Synthesis of symmetrical and unsymmetrical N-aryl-substituted cyclic ureas through copper(I) iodide catalyzed Goldberg-Buchwald-Nandakumar C-N coupling reactions

Article abstract of DOI:10.1055/s-2008-1042946

The catalytic conditions of copper(I) iodide/potassium carbonate/trans-N, N′-dimethylcyclohexane-1,2-diamine, either in toluene at reflux temperature, or by heating neat at 150°C effectively promoted the C-N coupling of aryl bromides with cyclic ureas. By

Full text of DOI:10.1055/s-2008-1042946

PAPER
1359
Synthesis of Symmetrical and Unsymmetrical N-Aryl-Substituted Cyclic
Ureas through Copper(I) Iodide Catalyzed Goldberg–Buchwald–
Nandakumar C–N Coupling Reactions
S
ynthesis of
N
-
A
h
u
U
r
n
a
Department of Chemistry, National Taiwan University, 1 Roosevelt Road, Section 4, Taipei, Taiwan 106
Institute of Polymer Science and Engineering, National Taiwan University, 1 Roosevelt Road, Section 4, Taipei, Taiwan 106
Fax +886(2)33636359; E-mail: mkleung@ntu.edu.tw
b
Received 10 December 2007; revised 17 January 2008
of amides.15 In contrast, examples of the diarylation of
ureas are rare.18 Buchwald has reported the copper-cata-
lyzed 1,3-diarylation of imidazolidin-2-one with ethyl-
enediamine as a ligand in N,N-dimethylformamide under
Abstract: The catalytic conditions of copper(I) iodide/potassium
carbonate/trans-N,N¢-dimethylcyclohexane-1,2-diamine, either in
toluene at reflux temperature, or by heating neat at 150 °C effective-
ly promoted the C–N coupling of aryl bromides with cyclic ureas.
By employing a protection–deprotection strategy, unsymmetrical microwave irradiation.18a Nandakumar has recently re-
diaryl-substituted cyclic ureas could also be synthesized.
ported the arylation of urea using copper(I) iodide/cyclo-
hexane-1,2-diamine (CHDA)/tripotassium phosphate in
N,N-dimethylformamide at 80 °C, which gave arylureas
in moderate yields.18b
Key words: arylation, copper, cross-coupling, homogeneous catal-
ysis, heterocycles
Continuing our interest in the chemistry of ureas,19 we
have recently investigated alternative conditions for the
copper(I) iodide promoted N,N¢-diarylurea synthesis. Al-
though Goldberg reactions usually proceeded effectively
in coordinating solvents such as N,N-dimethylformamide
or dioxane,20 we are looking for catalytic conditions that
would proceed smoothly in other solvents such as toluene.
It has been known that the reactivity of the copper catalyst
strongly relies on the ligand system used in the reac-
tion.17a–f Effective ligands, including ethylenediamine and
derivatives such as trans-N,N¢-dimethylcyclohexane-1,2-
diamine (DMCHDA), are known to promote the Goldberg
reaction.12,15
N-Aryl-substituted ureas have attracted investigations by
many synthetic chemists because of their wide applica-
tions in different fields such as medicinal chemistry,1
host-guest chemistry,2 and anion sensors.3 Conventional
methods4 for urea synthesis usually involve hazardous
and toxic reagents such as isocyanates,5 phosgene,6 or car-
bon monoxide.7 Alternative strategies utilizing transition-
metal-catalyzed C–N bond-formation have been devel-
oped. A few examples of the palladium-catalyzed aryla-
tion of ureas with aryl halides have been reported.8 These
included the cross-coupling of N-alkyl- and N-phenyl-
substituted acyclic ureas and cyclic ureas with aryl
halides8i,9 or heteroaryl halides,10 and intramolecular pal-
ladium-catalyzed arylation of ureas.11 In spite of the ac- Table 1 Copper(I) Iodide Catalyzed Cross-Coupling of 4-Bromo-
toluene with Imidazolidin-2-one in Toluene under Different Base-
cessibility of the palladium-catalyzed reactions, some
limitations still remain. For example, the C–N coupling of
and-Ligand Assisted Conditionsa
O
O
ureas with electron-rich aryl halides, and ortho-substitut-
ed aryl halides could be difficult.9a,12 Moreover, the re-
moval of the palladium residues from polar reaction
products, particularly in the latter stages of the synthesis
of pharmaceutical substances, could be challenging.12 The
high cost of palladium has invited the investigation of less
expensive synthetic alternatives.
The well-documented Goldberg reaction,13,14 using cop-
per(I) iodide catalyzed N-arylation, provided a less expen-
sive route for C–N bond formation in amide synthesis;
however, the reaction conditions were relatively harsh.
Ligand-assisted Goldberg reactions were therefore devel-
oped.12,15–17 It is worth mentioning that the presence of
strongly electron-donating substituents at the ortho or
para positions has no deleterious effects on the arylation
4-MeC6H4Br
(2.2 equiv)
HN
NH
N
N
CuI, diamine
base, PhMe
1
2
Entry
Base
Diamine ligand
CHDA
Yieldb (%)
1
2
3
4
5
6
K3PO4
K2CO3
Cs2CO3
K3PO4
K2CO3
Cs2CO3
2
62
19
54
92
44
CHDA
CHDA
DMCHDA
DMCHDA
DMCHDA
a 1 (1.2 mmol), CuI (10 mol%), ligand (20 mol%), base (2.5 mmol),
toluene (1 mL).
SYNTHESIS 2008, No. 9, pp 1359–1366
Advanced online publication: 18.03.2008
x
x
.
x
x
.2
0
0
8
b Isolated yield.
DOI: 10.1055/s-2008-1042946; Art ID: F22607SS
© Georg Thieme Verlag Stuttgart · New York

1360
C.-C. Lee et al.
PAPER
Therefore, we first attempted to carry out phenylation of
N,N¢-dimethylurea with bromobenzene under the catalytic
conditions of copper(I) iodide (10 mol%), tripotassium
phosphate (2.2 equiv), and trans-N,N¢-dimethylcyclohex-
ane-1,2-diamine (DMCHDA, 20 mol%) in toluene at re-
flux temperature, but these conditions failed and the
starting materials were recovered according to NMR anal-
ysis. When the reagents CuI/K2CO3/DMCHDA were
used, only some unidentified products were obtained.
Since cesium carbonate has been known to effectively
promote C–N coupling reactions,8a we, therefore, attempt-
ed to use cesium carbonate as the base in our synthesis. In-
terestingly, when cesium carbonate was applied, around
5% of N-methylaniline was isolated. We suspected that
the phenylation process might proceed first to give the
urea products, followed by in situ hydrolysis or aminoly-
sis with the diamine ligand to give N-methylaniline. This
result urged us to investigate the cross-coupling of aryl
halides with imidazolidin-2-one, a cyclic urea with higher
resistance against hydrolysis. When similar conditions
were applied to imidazolidin-2-one with 4-bromotoluene
in toluene, using cyclohexane-1,2-diamine as the ligand
and potassium carbonate as the base, 221 was obtained in
62% yield (Table 1). Other bases such as tripotassium
phosphate or cesium carbonate were less effective.22
Table 2 Copper(I) Iodide Catalyzed Cross-Coupling of Aryl
Bromides with Imidazolidin-2-one in Toluene
O
O
ArBr (2.2 equiv)
Ar
Ar
HN
NH
N
N
CuI, DMCHDA
base, PhMe
1
2–12
Entry
ArBr
Product
Yielda (%)
b
c
K2CO3
Cs2CO3
56
36
18
76
56
58
64
–
1
2
4-MeC6H4
4-EtO2CC6H4
4-O2NC6H4
4-MeOC6H4
4-MeSC6H4
4-NCC6H4
4-AcC6H4
Ph
221
39f
92
73
54
88
76
84
81
85
95
83
82
3
423
521,24
6
4
5
6
7
7
8
8
921,25
10
9
2-MeOC6H4
1-naphthyl
2-pyridyl
57
71
–
10
11
11
When trans-N,N¢-dimethylcyclohexane-1,2-diamine was
employed, the yields of 2 were boosted significantly.
Among the bases we tried, potassium carbonate gave the
best yield of 92%. On the other hand, when cesium car-
bonate was used, a stoichiometric amount of copper(I) io-
dide was required to afford the desired ureas in moderate
yields (Table 2).
1210
a Isolated yield.
b 1 (1.2 mmol), CuI (10 mol%), ligand (20 mol%), base (2.5 mmol),
toluene (1 mL), reflux, 24 h.
c 1 (1.2 mmol), CuI (100 mol%), ligand (200 mol%), base (2.5 mmol),
mesitylene (1 mL), reflux, 48 h.
The reaction could be applied to a large variety of aryl ha-
lides. Many functional groups, including ether, sulfide, ni-
trile, nitro, ester, and carbonyl groups, were compatible
with the copper(I) iodide catalyzed N-arylation protocol.
The reaction could also be applied to heterocyclic halides
such as 2-bromopyridine to give 12 in good yield. Al-
though substituent electronic effects were less significant,
the yield of 39f (73%) and 4 (54%) in the cross-coupling
reaction were noticeably low, indicating that the C–N
coupling reactions were less effective if aryl halides bear-
ing electron-withdrawing groups were used. This tenden-
cy in its reactivity is the reverse of that for other known
methods.9a,12
The C–N coupling reaction also proceeded smoothly
when sterically hindered aryl halides were used. For ex-
ample, ortho-substituted 2-bromoanisole reacted to give
10 in 95% yield. In addition, 1-bromonaphthalene could
Figure 1 ORTEP of 11 proved the success of the C–N coupling re-
action
also react to give 11 in 83% yield. The structural identifi- The method could be extended to other cyclic and acyclic
cation of 11 was further supported by X-ray crystallo- urea substrates, such as 2-hydroxy-1H-benzimidazole and
graphic analysis. Single crystals of 11 were successfully 1,3-diphenylurea. The reactions were conducted smoothly
prepared by slow diffusion of hexane into the correspond- under the same conditions, which gave 13–15 in moderate
ing chloroform solution (Figure 1). The result also con- yields (Scheme 1). A single crystal of 15 was successfully
firmed that N,N¢-diarylation, rather than N,O-diarylation, prepared by slow evaporation of the solvents from the cor-
of imidazolidin-2-one was obtained.
responding dichloromethane–ethyl acetate solution for X-
ray crystallographic analysis (Figure 2). The result also
Synthesis 2008, No. 9, 1359–1366 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Aryl-Substituted Cyclic Ureas
1361
O
O
R
R
O
4-RC6H4Br
R
R
4-RC6H4Br
(2.2 equiv)
O
(6 equiv; neat)
HN
HN
NH
N
N
NH
N
N
CuI, DMCHDA
K2CO3, 150 °C
CuI, DMCHDA
K2CO3, PhMe
16 R = OMe (84%)
17 R = NO2 (67%)
13 R = OMe (82%)
14 R = NO2 (23%)
Scheme 2 Copper(I) iodide catalyzed cross-coupling of aryl bro-
mides with tetrahydropyrimidin-2-one under neat conditions.
O
N
Br
O
CuI (10 mol%)
O
(2.2 equiv)
N
N
DMCHDA (20 mol%)
MeS
Br
+
N
N
CuI, DMCHDA
K2CO3, PhMe
HN
NH
H
H
N
K2CO3 (2.2 equiv)
PhMe, reflux
N
1
O
O
15 (21%)
SMe
SMe
MeS
H
N
N
N
N
18 (23%)
Scheme 1 Copper(I) iodide catalyzed cross-coupling of aryl bro-
mides with different urea substrates
+
6 (39%)
Scheme 3
1
bromothioanisole and 1. However, H NMR analysis of
the crude mixture revealed that the ratio of 18 and 6 was
1:1.65, indicating that the preference for mono- versus di-
arylation was low (Scheme 3).
Similar results were also obtained when 2-bromopyridine
was employed. In this trial, almost equal amounts of 12
and 1910 were identified even when excess imidazolidin-
2-one (5 equiv) was used (Scheme 4).
CuI (10 mol%)
O
CHDA (15 mol%)
Br
HN
NH
K2CO3 (2 equiv)
N
PhMe, reflux, 24 h
1
5 equiv
1 equiv
Figure 2 ORTEP of 15 revealed the two phenyl rings were located
in the Z,Z-positions
O
N
O
revealed the stereochemistry of 15, in which two phenyl
rings were located in the Z,Z-positions.
+
H
N
N
N
N
N
N
19 (39%)
This reaction could be further applied to 1,3-diaryltetrahy-
dropyrimidin-2-one synthesis. However, both 4-bromo-
anisole and 1-bromo-4-nitrobenzene were coupled with
tetrahydropyrimidin-2-one in low yields. According to the
NMR analysis of the crude products, both unreacted tet-
rahydropyrimidin-2-one and the monoarylation product
were found, implying that tetrahydropyrimidin-2-one was
less reactive than imidazolidin-2-one. By modifying the
catalyst loading, concentration, and reaction temperature,
the best yield of 16 was obtained when the reactions were
conducted in the presence of 0.3 equivalents of copper(I)
iodide and excess aryl bromide (6 equiv) under neat con-
dition at 150 °C (Scheme 2).
12 (45%)
Scheme 4
To make the synthesis of unsymmetrical cyclic urea suc-
cessful, another approach, protection–deprotection strate-
gy, was adopted to bypass this problem (Scheme 4).
Commercially available 1-tert-butylimidazolidin-2-one
(20) was employed as the starting material. The coupling
of 20 with 4-bromothioanisole afforded 21 in high yield.
Deprotection of 21 by removal of the tert-butyl group in
aqueous hydrochloric acid (20%) afforded 18.26 Finally,
the cross-coupling of 18 with ethyl 4-bromobenzoate af-
forded unsymmetrical 1,3-diarylimidazolidin-2-one 22 in
moderate yield (Scheme 5).
To extend the scope of the C–N coupling method to un-
symmetrical cyclic urea synthesis, we attempted the prep-
aration of 1-arylimidazolidin-2-one by limiting the
number of equivalents of the aryl halides used in the reac-
tion. In the first trial, we prepared 4-(methylsulfany)phe-
nyl-substituted 18 by reacting equivalent amounts of 4-
In summary, the foregoing methodology offers a highly
accessible approach for the synthesis of mono- and disub-
stituted cyclic ureas. Either symmetrical or unsymmetri-
cal cyclic ureas could be successfully prepared.
Synthesis 2008, No. 9, 1359–1366 © Thieme Stuttgart · New York

1362
C.-C. Lee et al.
PAPER
1,3-Bis[4-(ethoxycarbonyl)phenyl]imidazolidin-2-one (3)9f
Purified by flash chromatography (CHCl3); white solid; yield: 73%;
mp 222 °C.
O
O
Br
S
S
N
N
HN
N
CuI (10 mol%)
IR (KBr): 2981, 2906, 1708, 1606 cm–1.
DMCHDA (20 mol%)
K2CO3 (2.3 mmol)
PhMe, reflux, 24 h
20
21 (94%)
1H NMR (400 MHz, CDCl3): d = 8.04 (dd, J = 7.0, 3.8 Hz, 4 H,
H3¢), 7.67 (dd, J = 7.0, 3.8 Hz, 4 H, H2¢), 4.35 (q, J = 7.1 Hz, 4 H,
OCH2CH3), 4.02 (s, 4 H, H4), 1.38 (t, J = 7.2 Hz, 6 H, OCH2CH3).
O
13C NMR (100 MHz, CDCl3): d = 166.2, 154.1, 143.5, 130.6, 124.9,
S
Br
CuI (10 mol%)
CO2Et
117.0, 60.8, 41.6, 14.4.
HCl (20%)
reflux
N
NH
HRMS (EI): m/z calcd for C21H22N2O5: 382.1529; found: 382.1530.
DMCHDA (20 mol%)
K2CO3 (2.2 mmol)
PhMe, reflux, 24 h
18 (64%)
Anal. Calcd for C21H22N2O5: C, 65.96; H, 5.80; N, 7.33. Found: C,
65.90; H, 5.79; N, 7.22.
O
O
1,3-Bis(4-nitrophenyl)imidazolidin-2-one (4)23
Purified by flash chromatography (CHCl3); yellow solid; yield:
54%; mp 306 °C (Lit.23 299 °C).
S
O
N
N
IR (KBr): 1708, 1596 cm–1.
22 (76%)
1H NMR (400 MHz, CD3CN): d = 8.26 (d, J = 9.4 Hz, 4 H, H3¢),
7.88 (d, J = 9.4 Hz, 4 H, H2¢), 4.07 (s, 4 H, H4).
Scheme 5 Synthesis of unsymmetrically substituted 1,3-diarylimi-
dazolidin-2-one 22
13C NMR (125 MHz, DMSO-d6): d = 153.6, 145.4, 141.7, 124.7,
117.4, 41.4.
All commercially available reagents, including imidazolidin-2-one,
1-tert-butylimidazolidin-2-one, aryl bromides, CuI, and K2CO3
were obtained commercially and were used without further purifi-
cation. trans-N,N¢-Dimethylcyclohexane-1,2-diamine (DMCHDA)
was prepared according to the supporting information in literature.27
Toluene was dried over calcium hydride and distilled before use.
Liquid chromatography was performed with silica gel (230–400
mesh). Solvents were evaporated under reduced pressure by using a
rotary evaporator. All yields given refer to as isolated yields. NMR
spectra were recorded on a 400 MHz spectrometer. IR spectra were
recorded on a FT-IR spectrophotometer. MS and HRMS experi-
ments were performed on a high-/low-resolution magnetic sector
mass spectrometer.
HRMS (EI): m/z calcd for C15H12N4O5: 328.0808; found: 328.0811.
Anal. Calcd for C15H12N4O5: C, 54.88; H, 3.68; N, 17.07. Found: C,
54.61; H, 3.70; N, 17.27.
1,3-Bis(4-methoxyphenyl)imidazolidin-2-one (5)21,24
Purified by flash chromatography (CHCl3); white solid; yield: 88%;
mp 278–279 °C (Lit.21 266 °C).
IR (KBr): 2952, 2908, 1874, 1685, 1522 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.46 (d, J = 9.0 Hz, 4 H, H2¢), 6.89
(d, J = 9.0 Hz, 4 H, H3¢), 3.91 (s, 4 H, H4), 3.78 (s, 6 H, OCH3).
13C NMR (125 MHz, CDCl3): d = 155.4 (2 C based on HMBC ex-
periment), 133.3, 119.8, 114.0, 55.4, 42.4.
1,3-Diarylimidazolidin-2-ones 2–12, 1,3-Diaryl-1,3-dihydro-
2H-benzimidazol-2-ones 13,14 and 1,3-Diphenyl-1,3-di-2-py-
ridylurea (15); General Procedure
HRMS (EI): m/z calcd for C17H18N2O3: 298.1317; found: 298.1320.
Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. Found: C,
68.23; H, 6.09; N, 9.38.
To a 2-necked flask were charged imidazolidin-2-one (1, 0.10 g, 1.2
mmol), CuI (0.02 g, 10 mol%), DMCHDA (0.03 mL, 20 mol%),
aryl bromide (2.2 equiv), K2CO3 (0.35 g, 2.5 mmol), and toluene (1
mL, 1 M) under argon. The mixture was refluxed for 24 h and then
cooled to r.t., diluted with CHCl3 (10 mL), and filtered through
Celite and washed with CHCl3 (3 × 15 mL). The organic filtrate was
washed with H2O (3 × 15 mL), dried (anhyd MgSO4), and concen-
trated. The crude product was purified by flash chromatography
(silica gel).
1,3-Bis[4-(methylsulfanyl)phenyl]imidazolidin-2-one (6)
Purified by flash chromatography (CHCl3); white solid; yield: 76%;
mp 274–276 °C.
IR (KBr): 2922, 2917, 1685 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.51 (d, J = 8.8 Hz, 4 H, H2¢), 7.23
(d, J = 8.8 Hz, 4 H, H3¢), 3.93 (s, 4 H, H4), 2.46 (s, 6 H, SCH3).
13C NMR (125 MHz, CDCl3): d = 154.8, 137.7, 132.1, 128.3, 118.6,
41.9, 17.0.
1,3-Di-4-tolylimidazolidin-2-one (2)21
Purified by flash chromatography (CHCl3); white solid; yield: 92%;
HRMS (EI): m/z calcd for C17H18N2OS2: 330.0861; found:
330.0865.
mp 233–234 °C (Lit.21 224 °C).
IR (KBr): 3032, 2991, 2912, 2857, 1686 cm–1.
Anal. Calcd for C17H18N2OS2: C, 61.79; H, 5.49; N, 8.48; S, 19.41.
Found: C, 61.73; H, 5.20; N, 8.29; S, 18.95.
1H NMR (400 MHz, CDCl3): d = 7.45 (dd, J = 6.6, 4.0 Hz, 4 H,
H2¢), 7.15 (d, J = 8.2 Hz, 4 H, H3¢), 3.89 (s, 4 H, H4), 2.31 (s, 6 H,
CH3).
13C NMR (100 MHz, CDCl3): d = 155.1, 137.6, 132.4, 129.3, 118.0,
42.0, 20.7.
1,3-Bis(4-cyanophenyl)imidazolidin-2-one (7)
Purified by flash chromatography (CHCl3); white solid; yield: 84%;
mp 326–328 °C.
IR (KBr): 2222, 1713, 1604 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.72 (d, J = 9.2 Hz, 4 H, H2¢), 7.66
(d, J = 9.2 Hz, 4 H, H3¢), 4.04 (s, 4 H, H4).
HRMS (EI): m/z calcd for C17H18N2O: 266.1419; found: 266.1417.
Anal. Calcd for C17H18N2O: C, 76.66; H, 6.81; N, 10.52. Found: C,
76.53; H, 6.85; N, 10.49.
13C NMR (125 MHz, CDCl3): d = 153.7, 143.1, 133.2, 118.8, 117.8,
106.4, 41.4.
Synthesis 2008, No. 9, 1359–1366 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Aryl-Substituted Cyclic Ureas
1363
HRMS (EI): m/z calcd for C17H12N4O: 288.1011; found: 288.1012.
mm. q Range for data collection: 2.47 to 27.49°. Limiting indices:
–17 £ h £ 17, –14 £ k £ 12, –16 £ l £ 16. Reflections collected:
12289. Independent reflections: 3938 [Rint = 0.0767]. Completeness
to q = 27.49o: 99.8%. Refinement method: Full-matrix least-squares
on F2. Data/restraints/parameters: 3938/0/236. Goodness-of-fit on
F2: 1.018. Final R indices [I > 2s(I)]: R1 = 0.0534, wR2 = 0.1191.R
indices (all data) R1 = 0.1052, wR2 = 0.1451. Largest diff. peak and
hole: 0.212 and –0.252 e Å–3. Selected bond lengths (Å) and angles
(°): O1–C1 1.213(2), N1–C1 1.382(2), N1–C14 1.431(2), N1–C2
1.457(2), C14–C23 1.423(2), C1–N1–C14 123.01(14), C1–N1–C2
110.24(14), C14–N1–C2 122.04(14), O1–C1–N1 126.66(16), C23–
C14–N1 119.56(16).
Anal. Calcd for C17H12N4O: C, 70.82; H, 4.20; N, 19.43. Found: C,
70.70; H, 4.18; N, 19.67.
1,3-Bis(4-acetylphenyl)imidazolidin-2-one (8)
Purified by flash chromatography (CHCl3); white solid; yield: 81%;
mp 284 °C.
IR (KBr): 2989, 2917, 1686, 1673, 1605 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.99 (d, J = 8.8 Hz, 4 H, H3¢), 7.70
(d, J = 8.8 Hz, 4 H, H2¢), 4.06 (s, 4 H, H4), 2.58 (s, 6 H, COCH3).
13C NMR (100 MHz, CDCl3): d = 196.9, 154.1, 143.7, 132.0, 129.6,
117.1, 41.6, 26.4.
1,3-Di-2-pyridylimidazolidin-2-one (12)10
HRMS (EI): m/z calcd for C19H18N2O3: 322.1317; found: 322.1313.
Purified by flash chromatography (CHCl3); white solid; yield: 82%;
mp 182–184 °C (Lit.10 182–184 °C).
Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C,
70.71; H, 5.61; N, 8.52.
IR (KBr): 3003, 2985, 2915, 1712, 1587 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.31–8.28 (m, 4 H, H2¢, H5¢), 7.65
(td, J = 8 Hz, 2.2 Hz, 2 H, H3¢), 6.95 (td, J = 6.2 Hz, 1.2 Hz, 2 H,
H4¢), 4.16 (s, 4 H, H4).
13C NMR (100 MHz, CDCl3): d = 153.7, 151.5, 146.9, 136.9, 118.0,
113.1, 40.9.
1,3-Diphenylimidazolidin-2-one (9)21,25
Purified by flash chromatography (CHCl3); white solid; yield: 85%;
mp 219–220 °C (Lit.21 212–213 °C).
IR (KBr): 2292, 2904, 1687, 1601 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.59–7.57 (m, 4 H, H2¢), 7.37–
7.34 (m, 4 H, H3¢), 7.09–7.06 (m, 2 H, H4¢), 3.95 (s, 4 H, H4).
13C NMR (100 MHz, CDCl3): d = 155.0, 140.0, 128.9, 123.0, 118.1,
42.0.
HRMS (EI): m/z calcd for C13H12N4O: 240.1011; found: 240.1014.
Anal. Calcd for C13H12N4O: C, 64.99; H, 5.03; N, 23.32. Found: C,
64.81; H, 4.96; N, 23.45.
HRMS (EI): m/z calcd for C15H14N2O: 238.1106; found: 238.1103.
1,3-Bis(4-methoxyphenyl)-1,3-dihydro-2H-benzimidazol-2-one
(13)
Anal. Calcd for C15H14N2O: C, 75.61; H, 5.92; N, 11.76. Found: C,
75.53; H, 5.91; N, 11.72.
Purified by flash chromatography (CHCl3); white solid; yield: 82%;
mp 186–187 °C.
IR (KBr): 2939, 1706, 1613, 1514 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.47 (dd, J = 6.7, 2.1 Hz, 4 H,
H2¢), 7.06–7.02 (m, 8 H, H3¢, H4, H5), 3.85 (s, 6 H, OCH3).
13C NMR (100 MHz, CDCl3): d = 159.0, 152.9, 130.0, 127.6, 127.2,
121.9, 114.8, 108.7, 55.5.
1,3-Bis(2-methoxyphenyl)imidazolidin-2-one (10)
Purified by flash chromatography (CHCl3); yellow liquid; yield:
95%.
IR (CHCl3): 3011, 2400, 1713 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.44 (dd, J = 7.8, 1.6 Hz, 2 H,
H6¢), 7.22–7.18 (m, 2 H, H4¢), 6.98–6.93 (m, 4 H, H3, H5¢), 3.90 (s,
4 H, H4), 3.86 (s, 6 H, OCH3).
HRMS (EI): m/z calcd for C21H18N2O3: 346.1317; found: 346.1328.
Anal. Calcd for C21H18N2O3: C, 72.82; H, 5.24; N, 8.09. Found: C,
72.69; H, 5.18; N, 7.96.
13C NMR (100 MHz, CDCl3): d = 158.3, 154.9, 128.6, 128.3, 127.3,
120.8, 112.0, 55.6, 45.0.
HRMS (EI): m/z calcd for C17H18N2O3: 298.1317; found: 298.1311.
1,3-Bis(4-nitrophenyl)-1,3-dihydro-2H-benzimidazol-2-one
(14)
Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. Found: C,
68.24; H, 6.11; N, 9.51.
Purified by flash chromatography (CHCl3); yellow solid; yield:
23%; mp 326 °C (dec).
IR (KBr): 3115, 3076, 1729, 1593, 1522, 1395 cm–1.
1,3-Di-1-naphthylimidazolidin-2-one (11)
Purified by flash chromatography (CHCl3); white solid; yield: 83%;
mp 198–200 °C.
IR (KBr): 3042, 2878, 1697, 1595 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.46 (d, J = 8.6 Hz, 4 H, H3¢),
7.98 (d, J = 8.6 Hz, 4 H, H2¢), 7.31 (d, J = 2.9 Hz, 2 H, H4), 7.24 (s,
2 H, H5).
1H NMR (400 MHz, CDCl3): d = 8.13 (dd, J = 8.4, 0.6 Hz, 2 H,
H8¢), 7.91–7.88 (m, 2 H, H5¢), 7.82 (d, J = 8.0 Hz, 2 H, H7¢), 7.60–
7.50 (m, 8 H, H2¢, H3¢, H4¢, H6¢), 4.12 (s, 4 H, H4).
13C NMR (100 MHz, CDCl3): d = 159.1, 136.5, 134.6, 130.5, 128.4,
127.7, 126.4, 126.2, 125.7, 124.2, 123.1, 47.4.
HRMS (EI): m/z calcd for C19H12N4O5: 376.0808; found: 376.0819.
Anal. Calcd for C19H12N4O5: C, 60.64; H, 3.21; N, 14.89. Found: C,
60.57; H, 3.26; N, 14.75.
1,3-Diphenyl-1,3-di-2-pyridylurea (15)
Purified by flash chromatography (CHCl3); white solid; yield: 21%;
mp 228–230 °C.
IR (KBr): 1672, 1593 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.30 (dd, J = 5.0 Hz, 1.6 Hz, 2 H,
H6), 7.48 (td, J = 7.2 Hz, 1.6 Hz, 2 H, H4), 7.17 (t, J = 7.6 Hz, 4 H,
H3¢), 7.05–7.09 (m, 2 H, H4¢), 6.98–7.02 (m, 6 H, H2¢, H3), 6.92–
6.96 (m, 2 H, H5).
HRMS (EI): m/z calcd for C23H18N2O: 338.1419; found: 338.1411.
Anal. Calcd for C23H18N2O: C, 81.63; H, 5.36; N, 8.28. Found: C,
81.43; H, 5.36; N, 8.18.
X-ray crystal structure analysis: formula C23H18N2O, M = 338.39,
T = 295(2) K, l = 0.71073 Å, crystal system: monoclinic, space
group P21/c. Unit cell dimensions: a = 13.2790(3) Å,
b = 10.8498(3) Å, c = 12.4770(4) Å, b = 107.042(17)°,
V = 1718.68(8) Å3, Z = 4. rcalcd = 1.308 mg/m3, absorption coeffi-
cient: 0.081 mm–1. F(000) = 712. Crystal size: 0.30 × 0.20 × 0.15
13C NMR (100 MHz, CDCl3): d = 158.6, 155.9, 148.4, 141.9, 137.2,
128.7, 126.2, 125.7, 119.8, 119.4.
Synthesis 2008, No. 9, 1359–1366 © Thieme Stuttgart · New York

1364
C.-C. Lee et al.
PAPER
HRMS (EI): m/z calcd for C23H18N4O: 366.1481; found: 366.1476.
der argon. The mixture was refluxed for 20 h, then cooled to r.t., di-
luted with CH2Cl2, and filtered through Celite and washed with
CH2Cl2. The organic filtrate was washed with H2O, dried (anhyd
MgSO4), and concentrated. The crude product was purified by flash
chromatography (silica gel, CH2Cl2–EtOAc, 2:1) to give 19 as a
white solid; yield: 39%; mp 165–166 °C (Lit.10 165–167 °C).
Anal. Calcd for C23H18N4O: C, 75.39; H, 4.95; N, 15.29. Found: C,
74.91; H, 4.84; N, 15.30.
X-ray crystal structure analysis: formula C23H18N4O, M = 366.41,
T = 295(2) K, l = 0.71073 Å, crystal system: orthorhombic, space
group Pbcn. Unit cell dimensions: a = 11.3440(2) Å,
b = 11.7670(2) Å, c = 14.1680(3) Å, V = 1891.21(6) Å3, Z = 4.
IR (KBr): 3231, 3106, 2909, 1698, 1590 cm–1.
r
calcd = 1.287 mg/m3, absorption coefficient: 0.082 mm–1.
1H NMR (400 MHz, CDCl3): d = 8.26 (ddd, J = 6.2 Hz, 1.6 Hz, 0.8
Hz, 1 H, H6¢), 8.22 (d, J = 8 Hz, 1 H, H3¢), 7.60 (td, J = 8 Hz, 2.2
Hz, 1 H, H4¢), 6.90 (td, J = 6.2 Hz, 1.2 Hz, 1 H, H5¢), 5.40 (s, 1 H,
NH), 4.16 (t, J = 8.2 Hz, 2 H, H5), 3.56 (t, J = 8.2 Hz, 2 H, H4).
13C NMR (100 MHz, CDCl3): d = 158.8, 151.8, 146.7, 136.7, 117.3,
112.6, 44.1, 37.6.
F(000) = 768. Crystal size: 0.30 × 0.25 × 0.25 mm. q Range for
data collection: 2.49 to 27.48°. Limiting indices: –14 £ h £ 14, –15
£ k £ 15, –18 £ l £ 18. Reflections collected: 11964. Independent re-
flections: 2169 [Rint = 0.0449]. Refinement method: Full-matrix
least-squares on F2. Data/restraints/parameters: 2159/0/129. Good-
ness-of-fit on F2: 1.071. Final R indices [I > 2s(I)]: R1 = 0.0493,
wR2 = 0.1103. R indices (all data) R1 = 0.0696, wR2 = 0.1215.
Largest diff. peak and hole: 0.290 and –0.338 e Å–3. Selected bond
lengths (Å) and angles (°): O1–C1 1.217(2), N1–C1 1.388(2), N1–
C2 1.425(2), N1–C7 1.436(2), N2–C2 1.339(2), C2–C3 1.383(2),
C1–N1–C2 121.78(11), C1–N1–C7 118.59(12), C2–N1–C7
118.90(11), C2–N2–C6 116.63(14), O1–C1–N1 122.42(8).
HRMS (FAB): m/z [M + H]+ calcd for C8H10N3O: 164.0824; found:
164.0828.
Anal. Calcd for C8H9N3O: C, 58.88; H, 5.56; N, 25.75. Found: C,
58.90; H, 5.51; N, 26.08.
1-tert-Butyl-3-[4-(methylsulfanyl)phenyl]imidazolidin-2-one
(21)
1,3-Diaryltetrahydropyrimidin-2(1H)-ones 16,17; General Pro-
cedure
A soln of 1-tert-butylimidazolidin-2-one (20, 0.21 g, 1.4 mmol),
CuI (0.03 g, 10 mol%), K2CO3 (0.32 g, 2.3 mmol), DMCHDA (0.03
mL, 20 mol%), and 4-bromothioanisole (0.45 g, 2.4 mmol) in tolu-
ene (2 mL) was reacted according to the general procedure to give
crude product and further purified by flash chromatography (silica
gel, CHCl3) to give 21 as a white solid; yield: 94%; mp 116–118 °C.
To a double-necked flask were charged tetrahydropyrimidin-2-one
(0.2 g, 2.0 mmol), CuI (0.11 g, 30 mol%), DMCHDA (0.13 mL, 60
mol%), aryl bromide (6 equiv), and K2CO3 (0.88 g, 6.4 mmol) under
argon. The mixture was heated to 150 °C for 24 h, then cooled to
r.t., diluted with CHCl3 (20 mL), and filtered through Celite and
washed with CHCl3 (3 × 30 mL). The organic filtrate was washed
with H2O (3 × 30 mL), dried (anhyd MgSO4), and concentrated.
The crude product was purified by flash chromatography (silica
gel).
IR (KBr): 2969, 2859, 1685, 1498 cm–1.
1H NMR (400 MHz, acetone-d6): d = 7.58 (dd, J = 6.8, 4.2 Hz, 2 H,
H2¢), 7.25 (dd, J = 6.8, 4.2 Hz, 2 H, H3¢), 3.73–3.69 (m, 2 H, H4),
3.56–3.52 (m, 2 H, H5), 2.44 (s, 3 H, SCH3), 1.40 (s, 9 H, t-Bu).
13C NMR (100 MHz, acetoned6): d = 158.4, 140.4, 131.1, 129.0,
1,3-Bis(4-methoxyphenyl)tetrahydropyrimidin-2(1H)-one (16)
Purified by flash chromatography (CHCl3–EtOAc, 2:1); white sol-
id; yield: 84%; mp 168–170 °C.
IR (KBr): 2950, 2906, 2834, 1636, 1509 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.25–7.21 (m, 4 H, H2¢), 6.86–
6.82 (m, 4 H, H3¢), 3.82–3.70 (m, 10 H, H4, OCH3), 2.26–2.20 (m,
2 H, H5).
118.6, 54.0, 42.7, 40.6, 27.6, 17.0.
HRMS (EI): m/z calcd for C14H20N2OS: 264.1296; found:
264.1289.
Anal. Calcd for C14H20N2OS: C, 63.60; H, 7.62; N, 10.60; S, 12.13.
Found: C, 63.59; H, 7.34; N, 10.42; S, 11.90.
1-[4-(Methylsulfanyl)phenyl]imidazolidin-2-one (18)
13C NMR (100 MHz, CDCl3): d = 157.0, 154.6, 136.9, 127.0, 113.7,
55.2, 49.4, 22.9.
To an oven-dried flask (25 mL) was charge a soln of 21 (1.15 g, 4
mmol) in 20% HCl (26 mL). The mixture was stirred and heated at
110 °C for 18 h. The resulting suspension was cooled, and neutral-
ized with aq NaOH. The mixture was extracted with CHCl3 (3 × 30
mL). The collected organic extracts were dried (anhyd MgSO4) and
concentrated. The crude products were purified by recrystallization
(CH2Cl2) to give 18 as a white solid; yield: 64%; mp 210–214 °C.
HRMS (EI): m/z calcd for C18H20N2O3: 312.1474; found: 312.1465.
Anal. Calcd for C18H20N2O3: C, 69.21; H, 6.45; N, 8.97. Found: C,
68.99; H, 6.65; N, 8.83.
1,3-Bis(4-nitrophenyl)tetrahydropyrimidin-2(1H)-one (17)
Purified by flash chromatography (CHCl3); yellow solid; yield:
67%; mp 236–238 °C.
IR (KBr): 2925, 2851, 1651, 1505 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.22–8.18 (m, 4 H, H3¢), 7.54–
7.50 (m, 4 H, H2¢), 3.92 (t, J = 6.0 Hz, 4 H, H4), 2.38–2.36 (m, 2 H,
H5).
IR (KBr): 3236, 3108, 2898, 1706, 1684, 1595 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.47–7.44 (m, 2 H, H2¢), 7.27–
7.25 (m, 2 H, H3¢), 4.96 (s, 1 H, NH), 3.90 (t, J = 7.4 Hz, 2 H, H5),
3.55 (t, J = 7.5 Hz, 2 H, H4), 2.44 (s, 3 H, SCH3).
13C NMR (100 MHz, CDCl3): d = 159.5, 137.9, 131.6, 128.4, 118.4,
45.3, 37.4, 17.1.
HRMS (EI): m/z calcd for C10H12N2OS: 208.0670; found:
208.0667.
13C NMR (100 MHz, CDCl3): d = 152.6, 148.3, 143.9, 124.7, 123.7,
48.6, 23.0.
Anal. Calcd for C10H12N2OS: C, 57.67; H, 5.81; N, 13.45; S, 15.40.
Found: C, 57.37; H, 5.70; N, 13.64; S, 15.72.
HRMS (EI): m/z calcd for C16H14N4O5: 342.0964; found: 342.0958.
Anal Calcd for C16H14N4O5: C, 56.14; H, 4.12; N, 16.37. Found: C,
56.13; H, 4.13; N, 16.27.
Ethyl 4-{3-[4-(Methylsulfanyl)phenyl]-2-oxoimidazolidin-1-
yl}benzoate (22)
A soln of 18 (0.08 g, 0.4 mmol), CuI (0.01 g, 10 mol%), K2CO3
(0.3022 g, 2.2 mmol), DMCHDA (0.01 mL, 20 mol%), and 4-
BrC6H4CO2Et (0.21 g, 0.9 mmol) in toluene (1 mL) was reacted ac-
cording to the general procedure and further purified by flash chro-
1-(2-Pyridyl)imidazolidin-2-one (19)10
A soln of imidazolidin-2-one (1, 14.26 g, 150 mmol), CuI (0.57 g,
10 mol%), CHDA (0.56 mL, 15 mol%), 2-bromopyridine (4.74 g,
30 mmol), K2CO3 (8.30 g, 60 mmol), and toluene (150 mL, 1 M) un-
Synthesis 2008, No. 9, 1359–1366 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Aryl-Substituted Cyclic Ureas
1365
matography (silica gel, CHCl3) to give 22 as a white solid; yield:
76%; mp 199–200 °C.
IR (KBr): 2978, 2918, 1702, 1612 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.02 (d, J = 9.0 Hz, 2 H, H3), 7.65
(d, J = 9.0 Hz, 2 H, H2), 7.51 (d, J = 8.8 Hz, 2 H, H2¢), 7.28 (d,
J = 8.8 Hz, 2 H, H3¢), 4.34 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.98–
3.96 (m, 4 H, NCH2CH2N), 2.46 (s, 3 H, SCH3), 1.37 (t, J = 7.1 Hz,
3 H, OCH2CH3).
(7) (a) Orito, K.; Miyazawa, M.; Nakamura, T.; Horibata, A.;
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T. J. K.; Holmes, I. P. Adv. Synth. Catal. 2006, 348, 851.
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Buchwald, S. L. Organometallics 2006, 25, 82. (h) Abbiati,
G.; Beccalli, E. M.; Broggini, G.; Paladino, G.; Rossi, E.
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Sergeev, A. G.; Beletskaya, I. P. Russ. J. Org. Chem. 2002,
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Tschierske, C. Chem. Commun. 2007, 2596.
(10) Abad, A.; Agulló, C.; Cuñat, A. C.; Vilanova, C. Synthesis
2005, 915.
(11) Ferraccioli, R.; Carenzi, D. Synthesis 2003, 1383.
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2002, 124, 7421.
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Chem. 1978, 43, 4975. (c) Renger, B. Synthesis 1985, 856.
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A. Synth. Commun. 1989, 19, 2077. (e) Ito, A.; Saito, T.;
Tanaka, K.; Yamabe, T. Tetrahedron Lett. 1995, 36, 8809.
(f) Lange, J. H. M.; Hofmeyer, L. J. F.; Hout, F. A. S.;
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13C NMR (100 MHz, CDCl3): d = 166.3, 154.4, 143.9, 137.3, 132.7,
130.6, 128.1, 124.5, 118.9, 116.7, 60.8, 41.8, 41.7, 16.8, 14.4.
HRMS (EI): m/z calcd for C19H20N2O3S: 356.1195; found:
356.1198.
Anal. Calcd for C19H20N2O3S: C, 64.02; H, 5.66; N, 7.86; S, 9.00.
Found: C, 64.19; H, 5.79; N, 7.83; S, 9.22.
Acknowledgment
The work was supported by National Science Council [NSC 95-
2113-M-002-021-MY3] and Ministry of Education, Taiwan.
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