Facile synthesis of 4-arylidene-1 H-imidazol-5(4H)-ones by an Ugi-aza-Wittig sequence

Article abstract of DOI:10.1055/s-0033-1338566

Vinyl azides, obtained from the Ugi-type reaction of 2-azido-3-arylacrylic acid, secondary amine, aldehyde, and isocyanide, react with triphenylphosphine to give a variety of 4-arylidene-1H-imidazol-5(4H)-ones in high yields via sequential Staudinger and intramolecular aza-Wittig reaction. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338566

336▌
PAPER
paper
Facile Synthesis of 4-Arylidene-1H-imidazol-5(4H)-ones by an Ugi–Aza-Wittig
Sequence
Facile Synthesis of 4-Arylidene-1H-imidazol-5(4H)-ones
Ying Wang,a Hai Xie,b Yu-Rong Pan,a Ming-Wu Ding*a
a
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan 430079, P. R. of China
Fax +86(27)67862041; E-mail: mwding@mail.ccnu.edu.cn
b
College of Chemistry & Chemical Engineering, Shanxi Datong University, Shanxi 037009, P. R. of China
Received: 05.10.2013; Accepted after revision: 04.11.2013
phosphoranes has received increased attention in view of
Abstract: Vinyl azides, obtained from the Ugi-type reaction of 2-
its utility in the synthesis of N-heterocycles.16 Recently,
azido-3-arylacrylic acid, secondary amine, aldehyde, and isocya-
the sequence of Ugi and Passerini reaction, followed by
nide, react with triphenylphosphine to give a variety of 4-arylidene-
postcondensation Staudinger and aza-Wittig reaction, has
been utilized in synthesis of a series of biologically useful
heterocycles.17 Continuing our interest in the synthesis of
various heterocycles via the aza-Wittig reaction,18 we
wish to report herein a new synthetic approach to multi-
substituted 4-arylidene-1H-imidazol-5(4H)-ones by a se-
quential Ugi 4CC–Staudinger–aza-Wittig reaction,
starting from the easily accessible, corresponding 2-azi-
do-3-arylacrylic acid, aldehyde, secondary amine, and
isocyanide.
1H-imidazol-5(4H)-ones in high yields via sequential Staudinger
and intramolecular aza-Wittig reaction.
Key words: 1H-imidazol-5(4H)-ones, Ugi reaction, aza-Wittig re-
action, iminophosphoranes, azides
The imidazolone unit represents an important structural
motif found in some biologically relevant compounds.
Many derivatives of this ring system have been used as
potential antagonists of some receptors including the neu-
rokinin-1 receptor,1 the CGRP receptor,2 dopamine recep-
tors,3 the angiotensin II receptor,4 and the 3-adrenergic
receptor.5 Some 4-arylidene-1H-imidazol-5(4H)-ones ex-
hibit interesting photochemical and optoelectronic prop-
erties.6 The most representative structure is 4-(4-
A mixture of aldehyde (1 equiv), secondary amine (1
equiv), isocyanide (1 equiv), and 2-azido-3-arylacrylic
acid (1 equiv) was stirred in anhydrous dichloromethane
in the presence of 4-Å molecular sieves at room tempera-
ture for 48–72 hours (Scheme 1). When an aromatic alde-
hyde (R1 = aryl) was used, the Ugi-type reaction occurred
smoothly and the azide products 1 were obtained in mod-
erate yields (Scheme 1 and Table 1). This Ugi-type reac-
tion with a secondary amine (no Mumm rearrangement is
possible) results in a product with a different structure to
the classical α-acylamino amide adduct.17b When aliphatic
aldehyde (R1 = Pr, Bu) was utilized, the reaction gave a
complex mixture and none of the desired product was ob-
tained.
hydroxybenzylidene)-1H-imidazol-5(4H)-one,
which
constitutes the core chromophore of the green fluorescent
protein (GFP).7 Other imidazolones also appear in various
alkaloids in which a common structural unit is a deriva-
tized 4-arylidene-1H-imidazol-5(4H)-one moiety.8 Al-
though there are many known methods for the synthesis of
1H-imidazol-5(4H)-ones,9 few synthetic routes have been
utilized for the preparation of their 4-arylidene deriva-
tives. For example, some 4-arylidene-1H-imidazol-
5(4H)-ones can be prepared by the reaction of oxazoli-
nones with amines,10 or by the coupling of imidates with
amino acid esters,11 or by the copper-catalyzed reaction of
2-bromo-3-alkylacrylic acids with amidines.12 We have
also previously prepared some 4-arylidene-1H-imidazol-
5(4H)-ones by using the aza-Wittig reaction of imino-
phosphoranes with isocyanates (or CS2), and then reaction
with various nucleophiles.13
COOH
O
R4
Ar
N3
R1CHO
R2R3NH
R4NC
N
O
R1
CH2Cl2
4 Å MS
r.t.
Ar
N3
NR2R3
1
Scheme 1
The Ugi reaction is a powerful, atom-economical reaction
that produces α-acylamino amide adducts.14 The sequence
of Ugi isocyanide multicomponent reaction, followed by
postcondensation transformations, constitutes an ex-
tremely powerful synthetic tool for the preparation of
structurally diverse complex molecules, especially het-
erocyclic compounds.15 The aza-Wittig reaction of imino-
When azides 1 were reacted with triphenylphosphine in
anhydrous dichloromethane at room temperature for 1–4
hours, the previously unreported multisubstituted 4-aryli-
dene-1H-imidazol-5(4H)-ones 3 were produced in good
to high yields (80–94%) (Scheme 2 and Table 1). The for-
mation of 4-arylidene-1H-imidazol-5(4H)-ones 3 can be
viewed as a Staudinger reaction between the azide 1 and
triphenylphosphine to create the iminophosphorane inter-
mediate 2. Further intramolecular aza-Wittig reaction of 2
produces cyclized compound 3. It is noteworthy that the
SYNTHESIS 2014, 46, 0336–0342
Advanced online publication: 22.11.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338566; Art ID: SS-2013-H0663-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Facile Synthesis of 4-Arylidene-1H-imidazol-5(4H)-ones
337
Table 1 Preparation of Azides 1 and 4-Arylidene-1H-imidazol-5(4H)-ones 3
Entry
Ar
R1
NR2R3
R4
Product
Yielda (%) Product
Yieldb (%)
1
2
Ph
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
2-Tol
morpholino
morpholino
pyrrolidinyl
morpholino
morpholino
piperidinyl
morpholino
morpholino
morpholino
morpholino
morpholino
morpholino
morpholino
morpholino
pyrrolidinyl
Cy
Cy
Cy
Cy
Cy
Cy
Cy
n-Bu
n-Bu
Cy
Cy
Cy
Cy
Cy
Cy
1a
1b
1c
1d
1e
1f
69
58
52
66
54
50
54
62
66
58
52
58
56
68
56
3a
3b
3c
3d
3e
3f
94
93
84
90
91
88
82
80
87
91
92
85
87
90
83
4-MeOC6H4
4-Tol
4-Tol
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
3
4
5
6
7
1g
1h
1i
3g
3h
3i
8
9
Ph
4-Tol
10
11
12
13
14
15
Ph
2-ClC6H4
3-ClC6H4
2-FC6H4
1j
3j
Ph
1k
1l
3k
3l
4-Tol
4-Tol
4-Tol
Ph
4-F3CC6H4
4-FC6H4
1m
1n
1o
3m
3n
3o
4-ClC6H4
a Isolated yield based on acid.
b Isolated yield based on azide 1.
cyclization is completed under mild room temperature The structure of 4-arylidene-1H-imidazol-5(4H)-ones 3
conditions to give the multisubstituted 4-arylidene-1H- was confirmed by their spectroscopic data. For example,
imidazol-5(4H)-ones 3 in a facile operation.
the 1H NMR spectrum of 3a shows a singlet at 7.06 ppm
due to the alkenyl hydrogen. The signals attributable to
the protons of the aromatic rings are found at 8.19–7.36
ppm as multiplets. The CH signal is found at 4.64 ppm as
a singlet, while the signal of the cyclohexyl NCH appears
at 4.05–4.00 ppm as a multiplet. The morpholinyl protons
absorb at 3.80–3.75 (OCH2) and 2.79–2.55 (NCH2) ppm
as two multiplets. The signals of the other CH2 groups (cy-
clohexyl) appear at 2.30–0.84 ppm as multiplets. The 13C
NMR spectroscopic data for 3a show the signals of CON
and the C-2 carbon of the imidazolone at 171.1 and 162.9
ppm. The mass spectrum of 3a shows a molecular ion
peak at m/z 463 and an [M+ – morpholinyl + 1] peak at
m/z 378, with 1% and 64% abundance, respectively.
R4
O
R4
O
N
O
NR2R3
R1
N
O
R1
Ph3P
Ar
N3
NR2R3
Ar
N
PPh3
2
1
O
R4
N
Ar
+
Ph3PO
N
NR2R3
R1
3
In conclusion, we have developed a facile synthesis of
multisubstituted 4-arylidene-1H-imidazol-5(4H)-ones by
an Ugi–aza-Wittig sequence. The mild reaction condi-
tions and the easy availability of starting materials make
this method a valuable tool for generating 4-arylidene-
1H-imidazol-5(4H)-ones, which are of considerable inter-
est as potential biologically active compounds or photo-
chemical reagents.
Scheme 2
Since the above Ugi-type reaction and Staudinger/aza-
Wittig reaction take place in the same solvent, we then at-
tempted to perform the reaction in a one-pot fashion. After
a mixture of aldehyde, secondary amine, isocyanide, and
2-azido-3-arylacrylic acid was stirred in anhydrous di-
chloromethane in the presence of 4-Å molecular sieves at
room temperature for 48–72 hours, triphenylphosphine
was added directly to the solution. The 4-arylidene-1H-
imidazol-5(4H)-ones 3 were obtained in comparable
overall yields to the stepwise reaction.
Melting points were determined using a model X-4 apparatus and
are uncorrected. MS were measured on a Finnigan Trace MS spec-
trometer. NMR spectra were recorded in CDCl3 on a Varian Mercu-
ry 600 or 400 spectrometer; resonances are relative to TMS.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 336–342

338
Y. Wang et al.
PAPER
Elemental analyses were performed on a Vario EL III elemental
analysis instrument. 2-Azido-3-arylacrylic acids were obtained by
hydrolysis of 2-azido-3-arylacrylic acid esters13b in the presence of
NaOH solution at 40–50 °C.
IR (KBr): 2933, 2858, 2835, 2114, 1696, 1656, 1598, 1490, 1451
cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.62 (d, J = 7.8 Hz, 2 H, Ar-H),
7.26 (d, J = 7.8 Hz, 2 H, Ar-H), 7.21 (d, J = 7.8 Hz, 2 H, Ar-H), 7.07
(d, J = 7.8 Hz, 2 H, Ar-H), 6.30 (s, 1 H, CH=C), 4.39–4.35 (m, 1 H,
NCH), 4.30 (s, 1 H, CH), 3.68–3.61 (m, 4 H, 2 × OCH2), 2.39 (s, 3
H, CH3), 2.37–2.32 (m, 4 H, 2 × NCH2), 1.97–0.84 (m, 10 H,
5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 171.3, 169.7, 140.7, 134.4, 131.8,
130.9, 130.6, 130.4, 129.6, 129.4, 128.2, 126.2, 73.6, 66.0, 58.2,
49.5, 31.5, 29.2, 26.1, 26.0, 25.2, 21.5.
Azides 1a–o; General Procedure
A solution of an aldehyde (2 mmol) and a secondary amine (2
mmol) in anhydrous CH2Cl2 (10 mL) was stirred at r.t. for 10 min.
Then, a 2-azido-3-arylacrylic acid (2 mmol), an isocyanide (2
mmol), and 4-Å molecular sieves (1 g) were added sequentially.
The reaction mixture was stirred at r.t. until disappearance of the re-
actants (48–72 h, monitored by TLC). After removal of the solvent
under reduced pressure, the residue was purified by column chro-
matography (petroleum ether–Et2O, 4:1) to give the corresponding
azide 1a–o.
Anal. Calcd for C28H32ClN5O3: C, 64.42; H, 6.18; N, 13.42. Found:
C, 64.17; H, 6.03; N, 13.38.
2-Azido-3-(4-chlorophenyl)-N-cyclohexyl-N-[2-(4-methoxyphe-
nyl)-2-morpholinoacetyl]acrylamide (1e)
White solid; yield: 0.58 g (54%); mp 122–123 °C.
2-Azido-N-[2-(4-chlorophenyl)-2-morpholinoacetyl]-N-cyclo-
hexyl-3-phenylacrylamide (1a)
White solid; yield: 0.70 g (69%); mp 144–145 °C.
IR (KBr): 2953, 2933, 2857, 2115, 1684, 1649, 1611, 1513, 1490
cm–1.
IR (KBr): 2933, 2856, 2113, 1682, 1650, 1611, 1491, 1450 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.72 (d, J = 7.2 Hz, 2 H, Ar-H),
7.41–7.36 (m, 3 H, Ar-H), 7.26 (d, J = 8.4 Hz, 2 H, Ar-H), 7.07 (d,
J = 8.4 Hz, 2 H, Ar-H), 6.31 (s, 1 H, CH=C), 4.40–4.36 (m, 1 H,
NCH), 4.32 (s, 1 H, CH), 3.68–3.61 (m, 4 H, 2 × OCH2), 2.37–2.32
(m, 4 H, 2 × NCH2), 1.99–1.15 (m, 10 H, 5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 171.4, 169.6, 134.4, 132.3, 131.9,
131.8, 130.5, 130.2, 130.0, 128.7, 128.2, 125.5, 73.6, 65.9, 58.3,
49.4, 31.6, 29.1, 26.1, 26.0, 25.1.
1H NMR (600 MHz, CDCl3): δ = 7.66 (d, J = 7.8 Hz, 2 H, Ar-H),
7.35 (d, J = 8.4 Hz, 2 H, Ar-H), 7.04 (d, J = 7.8 Hz, 2 H, Ar-H), 6.81
(d, J = 7.8 Hz, 2 H, Ar-H), 6.18 (s, 1 H, CH=C), 4.38–4.35 (m, 1 H,
NCH), 4.24 (s, 1 H, CH), 3.77 (s, 3 H, OCH3), 3.69–3.61 (m, 4 H,
2 × OCH2), 2.38–2.32 (m, 4 H, 2 × NCH2), 1.96–1.13 (m, 10 H,
5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 172.2, 169.3, 159.6, 135.6, 132.3,
131.6, 131.0, 128.8, 123.8, 123.4, 113.5, 73.8, 66.0, 58.3, 55.2,
49.6, 31.4, 29.3, 26.1, 25.1.
Anal. Calcd for C27H30ClN5O3: C, 63.83; H, 5.95; N, 13.79. Found:
C, 63.57; H, 5.87; N, 13.82.
Anal. Calcd for C28H32ClN5O4: C, 62.50; H, 5.99; N, 13.02. Found:
C, 62.63; H, 6.06; N, 13.25.
2-Azido-N-[2-(4-chlorophenyl)-2-morpholinoacetyl]-N-cyclo-
hexyl-3-(4-methoxyphenyl)acrylamide (1b)
White solid; yield: 0.62 g (58%); mp 150–151 °C.
2-Azido-3-(4-chlorophenyl)-N-cyclohexyl-N-[2-(4-methoxyphe-
nyl)-2-(piperidin-1-yl)acetyl]acrylamide (1f)
White solid; yield: 0.54 g (50%); mp 129–130 °C.
IR (KBr): 2957, 2930, 2858, 2834, 2107, 1688, 1647, 1597, 1566,
1510, 1452 cm–1.
IR (KBr): 2933, 2859, 2831, 2119, 1693, 1650, 1610, 1586, 1511,
1487, 1453 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.69 (d, J = 8.4 Hz, 2 H, Ar-H),
7.24 (d, J = 7.8 Hz, 2 H, Ar-H), 7.09 (d, J = 7.8 Hz, 2 H, Ar-H), 6.91
(d, J = 9.0 Hz, 2 H, Ar-H), 6.28 (s, 1 H, CH=C), 4.37–4.33 (m, 1 H,
NCH), 4.26 (s, 1 H, CH), 3.86 (s, 3 H, OCH3), 3.68–3.61 (m, 4 H,
2 × OCH2), 2.38–2.33 (m, 4 H, 2 × NCH2), 1.95–0.86 (m, 10 H,
5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 171.1, 169.8, 161.0, 134.2, 132.5,
131.7, 130.4, 129.4, 128.1, 126.4, 125.0, 114.1, 73.5, 65.9, 57.9,
55.3, 49.5, 29.1, 26.0, 25.1.
1H NMR (600 MHz, CDCl3): δ = 7.71 (d, J = 9.0 Hz, 2 H, Ar-H),
7.36 (d, J = 8.4 Hz, 2 H, Ar-H), 6.98 (d, J = 8.4 Hz, 2 H, Ar-H), 6.82
(d, J = 8.4 Hz, 2 H, Ar-H), 6.21 (s, 1 H, CH=C), 4.44–4.40 (m, 1 H,
NCH), 4.29 (s, 1 H, CH), 3.78 (s, 3 H, OCH3), 2.30–1.18 (m, 20 H,
10 × CH2).
13C NMR (100 MHz, CDCl3): δ = 172.8, 168.4, 159.2, 135.2, 132.4,
132.1, 131.5, 131.3, 128.8, 123.7, 121.7, 113.0, 73.6, 58.1, 55.1,
49.8, 32.0, 28.7, 26.3, 25.2, 24.6, 23.4.
Anal. Calcd for C28H32ClN5O4: C, 62.50; H, 5.99; N, 13.02. Found:
C, 62.41; H, 5.82; N, 13.12.
Anal. Calcd for C29H34ClN5O3: C, 64.98; H, 6.39; N, 13.06. Found:
C, 65.04; H, 6.48; N, 13.11.
2-Azido-N-cyclohexyl-N-[2-(4-methoxyphenyl)-2-(pyrrolidin-
1-yl)acetyl]-3-(p-tolyl)acrylamide (1c)
2-Azido-3-(4-chlorophenyl)-N-[2-(4-chlorophenyl)-2-morpholi-
noacetyl]-N-cyclohexylacrylamide (1g)
White solid; yield: 0.52 g (52%); mp 120–121 °C.
White solid; yield: 0.59 g (54%); mp 141–142 °C.
IR (KBr): 2930, 2854, 2113, 1689, 1648, 1610, 1511, 1450 cm–1.
IR (KBr): 2927, 2851, 2120, 1691, 1650, 1612, 1591, 1490, 1450
cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.70 (d, J = 7.8 Hz, 2 H, Ar-H),
7.21 (d, J = 7.8 Hz, 2 H, Ar-H), 6.98 (d, J = 8.4 Hz, 2 H, Ar-H), 6.85
(d, J = 8.4 Hz, 2 H, Ar-H), 6.23 (s, 1 H, CH=C), 4.51 (s, 1 H, CH),
4.43–4.40 (m, 1 H, NCH), 3.78 (s, 3 H, OCH3), 2.48–2.42 (m, 4 H,
2 × NCH2), 2.39 (s, 3 H, CH3), 2.12–1.18 (m, 14 H, 7 × CH2).
13C NMR (100 MHz, CDCl3): δ = 172.8, 165.9, 159.1, 139.7, 132.2,
131.5, 130.3, 129.3, 123.9, 122.3, 113.2, 67.8, 57.5, 55.1, 47.1,
32.4, 28.5, 26.1, 25.3, 22.7, 21.4.
1H NMR (600 MHz, CDCl3): δ = 7.66 (d, J = 8.4 Hz, 2 H, Ar-H),
7.36 (d, J = 8.4 Hz, 2 H, Ar-H), 7.27 (d, J = 7.8 Hz, 2 H, Ar-H), 7.06
(d, J = 7.8 Hz, 2 H, Ar-H), 6.21 (s, 1 H, CH=C), 4.39–4.35 (m, 1 H,
NCH), 4.28 (s, 1 H, CH), 3.68–3.61 (m, 4 H, 2 × OCH2), 2.38–2.32
(m, 4 H, 2 × NCH2), 1.99–1.15 (m, 10 H, 5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 171.2, 169.1, 135.6, 134.2, 132.0,
131.8, 131.5, 130.7, 129.8, 128.7, 128.0, 123.4, 73.3, 65.7, 58.2,
49.1, 31.6, 28.9, 25.9, 25.0.
Anal. Calcd for C29H35N5O3: C, 69.44; H, 7.03; N, 13.96. Found: C,
69.36; H, 7.22; N, 13.71.
Anal. Calcd for C27H29Cl2N5O3: C, 59.78; H, 5.39; N, 12.91. Found:
C, 59.94; H, 5.47; N, 12.69.
2-Azido-N-[2-(4-chlorophenyl)-2-morpholinoacetyl]-N-cyclo-
hexyl-3-(p-tolyl)acrylamide (1d)
White solid; yield: 0.69 g (66%); mp 134–135 °C.
Synthesis 2014, 46, 336–342
© Georg Thieme Verlag Stuttgart · New York

PAPER
Facile Synthesis of 4-Arylidene-1H-imidazol-5(4H)-ones
339
2-Azido-N-butyl-N-[2-morpholino-2-(o-tolyl)acetyl]-3-phenyl-
acrylamide (1h)
White solid; yield: 0.57 g (62%); mp 93–94 °C.
2-Azido-N-cyclohexyl-N-[2-(2-fluorophenyl)-2-morpholinoace-
tyl]-3-(p-tolyl)acrylamide (1l)
White solid; yield: 0.59 g (58%); mp 154–155 °C.
IR (KBr): 2958, 2930, 2871, 2117, 1694, 1651, 1610, 1490, 1446
cm–1.
IR (KBr): 2932, 2856, 2107, 1689, 1646, 1612, 1452 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.67 (d, J = 7.8 Hz, 2 H, Ar-H),
7.31–7.02 (m, 6 H, Ar-H), 6.35 (s, 1 H, CH=C), 4.74 (s, 1 H, CH),
4.44–4.38 (m, 1 H, NCH), 3.71–3.62 (m, 4 H, 2 × OCH2), 2.42–
2.36 (m, 7 H, CH3 and 2 × NCH2), 2.03–0.86 (m, 10 H, 5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 171.1, 169.1, 162.3, 159.9, 140.3,
132.6, 131.1, 130.4, 130.1, 129.8, 129.3, 125.0, 123.5, 119.0, 118.8,
115.6, 115.4, 67.0, 65.8, 58.3, 48.9, 28.8, 26.1, 26.0, 25.1, 21.4.
1H NMR (600 MHz, CDCl3): δ = 7.60 (d, J = 7.8 Hz, 2 H, Ar-H),
7.36–7.32 (m, 3 H, Ar-H), 7.25–7.09 (m, 4 H, Ar-H), 5.98 (s, 1 H,
CH=C), 5.08 (s, 1 H, CH), 3.83–3.61 (m, 6 H, NCH2, 2 × OCH2),
2.59–2.54 (m, 4 H, 2 × NCH2), 2.26 (s, 3 H, CH3), 1.60–1.30 (m, 4
H, 2 × CH2), 0.91 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 174.2, 169.7, 137.9, 132.3, 131.7,
131.0, 130.2, 130.1, 129.8, 129.6, 128.5, 128.4, 125.6, 124.2, 69.0,
66.9, 49.8, 47.0, 30.9, 20.1, 19.4, 13.6.
Anal. Calcd for C28H32FN5O3: C, 66.52; H, 6.38; N, 13.85. Found:
C, 66.59; H, 6.64; N, 13.73.
Anal. Calcd for C26H31N5O3: C, 67.66; H, 6.77; N, 15.17. Found: C,
67.74; H, 6.83; N, 15.36.
2-Azido-N-cyclohexyl-N-{2-morpholino-2-[4-(trifluorometh-
yl)phenyl]acetyl}-3-(p-tolyl)acrylamide (1m)
White solid; yield: 0.62 g (56%); mp 138–139 °C.
2-Azido-N-butyl-N-[2-morpholino-2-(p-tolyl)acetyl]-3-phenyl-
acrylamide (1i)
White solid; yield: 0.61 g (66%); mp 133–134 °C.
IR (KBr): 2963, 2932, 2863, 2113, 1696, 1652, 1600, 1453 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.62 (d, J = 7.8 Hz, 2 H, Ar-H),
7.54 (d, J = 8.4 Hz, 2 H, Ar-H), 7.25 (d, J = 7.8 Hz, 2 H, Ar-H), 7.20
(d, J = 7.8 Hz, 2 H, Ar-H), 6.31 (s, 1 H, CH=C), 4.40–4.36 (m, 2 H,
2 × NCH), 3.69–3.62 (m, 4 H, 2 × OCH2), 2.39–2.36 (m, 7 H, CH3
and 2 × NCH2), 2.00–0.84 (m, 10 H, 5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 170.9, 169.7, 140.9, 135.8, 130.9,
130.8, 130.6, 130.2, 129.5, 129.4, 126.4, 124.9, 73.7, 65.9, 58.3,
49.4, 31.8, 29.0, 26.1, 25.1, 21.5.
IR (KBr): 2961, 2934, 2863, 2837, 2116, 1693, 1654, 1614, 1450
cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.67 (d, J = 7.2 Hz, 2 H, Ar-H),
7.40–7.35 (m, 3 H, Ar-H), 7.12 (d, J = 7.8 Hz, 2 H, Ar-H), 7.05 (d,
J = 7.8 Hz, 2 H, Ar-H), 6.08 (s, 1 H, CH=C), 4.53 (s, 1 H, CH),
3.83–3.63 (m, 6 H, NCH2, 2 × OCH2), 2.39–2.36 (m, 4 H,
2 × NCH2), 2.30 (s, 3 H, CH3), 1.65–1.30 (m, 4 H, 2 × CH2), 0.91
(t, J = 7.2 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 173.6, 169.7, 138.4, 132.5, 130.5,
130.3, 130.2, 129.6, 129.0, 128.9, 128.6, 123.8, 73.6, 66.3, 50.0,
47.2, 30.8, 21.0, 20.1, 13.6.
Anal. Calcd for C29H32F3N5O3: C, 62.69; H, 5.81; N, 12.61. Found:
C, 62.73; H, 5.97; N, 12.74.
2-Azido-N-cyclohexyl-N-[2-(4-fluorophenyl)-2-morpholinoace-
tyl]-3-(p-tolyl)acrylamide (1n)
White solid; yield: 0.69 g (68%); mp 125–126 °C.
IR (KBr): 2923, 2856, 2114, 1688, 1650, 1603, 1509, 1451 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.64 (d, J = 7.2 Hz, 2 H, Ar-H),
7.21 (d, J = 7.2 Hz, 2 H, Ar-H), 7.10–6.98 (m, 4 H, Ar-H), 6.32 (s,
1 H, CH=C), 4.39–4.35 (m, 1 H, NCH), 4.32 (s, 1 H, CH), 3.69–3.61
(m, 4 H, 2 × OCH2), 2.39 (s, 3 H, CH3), 2.37–2.31 (m, 4 H,
2 × NCH2), 1.97–1.15 (m, 10 H, 5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 171.5, 169.6, 163.8, 161.3, 140.6,
132.2, 130.9, 130.6, 129.6, 129.4, 127.6, 125.9, 115.0, 114.8, 73.5,
65.9, 58.2, 49.3, 31.4, 29.1, 26.1, 25.1, 21.5.
Anal. Calcd for C26H31N5O3: C, 67.66; H, 6.77; N, 15.17. Found: C,
67.95; H, 6.91; N, 15.23.
2-Azido-N-[2-(2-chlorophenyl)-2-morpholinoacetyl]-N-cyclo-
hexyl-3-phenylacrylamide (1j)
White solid; yield: 0.59 g (58%); mp 130–131 °C.
IR (KBr): 2955, 2931, 2858, 2117, 1691, 1654, 1609, 1448 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.74 (d, J = 7.8 Hz, 2 H, Ar-H),
7.38–7.22 (m, 7 H, Ar-H), 6.37 (s, 1 H, CH=C), 5.34 (s, 1 H, CH),
4.40–4.36 (m, 1 H, NCH), 3.68–3.59 (m, 4 H, 2 × OCH2), 2.56–
2.39 (m, 4 H, 2 × NCH2), 1.99–1.16 (m, 10 H, 5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 171.5, 169.4, 135.6, 132.5, 132.2,
131.6, 130.4, 129.8, 129.6, 129.5, 128.5, 126.1, 125.6, 68.2, 66.0,
58.2, 49.1, 31.5, 29.2, 26.1, 26.0, 25.1.
Anal. Calcd for C28H32FN5O3: C, 66.52; H, 6.38; N, 13.85. Found:
C, 66.71; H, 6.59; N, 13.70.
2-Azido-N-[2-(4-chlorophenyl)-2-(pyrrolidin-1-yl)acetyl]-N-cy-
clohexyl-3-phenylacrylamide (1o)
White solid; yield: 0.55 g (56%); mp 146–147 °C.
Anal. Calcd for C27H30ClN5O3: C, 63.83; H, 5.95; N, 13.79. Found:
C, 63.97; H, 6.02; N, 13.84.
IR (KBr): 2937, 2858, 2109, 1681, 1643, 1609, 1511, 1449 cm–1.
2-Azido-N-[2-(3-chlorophenyl)-2-morpholinoacetyl]-N-cyclo-
hexyl-3-phenylacrylamide (1k)
1H NMR (600 MHz, CDCl3): δ = 7.80 (d, J = 7.8 Hz, 2 H, Ar-H),
7.42–7.34 (m, 3 H, Ar-H), 7.03–7.02 (m, 4 H, Ar-H), 6.26 (s, 1 H,
CH=C), 4.58 (s, 1 H, CH), 4.44–4.41 (m, 1 H, NCH), 2.48–2.42 (m,
4 H, 2 × NCH2), 2.13–1.19 (m, 14 H, 7 × CH2).
13C NMR (100 MHz, CDCl3): δ = 172.3, 165.7, 163.5, 161.1, 132.9,
132.6, 132.2, 130.2, 129.3, 128.5, 127.3, 122.1, 114.8, 114.6, 67.6,
57.7, 47.0, 32.5, 28.4, 26.2, 26.0, 25.2, 22.7.
White solid; yield: 0.53 g (52%); mp 156–157 °C.
IR (KBr): 2956, 2930, 2862, 2113, 1688, 1652, 1609, 1449 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.74 (d, J = 6.0 Hz, 2 H, Ar-H),
7.40–7.23 (m, 5 H, Ar-H), 7.12–7.00 (m, 2 H, Ar-H), 6.33 (s, 1 H,
CH=C), 4.40–4.32 (m, 2 H, 2 × CH), 3.68–3.64 (m, 4 H,
2 × OCH2), 2.40–2.35 (m, 4 H, 2 × NCH2), 2.01–0.86 (m, 10 H,
5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 171.0, 169.4, 133.9, 133.6, 132.3,
132.2, 131.6, 130.5, 129.9, 129.0, 128.8, 128.6, 128.4, 125.4, 73.6,
65.8, 58.2, 49.2, 31.6, 29.0, 26.1, 25.1.
Anal. Calcd for C27H30ClN5O2: C, 65.91; H, 6.15; N, 14.23. Found:
C, 65.75; H, 6.33; N, 14.32.
4-Arylidene-1H-imidazol-5(4H)-ones 3a–o; General Procedure
To a well-stirred solution of an azide 1 (1 mmol) in anhydrous
CH2Cl2 (5 mL) was added dropwise a solution of Ph3P (0.26 g, 1
mmol) in CH2Cl2 (5 mL) at r.t. The reaction mixture was stirred for
1–4 h until the azide 1 had disappeared (by TLC detection). The
mixture was concentrated and the residue was chromatographed
Anal. Calcd for C27H30ClN5O3: C, 63.83; H, 5.95; N, 13.79. Found:
C, 63.56; H, 5.86; N, 13.95.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 336–342

340
Y. Wang et al.
PAPER
(petroleum ether–Et2O, 4:1) on a silica gel column to give the cor-
responding 4-arylidene-1H-imidazol-5(4H)-one 3a–o.
Anal. Calcd for C28H32ClN3O2: C, 70.35; H, 6.75; N, 8.79. Found:
C, 70.42; H, 6.97; N, 8.85.
4-Benzylidene-2-[(4-chlorophenyl)(morpholino)methyl]-1-cy-
clohexyl-1H-imidazol-5(4H)-one (3a)
Yellow solid; yield: 0.44 g (94%); mp 134–135 °C.
4-(4-Chlorobenzylidene)-1-cyclohexyl-2-[(4-methoxyphe-
nyl)(morpholino)methyl]-1H-imidazol-5(4H)-one (3e)
Yellow solid; yield: 0.45 g (91%); mp 190–191 °C.
1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 7.2 Hz, 2 H, Ar-H),
7.46–7.36 (m, 7 H, Ar-H), 7.06 (s, 1 H, CH=C), 4.64 (s, 1 H, CH),
4.05–4.00 (m, 1 H, NCH), 3.80–3.75 (m, 4 H, 2 × OCH2), 2.79–
2.55 (m, 4 H, 2 × NCH2), 2.30–0.84 (m, 10 H, 5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 171.1, 162.9, 138.7, 134.3, 134.2,
132.8, 132.4, 130.4, 130.2, 128.7, 128.6, 128.2, 69.3, 67.0, 54.5,
51.7, 29.3, 26.2, 26.0, 24.8.
1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 7.6 Hz, 2 H, Ar-H),
7.40–7.36 (m, 4 H, Ar-H), 6.97 (s, 1 H, CH=C), 6.91 (d, J = 8.0 Hz,
2 H, Ar-H), 4.56 (s, 1 H, CH), 4.02–3.97 (m, 1 H, NCH), 3.81–3.79
(m, 7 H, OCH3, 2 × OCH2), 2.79–2.58 (m, 4 H, 2 × NCH2), 2.22–
0.86 (m, 10 H, 5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 171.1, 164.2, 159.6, 139.2, 135.9,
133.4, 132.9, 132.8, 130.3, 128.8, 125.9, 114.0, 69.3, 67.0, 55.2,
54.5, 51.8, 29.2, 29.1, 26.2, 26.0, 24.8.
MS: m/z (%) = 463 (1) [M+], 378 (64), 297 (100).
MS: m/z (%) = 493 (2) [M+], 408 (100), 326 (99).
Anal. Calcd for C27H30ClN3O2: C, 69.89; H, 6.52; N, 9.06. Found:
C, 69.97; H, 6.63; N, 9.18.
Anal. Calcd for C28H32ClN3O3: C, 68.07; H, 6.53; N, 8.51. Found:
C, 68.11; H, 6.64; N, 8.68.
2-[(4-Chlorophenyl)(morpholino)methyl]-1-cyclohexyl-4-(4-
methoxybenzylidene)-1H-imidazol-5(4H)-one (3b)
Yellow solid; yield: 0.46 g (93%); mp 173–174 °C.
1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 7.6 Hz, 2 H, Ar-H),
7.45 (d, J = 7.2 Hz, 2 H, Ar-H), 7.36 (d, J = 7.2 Hz, 2 H, Ar-H), 7.03
(s, 1 H, CH=C), 6.95 (d, J = 7.6 Hz, 2 H, Ar-H), 4.63 (s, 1 H, CH),
4.04–3.98 (m, 1 H, NCH), 3.87 (s, 3 H, OCH3), 3.80–3.75 (m, 4 H,
2 × OCH2), 2.78–2.57 (m, 4 H, 2 × NCH2), 2.34–1.19 (m, 10 H,
5 × CH2).
4-(4-Chlorobenzylidene)-1-cyclohexyl-2-[(4-methoxyphe-
nyl)(piperidin-1-yl)methyl]-1H-imidazol-5(4H)-one (3f)
Yellow solid; yield: 0.43 g (88%); mp 170–171 °C.
1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 8.0 Hz, 2 H, Ar-H),
7.40–7.36 (m, 4 H, Ar-H), 6.94 (s, 1 H, CH=C), 6.90 (d, J = 8.4 Hz,
2 H, Ar-H), 4.58 (s, 1 H, CH), 4.17–4.13 (m, 1 H, NCH), 3.81 (s, 3
H, OCH3), 2.72–0.86 (m, 20 H, 10 × CH2).
13C NMR (100 MHz, CDCl3): δ = 171.2, 165.0, 159.3, 139.5, 135.7,
133.4, 132.9, 130.2, 128.7, 126.6, 125.3, 113.6, 70.0, 55.2, 54.4,
52.5, 29.1, 26.3, 26.2, 26.0, 24.9, 24.4.
13C NMR (100 MHz, CDCl3): δ = 171.0, 161.4, 161.3, 136.9, 134.3,
134.2, 132.9, 130.4, 128.6, 128.1, 127.1, 114.2, 69.2, 66.9, 55.3,
54.4, 51.6, 29.2, 26.2, 26.0, 24.8.
MS: m/z (%) = 491 (2) [M+], 410 (35), 408 (100), 362 (2), 327 (60).
MS: m/z (%) = 493 (1) [M+], 408 (65), 326 (100).
Anal. Calcd for C29H34ClN3O2: C, 70.79; H, 6.96; N, 8.54. Found:
C, 70.52; H, 7.09; N, 8.69.
Anal. Calcd for C28H32ClN3O3: C, 68.07; H, 6.53; N, 8.51. Found:
C, 68.31; H, 6.37; N, 8.63.
4-(4-Chlorobenzylidene)-2-[(4-chlorophenyl)(morpholi-
no)methyl]-1-cyclohexyl-1H-imidazol-5(4H)-one (3g)
Yellow solid; yield: 0.41 g (82%); mp 195–196 °C.
1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 8.8 Hz, 2 H, Ar-H),
7.45–7.36 (m, 6 H, Ar-H), 6.99 (s, 1 H, CH=C), 4.62 (s, 1 H, CH),
4.03–3.99 (m, 1 H, NCH), 3.82–3.74 (m, 4 H, 2 × OCH2), 2.77–
2.54 (m, 4 H, 2 × NCH2), 2.29–1.13 (m, 10 H, 5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 170.8, 163.3, 138.9, 136.0, 134.3,
133.4, 132.6, 132.5, 130.3, 128.8, 128.7, 126.4, 69.3, 66.9, 54.5,
51.6, 29.2, 26.2, 25.9, 24.7.
1-Cyclohexyl-2-[(4-methoxyphenyl)(pyrrolidin-1-yl)methyl]-4-
(4-methylbenzylidene)-1H-imidazol-5(4H)-one (3c)
Yellow solid; yield: 0.38 g (84%); mp 163–164 °C.
1H NMR (600 MHz, CDCl3): δ = 8.10 (d, J = 7.2 Hz, 2 H, Ar-H),
7.40 (d, J = 8.4 Hz, 2 H, Ar-H), 7.23 (d, J = 7.2 Hz, 2 H, Ar-H), 7.02
(s, 1 H, CH=C), 6.88 (d, J = 7.8 Hz, 2 H, Ar-H), 4.51 (s, 1 H, CH),
3.96–3.94 (m, 1 H, NCH), 3.80 (s, 3 H, OCH3), 2.72–2.69 (m, 4 H,
2 × NCH2), 2.40 (s, 3 H, CH3), 2.16–0.86 (m, 14 H, 7 × CH2).
13C NMR (100 MHz, CDCl3): δ = 171.4, 164.0, 159.2, 140.2, 138.4,
132.2, 131.6, 129.7, 129.2, 128.3, 127.3, 113.7, 68.2, 55.1, 54.2,
52.4, 29.0, 28.8, 25.9, 24.8, 23.2, 21.5.
MS: m/z (%) = 497 (1) [M+], 412 (60), 384 (2), 331 (100).
Anal. Calcd for C27H29Cl2N3O2: C, 65.06; H, 5.86; N, 8.43. Found:
C, 65.24; H, 5.79; N, 8.66.
MS: m/z (%) = 457 (4) [M+], 389 (16), 388 (100), 369 (2), 334 (2),
317 (2), 306 (83).
4-Benzylidene-1-butyl-2-[morpholino(o-tolyl)methyl]-1H-imid-
azol-5(4H)-one (3h)
Light yellow solid; yield: 0.33 g (80%); mp 111–112 °C.
Anal. Calcd for C29H35N3O2: C, 76.12; H, 7.71; N, 9.18. Found: C,
76.29; H, 7.47; N, 9.22.
1H NMR (600 MHz, CDCl3): δ = 8.23 (d, J = 7.2 Hz, 2 H, Ar-H),
7.47–7.38 (m, 4 H, Ar-H), 7.25–7.16 (m, 4 H, Ar-H and CH=C),
4.91 (s, 1 H, CH), 3.77–3.69 (m, 4 H, 2 × OCH2), 3.46–3.29 (m, 2
H, NCH2), 2.95–2.74 (m, 4 H, 2 × NCH2), 2.54 (s, 3 H, CH3), 1.23–
1.19 (m, 4 H, 2 × CH2), 0.82 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 170.9, 162.8, 138.2, 137.8, 134.2,
132.7, 132.4, 131.2, 130.2, 128.9, 128.6, 128.4, 126.0, 67.3, 64.5,
50.7, 40.6, 30.7, 20.0, 19.3, 13.5.
2-[(4-Chlorophenyl)(morpholino)methyl]-1-cyclohexyl-4-(4-
methylbenzylidene)-1H-imidazol-5(4H)-one (3d)
Yellow solid; yield: 0.43 g (90%); mp 140–141 °C.
1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 6.8 Hz, 2 H, Ar-H),
7.45 (d, J = 6.8 Hz, 2 H, Ar-H), 7.37 (d, J = 7.2 Hz, 2 H, Ar-H), 7.23
(d, J = 7.2 Hz, 2 H, Ar-H), 7.05 (s, 1 H, CH=C), 4.63 (s, 1 H, CH),
4.01–3.98 (m, 1 H, NCH), 3.80–3.75 (m, 4 H, 2 × OCH2), 2.77–
2.57 (m, 4 H, 2 × NCH2), 2.40 (s, 3 H, CH3), 2.30–0.87 (m, 10 H,
5 × CH2).
MS: m/z (%) = 332 (50) [M+ – morpholino + 1], 277 (4), 275 (19),
227 (100), 131 (10), 117 (17), 105 (9), 91 (13).
13C NMR (100 MHz, CDCl3): δ = 171.1, 162.1, 140.8, 138.0, 134.2,
132.8, 132.4, 131.4, 130.4, 129.4, 128.6, 128.3, 69.2, 67.0, 54.5,
51.6, 29.2, 26.2, 26.0, 24.8, 21.6.
Anal. Calcd for C26H31N3O2: C, 74.79; H, 7.48; N, 10.06. Found: C,
74.87; H, 7.55; N, 10.27.
MS: m/z (%) = 392 (55) [M+ – morpholino + 1], 311 (50), 295 (33),
267 (12), 210 (14), 207 (11), 131 (100).
Synthesis 2014, 46, 336–342
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Facile Synthesis of 4-Arylidene-1H-imidazol-5(4H)-ones
341
4-Benzylidene-1-butyl-2-[morpholino(p-tolyl)methyl]-1H-imid-
azol-5(4H)-one (3i)
1H NMR (600 MHz, CDCl3): δ = 8.05 (d, J = 7.8 Hz, 2 H, Ar-H),
7.67 (s, 4 H, Ar-H), 7.24 (d, J = 7.8 Hz, 2 H, Ar-H), 7.06 (s, 1 H,
CH=C), 4.74 (s, 1 H, CH), 4.08–4.02 (m, 1 H, NCH), 3.83–3.76 (m,
4 H, 2 × OCH2), 2.78–2.57 (m, 4 H, 2 × NCH2), 2.40 (s, 3 H, CH3),
2.32–0.83 (m, 10 H, 5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 171.0, 161.7, 141.0, 138.4, 137.9,
132.4, 131.4, 130.7, 129.6, 129.5, 128.7, 125.4, 125.3, 69.6, 67.0,
54.6, 51.6, 29.3, 26.2, 26.0, 24.8, 21.6.
Light yellow solid; yield: 0.36 g (87%); mp 117–118 °C.
1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 7.2 Hz, 2 H, Ar-H),
7.44–7.18 (m, 7 H, Ar-H), 7.14 (s, 1 H, CH=C), 4.53 (s, 1 H, CH),
3.78–3.41 (m, 6 H, NCH2 and 2 × OCH2), 2.79–2.60 (m, 4 H,
2 × NCH2), 2.36 (s, 3 H, CH3), 1.32–1.21 (m, 4 H, 2 × CH2), 0.86
(t, J = 6.8 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 171.0, 163.2, 138.5, 138.3, 134.2,
132.5, 130.8, 130.2, 129.4, 129.3, 128.6, 128.3, 68.3, 67.0, 51.5,
40.6, 30.8, 21.1, 20.0, 13.6.
MS: m/z (%) = 332 (53) [M+ – morpholino + 1], 289 (8), 275 (8),
227 (100), 130 (7), 117 (23), 105 (11), 91 (12).
MS: m/z (%) = 511 (1) [M+], 426 (45), 344 (42), 329 (25), 267 (8),
185 (5), 131 (100).
Anal. Calcd for C29H32F3N3O2: C, 68.09; H, 6.30; N, 8.21. Found:
C, 68.11; H, 6.42; N, 8.40.
1-Cyclohexyl-2-[(4-fluorophenyl)(morpholino)methyl]-4-(4-
methylbenzylidene)-1H-imidazol-5(4H)-one (3n)
Yellow solid; yield: 0.41 g (90%); mp 115–116 °C.
Anal. Calcd for C26H31N3O2: C, 74.79; H, 7.48; N, 10.06. Found: C,
74.93; H, 7.24; N, 10.12.
4-Benzylidene-2-[(2-chlorophenyl)(morpholino)methyl]-1-cy-
clohexyl-1H-imidazol-5(4H)-one (3j)
1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 7.2 Hz, 2 H, Ar-H),
7.48–7.05 (m, 7 H, Ar-H and CH=C), 4.64 (s, 1 H, CH), 3.99–3.96
(m, 1 H, NCH), 3.82–3.77 (m, 4 H, 2 × OCH2), 2.77–2.57 (m, 4 H,
2 × NCH2), 2.40 (s, 3 H, CH3), 2.28–0.85 (m, 10 H, 5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 171.2, 163.8, 162.4, 161.3, 140.8,
138.1, 132.4, 131.5, 130.9, 130.8, 130.0, 129.5, 128.4, 115.6, 115.4,
69.1, 67.0, 54.5, 51.7, 29.2, 26.2, 26.0, 24.8, 21.6.
Yellow solid; yield: 0.42 g (91%); mp 163–164 °C.
1H NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 7.2 Hz, 2 H, Ar-H),
7.57–7.30 (m, 7 H, Ar-H), 7.07 (s, 1 H, CH=C), 5.24 (s, 1 H, CH),
3.82–3.76 (m, 4 H, 2 × OCH2), 3.55–3.50 (m, 1 H, NCH), 2.85–
2.80 (m, 4 H, 2 × NCH2), 2.30–0.86 (m, 10 H, 5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 170.9, 163.2, 138.7, 134.8, 134.2,
132.3, 131.6, 131.4, 130.1, 129.9, 128.6, 127.8, 127.0, 67.1, 62.6,
54.5, 51.1, 29.4, 28.9, 26.1, 25.9, 24.8.
MS: m/z (%) = 376 (83) [M+ – morpholino + 1], 295 (90), 279 (60),
267 (11), 194 (8), 131 (100).
Anal. Calcd for C28H32FN3O2: C, 72.86; H, 6.99; N, 9.10. Found: C,
72.68; H, 7.13; N, 9.12.
MS: m/z (%) = 463 (1) [M+], 378 (59), 297 (100).
Anal. Calcd for C27H30ClN3O2: C, 69.89; H, 6.52; N, 9.06. Found:
C, 69.63; H, 6.36; N, 9.23.
4-Benzylidene-2-[(4-chlorophenyl)(pyrrolidin-1-yl)methyl]-1-
cyclohexyl-1H-imidazol-5(4H)-one (3o)
Yellow solid; yield: 0.37 g (83%); mp 163–164 °C.
4-Benzylidene-2-[(3-chlorophenyl)(morpholino)methyl]-1-cy-
clohexyl-1H-imidazol-5(4H)-one (3k)
Yellow solid; yield: 0.43 g (92%); mp 96–97 °C.
1H NMR (600 MHz, CDCl3): δ = 8.17 (d, J = 7.2 Hz, 2 H, Ar-H),
7.56 (s, 1 H, Ar-H), 7.45–7.32 (m, 6 H, Ar-H), 7.07 (s, 1 H, CH=C),
4.65 (s, 1 H, CH), 4.10–4.05 (m, 1 H, NCH), 3.83–3.77 (m, 4 H,
2 × OCH2), 2.80–2.55 (m, 4 H, 2 × NCH2), 2.32–0.86 (m, 10 H,
5 × CH2).
1H NMR (600 MHz, CDCl3): δ = 8.19 (d, J = 7.8 Hz, 2 H, Ar-H),
7.51–7.38 (m, 5 H, Ar-H), 7.07–7.05 (m, 3 H, Ar-H and CH=C),
4.58 (s, 1 H, CH), 4.03–3.99 (m, 1 H, NCH), 2.75–2.66 (m, 4 H,
2 × NCH2), 2.22–0.86 (m, 14 H, 7 × CH2).
13C NMR (100 MHz, CDCl3): δ = 171.3, 164.2, 163.5, 161.1, 139.0,
134.2, 132.3, 130.1, 129.9, 128.5, 127.6, 115.4, 115.2, 68.4, 54.3,
52.5, 29.1, 26.1, 25.9, 24.8, 23.3.
13C NMR (100 MHz, CDCl3): δ = 171.1, 162.6, 138.6, 136.2, 134.5,
134.1, 132.4, 130.2, 129.7, 129.0, 128.6, 128.3, 127.4, 69.5, 66.9,
54.5, 51.6, 29.2, 26.2, 25.9, 24.8.
MS: m/z (%) = 463 (1) [M+], 380 (15), 378 (49), 343 (3), 297 (68),
261 (100).
MS: m/z (%) = 376 (51) [M+ – pyrrolidinyl – 1], 294 (65), 279 (38),
267 (8), 194 (8), 131 (100).
Anal. Calcd for C27H30ClN3O: C, 72.39; H, 6.75; N, 9.38. Found: C,
72.63; H, 6.67; N, 9.25.
4-Benzylidene-2-[(4-chlorophenyl)(morpholino)methyl]-1-cy-
clohexyl-1H-imidazol-5(4H)-one (3a); Typical One-Pot Proce-
dure
Anal. Calcd for C27H30ClN3O2: C, 69.89; H, 6.52; N, 9.06. Found:
C, 69.91; H, 6.38; N, 9.34.
A solution of 4-chlorobenzaldehyde (0.28 g, 2 mmol) and morpho-
line (0.17 g, 2 mmol) in anhydrous CH2Cl2 (10 mL) was stirred at
r.t. for 10 min. Then, 2-azido-3-phenylacrylic acid (0.38 g, 2 mmol),
cyclohexyl isocyanide (0.22 g, 2 mmol), and 4-Å molecular sieves
(1 g) were added sequentially. After the reaction mixture was stirred
at r.t. for 48 h, a solution of Ph3P (0.52 g, 2 mmol) in CH2Cl2 (5 mL)
was added dropwise at r.t. The reaction mixture was stirred for 4 h
and then filtered. The filtrate was concentrated and the residue was
chromatographed (petroleum ether–Et2O, 4:1) on a silica gel col-
umn to give 3a as a yellow solid; yield: 0.57 g (61% overall).
1-Cyclohexyl-2-[(2-fluorophenyl)(morpholino)methyl]-4-(4-
methylbenzylidene)-1H-imidazol-5(4H)-one (3l)
Yellow solid; yield: 0.39 g (85%); mp 191–192 °C.
1H NMR (600 MHz, CDCl3): δ = 8.06 (d, J = 7.8 Hz, 2 H, Ar-H),
7.56 (t, J = 7.2 Hz, 1 H, Ar-H), 7.37–7.16 (m, 5 H, Ar-H), 7.06 (s,
1 H, CH=C), 5.09 (s, 1 H, CH), 3.82–3.77 (m, 4 H, 2 × OCH2),
3.62–3.58 (m, 1 H, NCH), 2.82–2.67 (m, 4 H, 2 × NCH2), 2.39 (s, 3
H, CH3), 2.26–0.86 (m, 10 H, 5 × CH2).
13C NMR (100 MHz, CDCl3): δ = 170.9, 161.9, 159.7, 140.7, 137.9,
132.3, 131.5, 130.4, 129.4, 128.1, 124.0, 120.4, 115.6, 115.4, 108.7,
67.0, 59.2, 54.7, 51.0, 29.3, 29.0, 26.0, 24.8, 21.5.
Acknowledgment
MS: m/z (%) = 461 (2) [M+], 376 (89), 295 (100).
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (No. 21172085,
21032001).
Anal. Calcd for C28H32FN3O2: C, 72.86; H, 6.99; N, 9.10. Found: C,
72.59; H, 6.83; N, 9.17.
1-Cyclohexyl-4-(4-methylbenzylidene)-2-{morpholino[4-(tri-
fluoromethyl)phenyl]methyl}-1H-imidazol-5(4H)-one (3m)
Yellow solid; yield: 0.44 g (87%); mp 112–113 °C.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 336–342

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Y. Wang et al.
PAPER
(11) Janongsik, T.; Johnson, A.-L.; Bergman, J. Tetrahedron
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Synthesis 2014, 46, 336–342
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