A phosphine-catalyzed preparation of 4-Arylidene-5-imidazolones

Article abstract of DOI:10.1021/jo501922j

A simple and efficient method for constructing 4-arylidene-5-imidazolones was developed using a phosphinecatalyzed tandem umpolung addition and intramolecular cyclization of amidine pronucleophiles on arylpropiolates. The reaction offers a robust route to heterocycle analogues of the fluorescent protein chromophores. (Chemical Equation Presented).

Full text of DOI:10.1021/jo501922j

Note
pubs.acs.org/joc
A Phosphine-Catalyzed Preparation of 4‑Arylidene-5-imidazolones
Sandra Gabillet, Olivier Loreau, Simon Specklin, Evelia Rasalofonjatovo, and Frederic Taran*
́
́
CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, Gif sur Yvette, F-91191, France
S
* Supporting Information
ABSTRACT: A simple and efficient method for constructing 4-
arylidene-5-imidazolones was developed using a phosphine-
catalyzed tandem umpolung addition and intramolecular cycliza-
tion of amidine pronucleophiles on arylpropiolates. The reaction
offers a robust route to heterocycle analogues of the fluorescent protein chromophores.
Scheme 2. Reaction of Arylpropiolates with Amidines and
Proposed Route to Imidazolones through Phosphine
Catalysis
lthough the 4-arylidene-5-imidazolone motif appears in
Aseveral natural or synthetic products displaying interesting
biological properties,1 it is mostly known as the ubiquitous core
chromophore of fluorescent proteins (FPs, Scheme 1).2 Green
fluorescence protein (GFP) in particular has drawn much
attention due to its numerous applications in molecular biology
and biochemistry.3
Scheme 1. Examples of 4-Arylidene-imidazolone Motifs
Occuring in Fluorescent Proteins (FPs)
used only once for the preparation of various pyridinone
derivatives.8 We, therefore, decided to reinvestigate this
reaction and to evaluate the capacity of phosphines to orient
the reaction to the exclusive formation of imidazolone
derivatives. The presence of phosphines should indeed catalyze
the umpolung addition of amidines to the α-position of
arylpropiolates. The mechanism of the reaction has some
similarities with the Mitsonobu reaction.9 Phosphines react
with arylpropiolates 1 to form a Michael phosphonium adduct,
addition of amidines 2 then undergoes in the position α with
respect to the ester group due to the electron-withdrawing
phosphonium moiety. After regeneration of the phosphine, the
resulting adduct should then undergo cyclization due to the
close proximity of the second N-nucleophile with respect to the
ester group, resulting in the formation of 4-arylidene-
imidazolones 3 (Scheme 2).
Phenylethylpropiolate 1a and benzamidine 2a were first used
as model substrates to investigate the influence of Lewis bases
on the reaction and to optimize the reaction conditions (Table
1). As described by Stapleton et al. in 1900, we confirmed that
the reaction of 1a with 2a led to a low yield of pure
imidazolone 3-1 when conducted at room temperature (Table
1, entry 1). Heating the same substrates at refluxed toluene
generated the pyrimidone 4-1 in a good yield with only traces
Despite the numerous structural analogues of the FPs
chromophores that have been synthesized, only a few synthetic
routes are reported in the literature.4 Among the plethora of
synthetic strategies to construct heterocycles, a series of
organocatalyzed reactions induced by phosphines have
emerged over the past decade as a powerful approach.5 In
particular, electron-deficient alkynes subjected to nucleophilic
phosphine catalysis conditions exhibit good reactivity toward
pronucleophiles, allowing the straightforward construction of
numerous cyclic products from simple building blocks.6
In the present work, we described a new synthetic route to 4-
arylidene-5-pyrazolones by exploiting the capacity of phos-
phines to redirect the addition of amidine nucleophiles from
the classical β- to the α-position of arylpropiolate Michael
acceptors.
The reaction between phenylpropiolate and benzamidine was
studied more than a century ago by Ruhemann and Stapleton,
who remarkably isolated two different products depending on
the temperature of the reaction.7 A five-membered ring
imidazolone product was obtained at room temperature, and
a six-membered ring pyridinone product was obtained when
heating the same substrates at 70 °C (Scheme 2). Since this
pioneering work, this reaction was surprisingly neglected and
Received: August 19, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo501922j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Influence of Lewis Bases on the Reaction between
Phenylpropiolate 1a and Benzamidine 2a
Scheme 3. Reaction of Arylpropiolates with Amidines
a
b
b
entry Lewis base
conditions
3-1 (Z/E)
4-1
1
2
no
toluene -25 °C - 15 h
toluene -110 °C - 15 h
toluene -25 °C - 15 h
toluene -25 °C - 15 h
toluene -25 °C - 15 h
toluene -25 °C - 15 h
toluene -25 °C - 2 h
MeOH - 25 °C - 15 h
iPrOH - 25 °C - 15 h
CH2Cl2 - 25 °C - 2 h
toluene -110 °C - 5 min
17% (97/03)
2% (100/0)
33% (100/0)
14% (100/0)
2% (100/0)
35% (97/03)
78% (100/0)
n.d.
n.d.
72%
27%
20%
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
no
3
DABCO
DMAP
Ph3P
MePh2P
Bu3P
Bu3P
Bu3P
Bu3P
Bu3P
4
5
6
7
8
9
23% (89/11)
68% (100/0)
77% (100/0)
10
11
a
Reactions conducted under argon; the concentration of the substrates
b
was 0.5 M. Isolated yields. n.d. = not detected.
of 3-1 (Table 1, entry 2). Although the addition of nucleophilic
tertiary or aromatic amines favored the formation of 4-1 at
room temperature (Table 1, entries 3 and 4), phosphines drive
the reaction toward the selective formation of imidazolone 3-1.
In accordance with previous findings from our group,10
nucleophilic Bu3P was found to be the most active within the
tested phosphines, allowing the exclusive formation of Z-
imidazolidinone 3-1 in good yields at room temperature (Table
1, entry 7). The capacity of Bu3P to direct the addition of 2a in
the position α of the electron-deficient alkyne 1a is particularly
highlighted at high temperature: pure Z-3-1 was obtained at
refluxed toluene in only 5 min reaction (Table 1, entry 11).
Following this optimization study, we then investigated the
scope of the reaction. Although the reaction might be
successfully run at room temperature in many cases, the
reaction conditions in refluxing toluene were found to be more
general. Using these conditions, various electron-rich or
electron-poor arylamidines successfully participated in this
transformation. On the contrary, reaction with alkylamidines
only led to traces of pyrimidones 4. A large variety of aryl- or
heteroaryl-propiolates also successfully participated in the
reaction. The reaction proceeds efficiently either from amidine
free bases (Scheme 3) or from amidine salts after treatment
with a carbonate base (Scheme 4).
Scheme 4. Reaction of Arylpropiolates with Amidine Salts
In conclusion, we have developed a simple and practical
method for the preparation of 4-arylidene-5-imidazolone
derivatives via an nBu3P-catalyzed tandem α-addition and
intramolecular cyclization of aryl-amidines to arylpropiolates.
The procedure presents two main practical advantages: the
reaction is trivial to run, and product recovery is very easy. In all
cases, the imidazolone products precipitate in solution and can
be obtained in good yields after simple filtration and washing.
This procedure is, therefore, well adapted to the preparation of
libraries of imidazolidinones whose use as synthetic building
blocks and as fluorophores is of great interest.
spectrophotometer and are reported as wavelength numbers (cm−1).
Infrared spectra for liquid products were obtained as a thin film on a
NaCl disk, and spectra for solid products were collected by preparing a
1
KBr pellet containing the title compound. H NMR (400 MHz) and
13C NMR (100 MHz) were measured on a 400 MHz spectrometer.
Chemical shifts are reported in parts per million (ppm, δ) downfield
from residual solvent peaks, and coupling constants are reported as
hertz (Hz). Splitting patterns are designated as singlet (s), doublet (d),
triplet (t), .... Splitting patterns that could not be interpreted or easily
visualized are designated as multiplet (m). Electrospray mass spectra
were obtained using an ESI/TOF mass spectrometer. Melting points
were determined on a capillary melting point apparatus and are
uncorrected. Arylpropiolates 1 were prepared according to our
previously described protocol.11
General Procedure A: Phosphine-Catalyzed Synthesis of
Imidazolone 3 from Free Base Amidines. To a solution of
tributylphosphine (10 μL, 0.04 mmol, 0.2 equiv) and arylamidine (0.2
mmol, 1 equiv) in anhydrous toluene (1 mL) was added
EXPERIMENTAL SECTION
■
General Experimental Details. Unless otherwise noted, dry
toluene and all other commercially available reagents and solvents
were purchased from commercial suppliers and used without further
purification. Infrared spectra (IR) were obtained on an FT-IR
B
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Note
1
arylpropriolate (0.2 mmol, 1 equiv) under argon. The reaction mixture
was refluxed for 2 h. After filtration, the precipitate was washed with
toluene to give the final product.
73%). H NMR (DMSO-d6, 400 MHz) δ 3.86 (s, 3H), 6.95 (s, 1H),
7.14 (d, J = 9.2 Hz, 2H), 7.30 (t, J = 8.8 Hz, 2H), 8.12 (d, J = 8.8 Hz,
2H), 8.36 (dd, J = 6.0 Hz, J = 8.4 Hz), 11.98 (br s, NH); 13C NMR
(DMSO-d6, 100 MHz) δ 56.0, 114.9, 116.1 (d, J = 22.1 Hz), 120.6,
122.7, 129.8, 131.7 (d, J = 3.0 Hz), 134.5 (d, J = 8.0 Hz), 140.7 (d, J =
3.0 Hz), 161.0, 162.6 (d, J = 249.5 Hz), 163.2, 172.5; IR (KBr, cm−1) ν
833, 922, 1031, 1174, 1258, 1435, 1503, 1601, 1648, 1702, 2933, 2977,
3072; MS (ESI) m/z 297 [M + H]+: HRMS (ESI) m/z calcd for
C17H14N2O2F [M + H]+: 297.1039; found: 297.1041; mp. 243 °C.
(Z)-4-(2-Methoxybenzylidene)-2-phenyl-1H-imidazol-5(4H)-one
General Procedure B: Phosphine-Catalyzed Synthesis of
Imidazolone 3 from Amidine Salts. To a suspension of dry sodium
carbonate (42.4 mg, 0.4 mmol, 2 equiv) in anhydrous toluene (1 mL)
was added arylamidine hydrochloride (0.2 mmol, 1 equiv) under
argon. The resulting mixture was stirred under reflux for 1 h and then
allowed to cool at room temperature. Arylpropiolate (0.2 mmol, 1
equiv) and tributylphosphine (10 μL, 40 μmol, 0.2 equiv) were added
under argon, and the mixture was refluxed for 2 h. After filtration, the
precipitate was washed with water and toluene to give the final
product.
(Z)-4-Benzylidene-2-phenyl-1H-imidazol-5(4H)-one (3-1). Follow-
ing general procedure A, yellow solid (39 mg, 78%). 1H NMR
(DMSO-d6, 400 MHz) δ 7.03 (s, 1H), 7.40−7.55 (m, 3H), 7.55−7.70
(m, 3H), 8.18 (d, J = 6.9 Hz, 2H), 8.32 (d, J = 7.3 Hz, 2H), 12.11 (br
s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 125.0, 127.4, 128.0, 128.8,
129.0, 130.0, 132.1, 132.6, 134.4, 140.6, 161.1, 172.2; IR (KBr, cm−1) ν
650, 686, 709, 753, 777, 890, 922, 1031, 1060, 1123, 1155, 1187, 1201,
1266, 1294, 1322, 1358, 1418, 1452, 1495, 1538, 1598, 1640, 1695,
1782, 3067; MS (ESI) m/z 249 [M + H]+; HRMS (ESI) m/z calcd for
C16H11N2O [M − H]−: 247.0871; found: 247.0880; mp. 276 °C.
(Z)-4-Benzylidene-2-(4-methoxyphenyl)-1H-imidazol-5(4H)-one
(3-2). Following general procedure A, yellow solid (41.2 mg, 74%). 1H
NMR (DMSO-d6, 400 MHz) δ 6.94 (s, 1H), 7.14 (d, J = 8.8 Hz, 2H),
7.40 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H), 8.14 (d, J = 8.8 Hz,
2H), 8.29 (d, J = 7.4 Hz, 2H), 11.93 (br s, 1H); 13C NMR (DMSO-d6,
100 MHz) δ 55.6, 114.5, 120.2, 123.5, 128.7, 129.4, 129.6, 131.8,
134.6, 140.7, 160.6, 162.8, 172.2; IR (KBr, cm−1) ν 687, 734, 777, 837,
891, 922, 1032, 1124, 1174, 1200, 1260, 1333, 1363, 1403, 1434, 1503,
1545, 1605, 1641, 1699, 3147; MS (ESI) m/z 279 [M + H]+; HRMS
(ESI) m/z calcd for C17H15N2O2 [M + H]+: 279.1134; found:
279.1126; mp. 290 °C.
1
(3-7). Following general procedure A, yellow solid (42 mg, 75%). H
NMR (DMSO-d6, 400 MHz) δ 3.89 (s, 3H), 7.09 (t, J = 7.6 Hz, 2H),
7.38 (s, 1H), 7.42 (dt, J = 1.2 Hz, J = 8.0 Hz, 1H), 7.54−764 (m, 3H),
8.15 (d, J = 6.8 Hz, 2H), 8.89 (dd, J = 1.2 Hz, J = 8.0 Hz, 1H), 12.07
(br s, NH); 13C NMR (DMSO-d6, 100 MHz) δ 55.8, 111.3, 118.1,
120.8, 122.7, 127.3, 128.1, 129.0, 131.9, 132.3, 132.4, 139.9, 158.6,
160.6, 172.1; IR (KBr, cm−1) ν 688, 755, 923, 1026, 1196, 1249, 1290,
1455, 1632, 1691, 2840, 3072, 3149; MS (ESI) m/z 277 [M + H]+;
HRMS (ESI) m/z calcd for C17H13N2O2 [M − H]−: 277.0977; found:
277.0982; mp. 276 °C.
(Z)-4-(2-Methoxybenzylidene)-2-(4-methoxyphenyl)-1H-imida-
zol-5(4H)-one (3-8). Following general procedure A, orange solid
(47.4 mg, 77%). 1H NMR (DMSO-d6, 400 MHz) δ 3.85 (s, 3H), 3.88
(s, 3H), 7.06−7.09 (m, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.31 (s, 1H),
7.39 (dt, J = 1.6 Hz, J = 8.8 Hz, 1H), 8.11 (d, J = 8.8 Hz, 2H), 8.89
(dd, J = 1.6 Hz, J = 8.0 Hz, 1H), 11.92 (br s, NH); 13C NMR (DMSO-
d6, 100 MHz) δ 56.0, 56.2, 111.6, 114.9, 117.1, 120.7, 121.1, 123.3,
129.7, 131.9, 132.5, 140.5, 158.8, 160.6, 163.1, 172.6; IR (KBr, cm−1) ν
475, 603, 750, 841, 922, 1023, 1177, 1241, 1293, 1436, 1504, 1605,
1635, 1705, 2840, 3070; MS (ESI) m/z 307 [M + H]+; HRMS (ESI)
m/z calcd for C18H15N2O3 [M − H]−: 307.1083; found: 307.1096;
mp. 290 °C.
(Z)-4-(4-(Dimethylamino)benzylidene)-2-phenyl-1H-imidazol-
5(4H)-one (3-9). Following general procedure A, orange solid (52.4
1
mg, 90%). H NMR (DMSO-d6, 400 MHz) δ 3.02 (s, 6H), 6.79 (d, J
(Z)-4-(4-Methoxybenzylidene)-2-phenyl-1H-imidazol-5(4H)-one
(3-3). Following general procedure A, yellow solid (39.5 mg, 71%). 1H
NMR (DMSO-d6, 400 MHz) δ 3.82 (s, 3H), 6.99 (s, 1H), 7.05 (d, J =
9.0 Hz, 2H), 7.55−7.63 (m, 3H), 8.14 (d, J = 6.4 Hz, 2H), 8.29 (d, J =
9.0 Hz, 2H), 11.99 (br s, NH); 13C NMR (DMSO-d6, 100 MHz) δ
55.7, 114.8, 125.8, 127.5, 127.6, 128.6, 129.4, 132.6, 134.5, 139.0,
159.9, 161.3, 172.4; IR (KBr, cm−1) ν 526, 562, 667, 690, 787, 828,
891, 922, 1028, 1123, 1171, 1200, 1264, 1303, 1317, 1361, 1420, 1455,
1496, 1512, 1539, 1596, 1641, 1700, 2837, 2971, 3065, 2121; MS
(ESI) m/z 277 [M + H]+; HRMS (ESI) m/z calcd for C17H13N2O2
[M − H]−: 277.0977; found: 277.0984; mp. 292 °C.
= 8.8 Hz, 2H), 6.92 (s, 1H), 7.54−7.56 (m, 3H), 8.09−8.17 (m, 4H),
11.61 (br s, NH); 13C NMR (DMSO-d6, 100 MHz) δ 112.2, 122.3,
127.2, 127.3, 129.0, 129.3, 132.0, 134.5, 136.7, 151.8, 157.6, 172.3; IR
(KBr, cm−1) ν 693, 796, 817, 920, 1185, 1364, 1456, 1525, 1593, 1635,
1696, 2863, 3000, 3062; MS (ESI) m/z 290 [M + H]+; HRMS (ESI)
m/z calcd for C18H18N3O [M + H]+: 292.1450; found: 292.1459; mp.
299 °C.
(Z)-4-(4-(Dimethylamino)benzylidene)-2-(4-methoxyphenyl)-1H-
imidazol-5(4H)-one (3-10). Following general procedure A, orange
solid (56 mg, 87%). 1H NMR (DMSO-d6, 400 MHz) (δ ppm) 3.01(s,
6H), 3.84 (s, 3H), 6.78 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H),
8.06 (d, J = 8.8 Hz, 2H), 8.14 (d, J = 8.8 Hz, 2H); 13C NMR (DMSO-
d6, 100 MHz) (δ ppm) 55.3, 55.9, 112.2, 114.8, 121.3, 122.5, 125.9,
129.1, 134.2, 137.0, 151.6, 157.5, 162.5, 172.4; IR (KBr, cm−1) υ 602,
689, 807, 838, 919, 1164, 1179, 1255, 1307, 1361, 1437, 1505, 1523,
1592, 1634, 1686, 2840, 3048; MS (ESI) m/z 322 [M + H]+; HRMS
(ESI) m/z calcd for C19H20N3O2 [M + H]+: 322.1556; found:
322.1561; mp. 345 °C.
(Z)-4-(4-Methoxybenzylidene)-2-(4-methoxyphenyl)-1H-imida-
zol-5(4H)-one (3-4). Following general procedure A, yellow solid (47
1
mg, 76%). H NMR (DMSO-d6, 400 MHz) δ 3.82 (s, 3H), 3.85 (s,
3H), 6.91 (s, 1H), 7.04 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H),
8.10 (d, J = 8.8 Hz, 2H), 8.26 (d, J = 8.8 Hz, 2H), 11.74 (br s, NH);
13C NMR (DMSO-d6, 100 MHz) δ 55.7, 55.9, 114.8, 114.9, 120.9,
124.3, 127.7, 129.5, 134.2, 139.2, 159.6, 161.0, 162.9, 172.5; IR (KBr,
cm−1) ν 527, 829, 922, 1027, 1172, 1254, 1300, 1438, 1505, 1598,
1640, 1702, 2838, 2955, 3070; MS (ESI) m/z 307 [M + H]+; HRMS
(ESI) m/z calcd for C18H15N2O3 [M − H]−: 307.1083; found:
307.1091; mp. 274 °C.
(Z)-4-((1-Methyl-1H-imidazol-5-yl)methylene)-2-phenyl-1H-imi-
dazol-5(4H)-one (3-11). Following general procedure A, yellow solid
1
(43.3 mg, 86%). H NMR (DMSO-d6, 400 MHz) (δ ppm) 3.77 (s,
3H), 6.91 (s, 1H), 7.54−7.62 (m, 3H), 7.86 (s,1H), 8.14 (d, J = 6.8
Hz, 2H), 8.16 (s, 1H), 11.87 (br s, NH); 13C NMR (CDCl3, 100
MHz) (δ ppm) 31.7, 111.6, 127.6, 128.5, 128.6, 129.4, 132.6, 137.6,
138.2, 141.8, 159.3, 171.5; IR (KBr, cm−1) υ 583, 666, 695, 914, 938,
1112, 1125, 1246, 1457, 1502, 1535, 1648, 1707, 2718, 2822, 3094,
3395; MS (ESI) m/z 251 [M-H]−; HRMS (ESI) m/z calcd for
C14H13N4O [M + H]+: 253.1089; found: 253.1097; mp. 306 °C.
(Z)-2-(4-Methoxyphenyl)-4-((1-methyl-1H-imidazol-5-yl)meth-
ylene)-1H-imidazol-5(4H)-one (3-12). Following general procedure
(Z)-4-(4-Fluorobenzylidene)-2-phenyl-1H-imidazol-5(4H)-one (3-
5). Following general procedure A, ochre solid (36 mg, 68%). 1H
NMR (DMSO-d6, 400 MHz) δ 7.04 (s, 1H), 7.32 (t, J = 8.8 Hz, 2H),
7.57−7.66 (m, 3H), 8.16 (d, J = 6.8 Hz, 2H), 8.39 (dd, J = 6.0 Hz, J =
8.8 Hz, 2H), 12.1 (br s, NH); 13C NMR (DMSO-d6, 100 MHz) δ
116.2 (d, J = 22.0 Hz), 124.2 (d, J = 1.0 Hz), 127.8, 128.3, 129.4, 131.5
(d, J = 3.0 Hz), 133.0, 134.8 (d, J = 9.0 Hz), 140.5 (d, J = 3.0 Hz),
161.4, 163.2 (d, J = 248.0 Hz), 172.4; IR (KBr, cm−1) ν 687, 784, 832,
922, 1158, 1229, 1264, 1418, 1454, 1503, 1537, 1597, 1648, 1710,
2987, 3067, 3129, 3157; MS (ESI) m/z 267 [M + H]+; HRMS (ESI)
m/z calcd for C16H10N2OF [M − H]−: 265.0777; found: 265.0788;
mp. 277 °C.
1
A, yellow solid (45.1 mg, 80%). H NMR (DMSO-d6, 400 MHz) (δ
ppm) 3.75(s, 3H), 3.84(s, 3H), 6.82 (s, 1H), 7.10 (d, J = 8.8 Hz, 2H),
7.83 (s, 1H), 8.10 (d, J = 8.8 Hz, 2H), 8.12 (s, 1H); 13C NMR
(CDCl3, 100 MHz) (δ ppm) 31.7, 55.9, 110.1, 120.8, 128.7, 129.6,
137.1, 138.5, 141.5, 159.2, 162.9, 171.6; IR (KBr, cm−1) υ 582, 665,
(Z)-4-(4-Fluorobenzylidene)-2-(4-methoxyphenyl)-1H-imidazol-
5(4H)-one (3-6). Following general procedure A, ochre solid (43.2 mg,
C
dx.doi.org/10.1021/jo501922j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
692, 837, 918, 1028, 1113, 1128, 1176, 1249, 1462, 1503, 1607, 1647,
1711, 2840, 3094, 3408; MS (ESI) m/z 281 [M-H]−; HRMS (ESI) m/
z calcd for C15H15N4O2 [M + H]+: 283.1195; found: 283.1205; mp.
287 °C.
MHz) δ 3.87 (s, 3H), 3.90 (s, 3H), 7.05 (s, 1H), 7.15 (d, J = 9.2 Hz,
2H), 7.20 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H),
7.89 (dd, J = 9.2 Hz, J = 12.8 Hz, 2H), 8.17 (d, J = 8.8 Hz, 2H), 8.56
(s, 1H), 8.59 (d, J = 8.8 Hz, 1H), 11.81 (br s, NH); 13C NMR
(DMSO-d6, 100 MHz) δ 55.8, 56.0, 106.6, 114.9, 119.5, 120.8, 124.4,
127.5, 128.7, 129.0, 129.8, 130.6, 130.8, 132.9, 135.3, 140.5, 159.0,
160.3, 163.1, 172.6; IR (KBr, cm−1) ν 603, 662, 801, 836, 851, 919,
1032, 1118, 1180, 1254, 1335, 1392, 1442, 1481, 1505, 1544, 1613,
1643, 1700, 2836, 2963, 3067, 3145; MS (ESI) m/z 359 [M + H]+;
HRMS (ESI) m/z calcd for C22H17N2O3 [M − H]−: 357.1239; found
357.1257; mp 293 °C.
(Z)-4-(phenanthren-9-ylmethylene)-2-phenyl-1H-imidazol-5(4H)-
one (3-19). Following general procedure A, yellow solid (49 mg,
70%). 1H NMR (DMSO-d6, 400 MHz) δ 7.57−7.78 (m, 8H), 8.15 (d,
J = 7.6 Hz, 1H), 8.25 (d, J = 6.8 Hz, 2H), 8.36−8.42 (m, 1H), 8.86 (d,
J = 8.4 Hz, 1H), 8.91−8.96 (m, 1H), 9.35 (s, 1H), 11.63 (br s, NH);
13C NMR (CDCl3, 100 MHz) (δ ppm) 119.9, 123.3, 124.0, 127.4,
(Z)-4-([1,1′-Biphenyl]-4-ylmethylene)-2-phenyl-1H-imidazol-
5(4H)-one (3-13). Following general procedure A, yellow solid (52
1
mg, 80%). H NMR (DMSO-d6, 400 MHz) δ 7.07 (s,1H), 7.38−7.41
(m, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.58−7.67 (m, 3H), 7.75 (d, J = 7.2
Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 8.18 (d, J = 6.8 Hz, 2H), 8.40 (d, J
= 8.4 Hz, 2H), 12.13 (br s, NH); 13C NMR (DMSO-d6, 100 MHz) δ
125.0, 127.1, 127.3, 127.8, 128.4, 129.4, 132.9, 133.1, 134.0, 139.7,
140.9, 141.7, 161.2, 172.4; IR (KBr, cm−1) ν 567, 643, 689, 759, 781,
841, 890, 922, 1064, 1121, 1181, 1219, 1269, 1319, 1340, 1358, 1418,
1454, 1488, 1534, 1596, 1634, 1699, 2843, 2986, 3063, 3121, 3151,
3372; MS (ESI) m/z 325 [M + H]+; HRMS (ESI) m/z calcd for
C22H17N2O [M + H]+: 325.1341; found 325.1357; mp. 299 °C.
(Z)-4-([1,1′-Biphenyl]-4-ylmethylene)-2-(4-methoxyphenyl)-1H-
imidazol-5(4H)-one (3-14). Following general procedure A, yellow
solid (52.4 mg, 74%). 1H NMR (DMSO-d6, 400 MHz) δ 3.86 (s, 3H),
6.98 (s, 1H), 7.15 (d, J = 9.0 Hz, 2H), 7.37−7.41 (m, 1H), 7.49 (t, J =
7.6 Hz, 2H), 7.75 (d, J = 7.6 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 8.14
(d, J = 9.0 Hz, 2H), 8.38 (d, J = 8.4 Hz, 2H); 13C NMR (DMSO-d6,
100 MHz) δ 56.0, 115.0, 120.7, 123.4, 127.1, 127.2, 128.3, 129.4,
129.8, 132.8, 134.2, 139.7, 141.1, 141.3, 161.0, 163.2, 172.5; IR (KBr,
cm−1) ν 685, 834, 921, 1030, 1124, 1175, 1256, 1317, 1333, 1404,
1446, 1486, 1503, 1602, 1640, 1700, 3071, 3378; MS (ESI) m/z 355
[M + H]+; HRMS (ESI) m/z calcd for C23H19N2O2 [M + H]+:
355.1447; found: 355.1446; mp. 324 °C.
127.8, 127.9, 128.0, 128.6, 128.8, 128.9, 129.4, 130.3, 130.4, 130.6,
130.7, 131.3, 133.1, 142.6, 163.3, 173.1; IR (KBr, cm−1) υ 506, 617,
699, 723, 746, 765, 787, 896, 920, 1126, 1183, 1209, 1248, 1354, 1418,
1454, 1494, 1535, 1579, 1634, 1705, 3063, 3120, 3166; MS (ESI) m/z
349 [M + H]+; HRMS (ESI) m/z calcd for C24H15N2O [M − H]−:
347.1184; found: 347.1190; mp. 297 °C.
(Z)-4-Benzylidene-2-(4-chlorophenyl)-1H-imidazol-5(4H)-one (3-
1
20). Following general procedure B, yellow solid (42 mg, 74%). H
NMR (DMSO-d6, 400 MHz) δ 7.05 (s, 1H), 7.4−7.55 (m, 3H), 7.69
(d, J = 8.6 Hz, 2H), 8.18 (d, J = 8.5 Hz, 2H), 8.31 (d, J = 7.2 Hz, 2H),
12.02 (br s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 125.4, 126.9,
128.7, 129.1, 129.2, 130.1, 132.1, 134.3, 137.3, 140.3, 160.0, 172.0; IR
(KBr, cm−1) ν 681, 724, 750, 774, 837, 893, 921, 1012, 1090, 1120,
1200, 1268, 1306, 1363, 1434, 1489, 1534, 1596, 1643, 1704, 3100;
MS (ESI) m/z 283 [C16 H1235ClN2O, M+H]+, 285 [C16 H1237ClN2O,
M+H]+; HRMS (ESI) m/z calcd for C16H12ClN2O [M + H]+:
283.0638; found: 283.0637; mp. 313 °C.
(Z)-2-Phenyl-4-(pyridin-2-ylmethylene)-1H-imidazol-5(4H)-one
(3-15). Following general procedure A, ochre solid (35.4 mg, 71%). 1H
NMR (DMSO-d6, 400 MHz) δ 6.93 (s, 1H), 7.38 (dd, J = 4.8 Hz, J =
6.4 Hz, 1H), 7.59−7.69 (m, 3H), 7.94 (dt, J = 1.6 Hz, J = 8.0 Hz, 1H),
8.20 (d, J = 7.2 Hz, 2H), 8.67 (d, J = 4.0 Hz, 1H), 8.93 (d, J = 8.0 Hz,
1H), 12.31 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 124.1, 124.9,
127.4, 128.0, 128.1, 129.5, 133.4, 137.0, 142.9, 150.3, 153.6, 163.2,
172.6; IR (KBr, cm−1) ν 558, 688, 784, 895, 922, 1055, 1116, 1153,
1177, 1250, 1275, 1298, 1340, 1414, 1432, 1452, 1495, 1536, 1599,
1643, 1701, 2986, 3061, 3129, 3384; MS (ESI) m/z 250 [M + H]+;
HRMS (ESI) m/z calcd for C15H12N3O [M + H]+: 250.0980; found:
250.0980; mp. 242 °C.
(Z)-2-(4-Chlorophenyl)-4-((6-methoxynaphthalen-2-yl)meth-
ylene)-1H-imidazol-5(4H)-one (3-21). Following general procedure B,
yellow solid (56 mg, 77%). 1H NMR (DMSO-d6, 400 MHz) δ 3.92 (s,
3H), 7.17 (s, 1H), 7.22 (dd, J = 2.5, 8.9 Hz, 1H), 7.37 (d, J = 2.3 Hz,
1H), 7.70 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 8.7 Hz, 1H), 7.93 (d, J = 9
Hz, 1H), 8.23 (d, J = 8.6 Hz, 2H), 8.59 (s, 1H), 8.61 (d, J = 8.7 Hz,
1H), 12.13 (br s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 55.4, 106.2,
119.2, 126.0, 127.0, 127.2, 128.3, 128.6, 129.1, 129.2, 129.9, 130.5,
133.2, 135.1, 137.2, 139.7, 158.8, 159.2, 171.9; IR (KBr, cm−1) ν 662,
723, 835, 853, 920, 1032, 1092, 1117, 1179, 1194, 1242, 1259, 1336,
1393, 1439, 1483, 1535, 1597, 1622, 1644, 1705, 3060; MS (ESI) m/z
363 [C21H1535ClN2O2, M + H]+, 365 [C21H1537ClN2O2, M + H]+;
HRMS (ESI) m/z calcd for C21H16N2O2Cl [M + H]+: 363.0900;
found: 363.0898; mp. 338 °C.
(Z)-2-(4-Methoxyphenyl)-4-(pyridin-2-ylmethylene)-1H-imidazol-
5(4H)-one (3-16). Following general procedure A, yellow solid (48
mg, 86%). 1H NMR (DMSO-d6, 400 MHz) δ 3.86 (s, 3H), 6.85
(s,1H), 7.14 (d, J = 8.8 Hz, 2H), 7.34 (dd, J = 4.6 Hz, J = 6.4 Hz, 2H),
7.92 (dt, J = 1.6 Hz, J = 8.0 Hz, 1H), 8.16 (d, J = 8.8 Hz, 2H), 8.64 (d,
J = 4.6 Hz, 1H), 8.90 (d, J = 8.0 Hz, 1H); 13C NMR (DMSO-d6, 100
MHz) δ 56.03, 115.0, 120.3, 123.1, 123.8, 127.1, 130.2, 136.9, 143.2,
150.2, 153.9, 163.0, 163.6, 172.8; IR (KBr, cm−1) ν 561, 609, 636, 780,
837, 920, 1023, 1056, 1092, 1120, 1193, 1261, 1301, 1358, 1404, 1435,
1481, 1503, 1545, 1563, 1585, 1606, 1642, 1728, 2851, 3016, 3212;
MS (ESI) m/z: 280 [M + H]+; HRMS (ESI) m/z calcd for
C16H14N3O2 [M + H]+: 280.1086; found: 280.1099. mp 249 °C.
(Z)-4-((6-Methoxynaphthalen-2-yl)methylene)-2-phenyl-1H-imi-
dazol-5(4H)-one (3-17). Following general procedure A, yellow solid
(Z)-4-Benzylidene-2-(3-nitrophenyl)-1H-imidazol-5(4H)-one (3-
1
22). Following general procedure B, yellow solid (40 mg, 68%). H
NMR (DMSO-d6, 400 MHz) δ 7.11 (s, 1H), 7.42−7.55 (m, 3H), 7.89
(t, J = 8 Hz, 1H), 8.31 (d, J = 7.2 Hz, 2H), 8.45 (dd, J = 1.4, 8.2 Hz,
1H), 8.58 (d, J = 7.9 Hz, 1H), 8.94 (s, 1H), 12.33 (br s, 1H); 13C
NMR (DMSO-d6, 100 MHz) δ 121.9, 126.6, 126.7, 128.8, 129.6,
130.4, 130.7, 132.2, 133.4, 134.1, 140.0, 148.3, 159.3, 171.7; IR (KBr,
cm−1) ν 645, 693, 756, 776, 817, 858, 891, 912, 955, 1060, 1137, 1198,
1260, 1352, 1417, 1443, 1491, 1531, 1615, 1639, 1699, 3085; MS
(ESI) m/z 294 [M + H]+; HRMS (ESI) m/z calcd for C16H12N3O3
[M + H]+: 294.0879; found: 294.0873; mp. 241 °C.
1
(54 mg, 82%). H NMR (DMSO-d6, 400 MHz) δ 3.90 (s, 3H), 7.14
(s, 1H), 7.20 (dd, J = 2.2 Hz, J = 8.8 Hz, 1H), 7.36 (d, J = 2.2 Hz, 1H),
7.58−7.66 (m, 3H), 7.90 (dd, J = 9.2 Hz, J = 13.6 Hz, 2H), 8.21 (d, J =
6.4 Hz, 2H), 8.58 (s, 1H), 8.61 (d, J = 8.8 Hz, 1H), 12.10 (br s, NH);
13C NMR (DMSO-d6, 100 MHz) δ 55.8, 106.6, 119.6, 125.9, 127.5,
127.8, 128.5, 128.7, 129.1, 129.4, 130.4, 130.9, 132.8, 133.4, 135.5,
140.3, 159.2, 160.6, 172.4; IR (KBr, cm−1) ν 415, 664, 693, 790, 858,
919, 1027, 1117, 1177, 1192, 1256, 1277, 1335, 1391, 1418, 1454,
1481, 1597, 1618, 1703, 3062, 3370; MS (ESI) m/z 329 [M + H]+;
HRMS (ESI) m/z calcd for C21H17N2O2 [M + H]+: 329.1290; found:
329.1303; mp. 299 °C.
(Z)-4-((6-Methoxynaphthalen-2-yl)methylene)-2-(4-methoxy-
phenyl)-1H-imidazol-5(4H)-one (3-18). Following general procedure
A, yellow solid (60.5 mg, 84%). The product 3-18 was isolated as a
90/10 mixture of two isomers Z/E. The reported NMR signals are
corresponding to the major Z isomer. 1H NMR (DMSO-d6, 400
(Z)-4-(4-Fluorobenzylidene)-2-(3-nitrophenyl)-1H-imidazol-
5(4H)-one (3-23). Following general procedure B, green solid (31 mg,
50%). 1H NMR (DMSO-d6, 400 MHz) δ 7.11 (s, 1H), 7.34 (t, J = 8.8
Hz, 2H), 7.88 (t, J = 8 Hz, 1H), 8.38 (dd, J = 5.9, 8.6 Hz, 2H), 8.44
(dd, J = 1.4, 8.2 Hz, 1H), 8.57 (d, J = 7.9 Hz, 1H), 8.92 (s, 1H), 12.3
(br s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 116 (d, J (13C-F) =
21.7 Hz), 121.9, 125.3, 126.7, 129.7, 130.7, 130.9 (d, J (13C-F) = 3
Hz), 133.4, 134.6 (d, J (13C-F) = 8.5 Hz), 139.8 (d, J (13C-F) = 2.6
Hz), 148.3, 159.6, 163.1 (d, J (13C-F) = 251 Hz), 171.9; IR (KBr,
cm−1) ν 699, 783, 833, 862, 894, 955, 1159, 1196, 1232, 1265, 1351,
1418, 1441, 1505, 1529, 1595, 1645, 1711, 3084; MS (ESI) m/z 312
D
dx.doi.org/10.1021/jo501922j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
[M + H]+; HRMS (ESI) m/z calcd for C16H11N3O3F [M + H]+:
312.0784; found: 312.0792; mp. 260 °C.
Methods 2005, 2, 255−257. (d) Zimmer, M. Chem. Rev. 2002, 102,
759−781.
(Z)-4-(4-(Dimethylamino)benzylidene)-2-(3-nitrophenyl)-1H-imi-
dazol-5(4H)-one (3-24). Following general procedure B, red solid (26
mg, 39%). 1H NMR (DMSO-d6, 400 MHz) δ 3.04 (s, 6 H), 6.80 (d, J
= 9 Hz, 2H), 7.00 (s, 1H), 7.85 (t, J = 8 Hz, 1H), 8.16 (d, J = 8.6 Hz,
2H), 8.38 (dd, J = 1.5, 8.2 Hz, 1H), 8.50 (d, J = 7.9 Hz, 1H), 8.89 (s,
1H), 12.05 (br s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 39.6, 111.8,
121.2, 121.6, 125.7, 128.5, 130.2, 130.6, 132.7, 134.4, 135.7, 148.3,
151.6, 155.1, 171.4; IR (KBr, cm−1) ν 621, 695, 807, 861, 900, 949,
1064, 1126, 1183, 1217, 1279, 1349, 1374, 1442, 1490, 1521, 1596,
1636, 1695, 2860, 3083; MS (ESI) m/z 337 [M + H]+; HRMS (ESI)
m/z calcd for C18H17N4O3 [M + H]+: 337.1301; found: 337.1287; mp.
304 °C.
(4) (a) Gong, X.; Yang, H.; Liu, H.; Jiang, Y.; Zhao, Y.; Fu, H. Org.
Lett. 2010, 12, 3128−3131. (b) Wu, L.; Burgess, K. J. Am. Chem. Soc.
2008, 130, 4089−4096. (c) Chen, Y.-H.; Lo, W.-J.; Sung, K. J. Org.
Chem. 2013, 78, 301−310. (d) Wang, Y.; Xie, H.; Pan, Y.-R.; Ding, M.-
W. Synthesis 2014, 46, 336−342. (e) Baldridge, A.; Kowalik, J.;
Tolbert, L. M. Synthesis 2010, 14, 2424−2436. (f) Pruger, B.; Bach, T.
̈
Synthesis 2007, 7, 1103−1106. (g) Lee, C.-Y.; Chen, Y.-C.; Lin, H.-C.;
Jhong, Y.; Chang, C.-W.; Tsai, C.-H.; Kao, C.-L.; Chien, T.-C.
Tetrahedron 2012, 68, 5898−5907.
(5) For reviews on phosphine-catalyzed reactions employing
electron-deficient alkynes or allenes, see: (a) Lu, X.; Zhang, C.; Xu,
Z. Acc. Chem. Res. 2001, 34, 535−544. (b) Methot, J. L.; Roush, W. R.
Adv. Synth. Catal. 2004, 346, 1035−1050. (c) Lu, X.; Du, Y.; Lu, C.
Pure Appl. Chem. 2005, 77, 1985−1990. (d) Valentine, D. H.;
Hillhouse, J. H. Synthesis 2003, 3, 317−334.
(6) (a) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc.
2005, 127, 9260−9266. (b) Liu, B.; Davis, R.; Joshi, B.; Reynolds, D.
W. J. Org. Chem. 2002, 67, 4595−4598. (c) Kuroda, H.; Tomita, I.;
Endo, T. Org. Lett. 2003, 5, 129−131. (d) Lu, C.; Lu, X. Org. Lett.
2002, 4, 4677−4679. (e) Yavari, I.; Souri, S.; Sirouspour, M.;
Djahaniani, H. Synthesis 2006, 19, 3243−3249. (f) Gabillet, S.;
(Z)-4-([1,1′-Biphenyl]-4-ylmethylene)-2-(3-nitrophenyl)-1H-imi-
dazol-5(4H)-one (3-25). Following general procedure B, orange solid
1
(42 mg, 57%). H NMR (DMSO-d6, 400 MHz) δ 7.18 (s, 1H), 7.42
(t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.79 (d, J = 7.4 Hz, 2H),
7.85 (d = 8.4 Hz, 2H), 7.93 (t, J = 8 Hz, 1H), 8.42 (d, J = 8.4 Hz, 2H),
8.48 (dd, J = 1.5, 8.2 Hz, 1H), 8.61 (d, J = 7.9 Hz, 1H), 8.98 (s, 1H),
12.39 (br s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 121.8, 126.1,
126.6, 126.7, 126.9, 128.0, 129.0, 130.6, 132.8, 133.2, 139.1, 140.0,
141.6, 148.2, 159.1, 171.6; IR (KBr, cm−1) ν 644, 695, 727, 771, 841,
858, 895, 923, 948, 1003, 1088, 1136, 1191, 1220, 1267, 1345, 1414,
1454, 1484, 1531, 1593, 1632, 1689, 3060; MS (ESI) m/z 368 [M-
H]−; HRMS (ESI) m/z calcd for C22H16N3O3 [M + H]+: 370.1192;
found: 370.1194; mp. 305 °C.
(Z)-4-(2-Methoxybenzylidene)-2-(3-nitrophenyl)-1H-imidazol-
5(4H)-one (3-26). Following general procedure B, yellow solid (38
mg, 59%). 1H NMR (DMSO-d6, 400 MHz) δ 3.89 (s, 3H), 7.03−7.13
(m, 2H), 7.38−7.47 (m, 2H), 7.84 (t, J = 8 Hz, 1H), 8.40 (dd, J = 1.5,
8.1 Hz, 1H), 8.52 (d, J = 7.9 Hz, 1H), 8.83 (dd, J = 1.4, 8 Hz, 1H),
8.89 (s, 1H), 12.95 (br s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ
55.8, 111.3, 119.7, 120.8, 121.8,122.4, 126.5, 129.7, 130.7, 132.3, 132.4,
133.2, 139.4, 148.2, 158.7, 158.8, 171.7; IR (KBr, cm−1) ν 701, 766,
860, 894, 955, 1026, 1165, 1198, 1245, 1293, 1349, 1436, 1485, 1529,
1597, 1633, 1709, 3173; MS (ESI) m/z 324 [M + H]+; HRMS (ESI)
m/z calcd for C17H14N3O4 [M + H]+: 324.0984; found: 324.0987; mp.
303 °C.
Lecercle,
2007, 4, 515−522. (g) Gabillet, S.; Lecercle,
M.; Dez
(7) Ruhemann, S.; Stapleton, H. E. J. Chem. Soc. 1900, 77, 239−244.
(8) Gupta, K. A.; Saxena, A. K.; Jain, P. C. Synthesis 1981, 11, 905−
907.
́
D.; Loreau, O.; Dez
́
ard, S.; Gomis, J.-M.; Taran, F. Synthesis
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D.; Loreau, O.; Carboni,
́
ard, S.; Gomis, J.-M.; Taran, F. Org. Lett. 2007, 9, 3925−3927.
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1753.
(10) Haned
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anian, M.; Loreau, O.; Sawicki, M.; Taran, F. Tetrahedron
2005, 61, 2287−2294.
(11) Lecercle,
1301−1311.
́
D.; Mothes, C.; Taran, F. Synth. Commun. 2007, 37,
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C NMR, and fluorescence properties for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: frederic.taran@cea.fr (F.T.).
■
Notes
The authors declare no competing financial interest
ACKNOWLEDGMENTS
This work was supported by ANR (ClickScreen project) and by
the labex Charmmmat.
■
REFERENCES
■
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dx.doi.org/10.1021/jo501922j | J. Org. Chem. XXXX, XXX, XXX−XXX