135.8, 134.6, 134.1, 129.9, 129.3, 128.6, 128.1, 125.8,
117.9, 60.8, 49.7, 33.7, 29.6, 25.2, 13.9; MS (EI, 70 eV) m/z (%) 423
(M+, 27), 352 (32), 350 (100), 218 (6), 138 (8), 128 (6), 117 (11), 91
(8). Anal. Calcd for C24H26ClN3O2: C, 68.00; H, 6.18; N, 9.91. Found:
C, 68.18; H, 6.01; N, 10.15.
Methyl 2-(4-Benzyl-1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)-1H-imi-
1
dazol-5-yl)acetate (7k). White solid (yield 83%): mp 68−69 °C; H
NMR (CDCl3, 600 MHz) δ (ppm) 7.41−7.15 (m, 9H), 3.89 (s, 2H),
3.46 (s, 3H), 3.18 (s, 2H), 3.06 (t, J = 6.6 Hz, 4H), 1.76−1.73 (m,
4H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 170.6, 151.3, 140.1,
135.7, 134.6, 134.1, 129.9, 129.3, 128.6, 128.1, 125.7, 117.3, 51.7, 49.6,
33.7, 29.3, 25.1; MS (EI, 70 eV) m/z (%) 409 (M+, 34), 352 (35), 350
(100), 334 (16), 218 (7), 138 (10), 128 (6), 117 (11), 91 (10). Anal.
698
dx.doi.org/10.1021/jo201846w | J. Org. Chem. 2012, 77, 696−700

The Journal of Organic Chemistry
Note
Calcd for C23H24ClN3O2: C, 67.39; H, 5.90; N, 10.25. Found: C,
67.62; H, 5.72; N, 10.19.
204 (10), 145 (14), 129 (11), 111 (21), 105 (100), 77 (99). Anal.
Calcd for C26H19Cl3N2O4: C, 58.94; H, 3.61; N, 5.29. Found: C,
59.21; H, 3.44; N, 5.10.
Isolation of the Guanidine Intermediate 5c. To a solution of
iminophosphorane 3a (1.43 g, 3 mmol) in dry methylene dichloride
(15 mL) was added 3-methylphenylisocyanate (0.40 g, 3 mmol) at
room temperature. After the reaction mixture was left to stand for 20
min at room temperature, to the reaction mixture was added
morpholine (0.26 g, 3 mmol). The reaction mixture was stirred at
ambient temperature for 2 h until a solid precipitated. The solid
formed was filtered off and recrystallized from ethanol/petroleum
ether (1:1) to give 5c as white solid.
Ethyl 2-(4-Benzoyl-2-(4-chlorophenoxy)-1-(p-tolyl)-1H-imidazol-
5-yl)acetate (11e). Light yellow solid (yield 73%): mp 150−152
1
°C; H NMR (CDCl3, 600 MHz) δ (ppm) 8.29 (d, J = 7.2 Hz, 2H),
7.52−7.19 (m, 11H), 4.14 (q, J = 6.0 Hz, 2H), 3.92 (s, 2H), 2.43 (s,
3H), 1.22 (t, J = 6.0 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm)
188.1, 169.3, 153.1, 147.6, 139.9, 137.8, 132.9, 132.0, 131.7, 130.4,
130.2, 130.1, 129.4, 129.3, 127.8, 127.1, 119.6, 61.2, 31.2, 21.2, 14.0;
MS (EI, 70 eV) m/z (%) 474 (M+, 37), 428 (100), 401 (45), 317
(14), 290 (16), 274 (13), 261 (11), 247 (15), 139 (14), 111 (22), 105
(78), 91 (34), 77 (74). Anal. Calcd for C27H23ClN2O4: C, 68.28; H,
4.88; N, 5.90. Found: C, 68.39; H, 5.02; N, 5.72.
Ethyl 4-((Morpholino(m-tolylamino)methylene)amino)-5-phenyl-
1
penta-2,4-dienoate (5c). White solid: mp 163−164 °C; H NMR
(CDCl3, 600 MHz) δ (ppm) 7.63−6.63 (m, 10H), 6.21 (s, 1H), 5.96
(d, J = 15.0 Hz, 1H), 5.56 (s, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.75−3.67
(m, 4H), 3.45−3.35 (m, 4H), 2.22 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H);
13C NMR (DMSO, 150 MHz) δ (ppm) 166.4, 150.2, 150.1, 146.0,
Ethyl 2-(4-Benzoyl-2-(4-chlorophenoxy)-1-(4-chlorophenyl)-1H-
imidazol-5-yl)acetate (11f). Light yellow solid (yield 72%): mp
1
170−172 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 8.28 (d, J = 7.2
Hz, 2H), 7.53−7.21 (m, 11H), 4.15 (q, J = 7.2 Hz, 2H), 3.92 (s, 2H),
1.24 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 188.2,
169.3, 152.9, 147.5, 137.7, 135.9, 133.3, 132.3, 131.3, 130.5, 130.0,
129.8, 129.5, 128.9, 127.9, 119.7, 61.4, 31.2, 14.1; MS (EI, 70 eV) m/z
(%) 494 (M+, 24), 448 (69), 420 (33), 310 (14), 247 (14), 204 (14),
139 (16), 111 (47), 105 (93), 77 (100). Anal. Calcd for
C26H20Cl2N2O4: C, 63.04; H, 4.07; N, 5.66. Found: C, 63.26; H,
4.33; N, 5.89.
143.6, 140.9, 140.8, 137.4, 137.3, 128.9, 128.1, 126.6, 122.7, 121.9,
119.4, 115.7, 66.0, 59.6, 47.1, 20.7, 14.2; MS (EI, 70 eV) m/z (%) 419
(M+, 40), 390 (4), 346 (100), 203 (9), 91 (25). Anal. Calcd for
C25H29N3O3: C, 71.57; H, 6.97; N, 10.02. Found: C, 71.78; H, 6.81;
N, 10.27.
General Procedure for Preparation of 4-Phenacylimidazoles
11a−11g. To the above prepared carbodiimide 4 in CH3CN (10
mL) were added phenol (3 mmol) and potassium carbonate (0.04 g,
0.3 mmol). The reaction mixture was stirred for 2−3 days at 40−50
°C. The solution was then concentrated under reduced pressure, and
the residue was subjected to chromatography on silica gel eluting with
Et2O/petroleum ether 1:4 to give 11a−g.
Ethyl 2-(4-Benzoyl-2-(4-chlorophenoxy)-1-phenyl-1H-imidazol-5-
yl)acetate (11a). Light yellow solid (yield 67%): mp 127−129 °C; 1H
NMR (CDCl3, 400 MHz) δ (ppm) 8.30 (d, J = 7.6 Hz, 2H), 7.52−
7.19 (m, 12H), 4.13 (q, J = 7.2 Hz, 2H), 3.93 (s, 2H), 1.21 (t, J = 7.2
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 188.3, 169.3, 153.1,
147.6, 137.8, 133.1, 132.9, 132.1, 131.6, 130.4, 129.6, 129.4, 129.2,
127.9, 127.5, 119.7, 116.6, 61.3, 31.3, 14.1; MS (EI, 70 eV) m/z (%)
460 (M+, 30), 414 (87), 387 (40), 276 (17), 247 (18), 204 (14), 139
(14), 111 (28), 105 (59), 91 (11), 11 (100). Anal. Calcd for
C26H21ClN2O4: C, 67.75; H, 4.59; N, 6.08. Found: C, 68.01; H, 4.82;
N, 6.02.
Ethyl 2-(4-Benzoyl-1-(4-chlorophenyl)-2-phenoxy-1H-imidazol-5-
yl)acetate (11b). Light yellow solid (yield 73%): mp 141−143 °C; 1H
NMR (CDCl3, 600 MHz) δ (ppm) 8.31−8.30 (m, 2H), 7.51−7.48
(m, 3H), 7.44−7.42 (m, 2H), 7.34−7.32 (m, 4H), 7.24−7.22 (m, 2H),
7.14 (m, 1H), 4.16−4.13 (m, 2H), 3.93 (s, 2H), 1.23 (t, J = 6.9 Hz,
3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 188.2, 169.3, 154.6,
147.7, 137.7, 135.7, 133.3, 132.1, 131.4, 131.2, 130.5, 129.8, 129.5,
128.8, 127.8, 124.5, 118.1, 61.3, 31.2, 14.1; MS (EI, 70 eV) m/z (%)
460 (M+, 27), 414 (57), 387 (35), 310 (7), 247 (6), 204 (8), 152 (5),
111 (8), 105 (66), 77 (100). Anal. Calcd for C26H21ClN2O4: C, 67.75;
H, 4.59; N, 6.08. Found: C, 67.98; H, 4.73; N, 6.33.
Methyl 2-(4-Benzoyl-2-(4-chlorophenoxy)-1-(p-tolyl)-1H-imida-
zol-5-yl)acetate (11g). Light yellow solid (yield 62%): mp 172−
1
173 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 8.30 (d, J = 7.8 Hz,
2H), 7.52−7.20 (m, 11H), 3.92 (s, 2H), 3.69 (s, 3H), 2.43 (s, 3H);
13C NMR (CDCl3, 150 MHz) δ (ppm) 188.2, 169.8, 153.1, 147.7,
140.0, 137.8, 133.0, 132.1, 131.6, 130.5, 130.4, 130.3, 130.1, 129.5,
129.4, 127.9, 127.2, 119.7, 52.3, 31.0, 21.2; MS (EI, 70 eV) m/z (%)
460 (M+, 30), 428 (95), 401 (33), 317 (12), 247 (17), 204 (12), 157
(12), 139 (18), 111 (31), 105 (100). Anal. Calcd for C26H21ClN2O4:
C, 67.75; H, 4.59; N, 6.08. Found: C, 67.94; H, 4.86; N, 6.25.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for compounds 2, 3, 7, and 11
and crystal data for 11b. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ding5229@yahoo.com.cn.
■
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (No. 21032001,
21172085) and the Program for Changjiang Scholars and
Innovative Research Team in University (No. IRT0953).
Ethyl 2-(4-Benzoyl-1-(4-chlorophenyl)-2-(p-tolyloxy)-1H-imida-
zol-5-yl)acetate (11c). Light yellow solid (yield 75%): mp 156−158
1
°C; H NMR (CDCl3, 600 MHz) δ (ppm) 8.31 (d, J = 7.8 Hz, 2H),
7.52−7.12 (m, 11H), 4.14 (q, J = 7.2 Hz, 2H), 3.93 (s, 2H), 2.31 (s,
3H), 1.23 (t, J = 6.9 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm)
188.2, 169.3, 152.4, 148.0, 137.7, 135.6, 134.1, 133.3, 132.1, 131.5,
131.0, 130.5, 129.9, 129.8, 128.8, 127.8, 118.0, 61.3, 31.2, 20.6, 14.0;
MS (EI, 70 eV) m/z (%) 474 (M+, 40), 428 (97), 400 (23), 294 (10),
204 (11), 119 (13), 111 (10), 105 (100), 91 (56), 77 (83). Anal.
Calcd for C27H23ClN2O4: C, 68.28; H, 4.88; N, 5.90. Found: C, 68.02;
H, 5.07; N, 6.15.
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