N-H insertion reactions of primary ureas: The synthesis of highly substituted imidazolones and imidazoles from diazocarbonyls

Article abstract of DOI:10.1021/jo048353u

Primary ureas have been used as substrates in rhodium-catalyzed N-H insertion reactions with an array of diazocarbonyls. The insertion reaction is efficient and gives excellent selectivity and yields. The products from the insertion reaction with diazoket

Full text of DOI:10.1021/jo048353u

N-H Insertion Reactions of Primary Ureas: The Synthesis of
Highly Substituted Imidazolones and Imidazoles from
Diazocarbonyls
Sang-Hyeup Lee,† Kazuhiro Yoshida,† Hana Matsushita,† Bruce Clapham,*,† Guido Koch,‡
Ju¨rg Zimmermann,‡ and Kim D. Janda*,†
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037, and Novartis Pharma AG, NIBR Basel,
Combinatorial Chemistry, WSJ-507.704, CH-4002 Basel, Switzerland
bclapham@scripps.edu; kdjanda@scripps.edu
Received September 16, 2004
Primary ureas have been used as substrates in rhodium-catalyzed N-H insertion reactions with
an array of diazocarbonyls. The insertion reaction is efficient and gives excellent selectivity and
yields. The products from the insertion reaction with diazoketones cyclize readily in the presence
of acid to yield the corresponding imidazolones that can be further derivatized by N-alkylation
with alkyl, allyl, and benzyl halides. Alternatively, the imidazolones were treated with phosphorus
oxybromide to form the corresponding 2-bromoimidazoles that were further functionalized using a
Suzuki coupling reaction.
Introduction
ketoesters that were subsequently converted using a
cyclodehydration reaction into the corresponding oxazoles
or pyrazinones.5 Similary, reaction with N-alkylanilines
gave the corresponding R-arylamino products that were
converted into the corresponding indoles.6 Accordingly,
we sought to further investigate the potential applica-
tions of other N-H functionalized insertion partners in
order to create more diverse combinatorial libraries.
From initial screening, we discovered that primary ureas
served as excellent substrates in N-H insertion reactions
with rhodium carbenoids derived from R-diazo-â-ke-
toesters; the desired insertion products were isolated in
good yields and no competing reaction was seen between
the -NH2 and -RNH groups.7 Furthermore, it was
discovered that these insertion products were converted
easily into the corresponding 1,3-dihydro-2H-imidazol-
2-ones (imidazolones) by acid-catalyzed cyclodehydration.
Since these imidazolones presented an ideal scaffold for
further elaboration and because many imidazolone-
containing compounds exhibit biological activity,8 we set
out to fully investigate new reactions of these compounds.
Herein the full details of our investigation of the N-H
insertion reactions of primary ureas with a series of
diversely functionalized diazocarbonyls and the trans-
Diazocarbonyl-functionalized molecules have a long-
standing importance within synthetic organic chemistry
since they form highly reactive intermediates that react
by a plethora of useful pathways, including insertion
(N-H, O-H, S-H, Si-H, C-H, etc.), dipolar cycloaddi-
tion, and cyclopropanation. Although some of the classical
reactions of diazocarbonyls could lead to multiple or
impure products, modern advances in catalysis, especially
rhodium catalysts, has enabled chemists to utilize these
substrates with high efficiency,1 especially within the
area of asymmetric synthesis.2 In addition, many of the
products from insertion reactions serve as very useful
intermediates for the synthesis of heterocycles.3
In our laboratory, we have utilized diazocarbonyl
functionalized substrates to prepare libraries of small
heterocycles for application in combinatorial type screen-
ing programs for basic drug discovery. Thus, a series of
polymer-bound R-diazo-â-ketoesters have been employed
as key modular building blocks for these library synthe-
ses.4 The rhodium-catalyzed N-H insertion reaction with
primary amides gave the corresponding R-acylamino-â-
* To whom correspondence should be addressed. Phone: 858 784-
2519. Fax: 858 784-2595.
† The Scripps Research Institute.
(5) (a) Clapham, B.; Spanka, C.; Janda, K. D. Org. Lett. 2001, 3,
2173. (b) Matsushita, H.; Lee, S.-H.; Yoshida, K.; Clapham, B.; Koch,
G.; Zimmermann, J.; Janda, K. D. Org. Lett., 2004, 6, 4627-4630.
(6) Lee, S.-H.; Clapham, B.; Koch, G.; Zimmermann, J.; Janda, K.
D. J. Comb. Chem. 2003, 5, 188.
(7) Lee, S.-H.; Clapham, B.; Koch, G.; Zimmermann, J.; Janda, K.
D. Org. Lett. 2003, 5, 511..
(8) For the solid-phase synthesis of imidazolone and imidazolidone
libraries see: (a) Cheng, J.-F.; Kaito, C.; Chen, M.; Arrhenius, T.;
Nadzan, A. Tetrahedron Lett. 2002, 43, 4571. (b) Nefzi, A.; Ostrech, J.
M.; Giulanotti, M.; Houghten, R. A. J. Comb. Chem. 1999, 1, 195. (c)
Goff, D. Tetrahedron Lett. 1998, 39, 1477.
‡ Novartis Pharma AG.
(1) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes
to Ylides; John Wiley & Sons Ltd.: New York, 1997.
(2) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
(3) (a) Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron, 2004,
60, 3967. (b) Moody, C. J.; Swann, E. Synlett 1998, 135. (c) Bagley, M.
C.; Buck, R. T.; Hind, S. L.; Moody, C. J.; Slawin, A. M. Z. Synlett
1996, 825.
(4) Clapham, B.; Lee, S.-H.; Koch, G.; Zimmermann, J.; Janda, K.
D. Tetrahedron Lett. 2002, 43, 5407.
10.1021/jo048353u CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/10/2004
J. Org. Chem. 2004, 69, 8829-8835
8829

Lee et al.
SCHEME 1a
TABLE 1. N-H Insertion Reactions of Ureas 2 with a
Series of Diazocarbonyls 1
entry
1
R1
1a CO2Et
1b
R2
R3 yield of 3/% yield of 4/%
1
2
OEt Ph
OEt Ph
OEt Ph
Ph
Me
Ph
86
40
91
a
H
3
1c PO(OEt)2
1d CO2Et
1e CO2Et
4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
85b
72b
74
5
a
6
1f
CONH,Ph
a
7
1g CONMe,Ph Me
6 (11)
8
1h CON(Me)2
Me
Ph
Me
Ph
Me
Ph
Ph
Ph
Ph
a
93
88
83
95
49
41
95
9
1i
1j
PO(OEt)2
PO(OEt)2
88
a
53
a
a
38
c
a
10
11
12
13
14
15
16
1k PhCO
1l COMe
1m COMe
1n
1o SO2Me
1p CO2Et
a Reagents and conditions: (a) 2 (1.5 equiv), Rh2Oct4 (2 mol %),
toluene/1,2-dichloroethane 1:1, 80 °C, 30 min. (b) TFA (10%-neat).
H
formation of these products into imidazolones and imi-
dazoles is reported.
85b
a Not isolated. b Previously published work added for compari-
son. c Product not detected.
Results and Discussion
The general reaction scheme for the N-H insertion
reaction of primary ureas and the conversion of these
products into imidazolones is outlined in Scheme 1. The
first objective of the study was to assess which diazocar-
bonyls, compounds 1, could be reacted with primary
ureas 2 in the presence of rhodium octanoate catalyst.
The first problem encountered was that the ureas 2 were
sparingly soluble in solvents such as chloroform or
toluene which are commonly employed in N-H insertion
reactions. When dimethylformamide (DMF) or N,N-
dimethylacetamide was employed, ureas 2 were fully
solublized; however, the desired reaction products were
not observed by thin-layer chromatography (TLC). Upon
additional experimentation, it was discovered that a 1:1
mixture of 1,2-dichloroethane and toluene gave the best
results. It was also revealed that the yields of desired
products were improved when the urea starting materials
2 were ground into a fine powder prior to the reaction.
Finally, it should be noted that the method of addition
of the catalyst is critical for the success of the reaction.
When the catalyst was added in one portion, several
unidentifiable side products were observed by TLC. The
best method for performing the reaction required the
preparation of a fine suspension of the catalyst by
sonication in toluene. The diazocarbonyl 1 and urea 2
were heated to 80 °C in the mixed solvent system, and
the catalyst suspension was slowly added by pipet. The
results from this study are outlined in Table 1. Several
diazocarbonyls 1 were employed and in some cases the
insertion products 3 were isolated directly from the
reaction (entries 1-3, 9, 11, and 14). However, some of
the insertion products 3 were cyclized to the correspond-
ing imidazolones 4 in the presence of even mild acid such
as silica gel. In these cases, after the insertion reaction
had been performed, trifluoroacetic acid was added to the
reaction and the imidazolones 4 were isolated by column
chromatography of the concentrated crude product.
SCHEME 2a
a Reagents and conditions: (a) (i) 2 (1.5 equiv), Rh2Oct4 (2 mol
%), toluene/1,2-dichloroethane 1:1, 80 °C, 30 min; (ii) TFA (10%-
neat). (b) NaBH4, MeOH, 30 min.
and 4. An interesting observation was made when the
unsymmetrical 2-diazo-1-phenylbutane-1,3-dione 1m was
employed (entry 13). In this instance, the imidazolone
cyclization reaction occurs selectively at the methyl
carbonyl group; to validate this structure, ketone 4m was
converted into the corresponding alcohol 5 by using
sodium borohydride and the structure was determined
1
by H NMR spectroscopic analysis, Scheme 2.
When R-diazo-ketone 1n was employed, the desired
insertion product 3n was only isolated in 38% yield (entry
14). The higher reactivity associated with diazoketones
led us to speculate that unwanted side reactions such as
dimerization of the carbenoid resulted in this lower yield.
R-Diazo-â-ketoamides also gave good results in the NH
insertion reaction with urea 2, with one exception. When
2-diazo-N-methyl-3-oxo-3-phenylpropionamide 1f was uti-
lized, the desired secondary amide functionalized imida-
zolone 4f was isolated in 74% yield (entry 6). Similarly,
when 2-diazo-N,N-dimethyl-3-oxo-3-phenylpropionamide
1h was employed, the desired tertiary amide function-
alized imidazolone 4h was isolated in 93% yield (entry
8). Despite these two successful reactions, when 2-diazo-
N-methyl-3-oxo-N-phenylbutyramide 1g was employed in
the reaction with urea 2, the competing intramolecular
C-H insertion reaction into the aryl ring occurred
selectively to form indole 6 and no N-H insertion
products were isolated (entry 7). This indole formation
In most cases, both the insertion and imidazolone
formation reactions worked well. In addition to the
successful experiments where the R-diazo-â-ketoesters
were employed (entries 4, 5, and 16), R-diazo-â-ketophos-
phonates (entries 9 and 10) and symmetrical R-diazo-1,3-
diketones (entries 12 and 13) both gave modest to
excellent yields of insertion and imidazolone products 3
8830 J. Org. Chem., Vol. 69, No. 25, 2004

Synthesis of Imidazolones and Imidazoles
SCHEME 3a
TABLE 2. N-Alkylation of Polymer-Bound Imidazolones
8
purity/ yield/
a
b
entry R2
R3
R4
product
%
%
1
2
3
4
5
6
7
8
Bn Me
MeO
MeO
MeO
MeO
MeO
MeO
9a
9b
9c
9d
9e
9f
94
95
97
98
98
97
98
95
74
75
77
77
74
86
50
40
Me Bn
Ph Me
Ph Bn
Ph Allyl
Ph PhCOCH2
Ph 3-Ph-(CH2)3 MeO
Ph cyclopropyl- MeO
methyl
9g
9h
9
Ph Me
piperidine-
morpholine-
PhNH-
Ph(CH2)2NH-
Ph,MeN-
9i
9j
9k
9l
9m
98
96
94
99
88
67
69
81
66
85
10 Ph Me
11 Ph Bn
12 Ph Bn
13 Ph Bn
a Reagents and conditions: (a) CH3I or BnBr (3 equiv), K2CO3
(3 equiv) DMF, 3 h. (b) (i) Alkyl iodide or bromide (10 equiv),
tetrabutylammonium iodide (5 equiv, when R3X ) R3Br), LiOtBu
(5 equiv), DMF/THF 1:1, rt to 40 °C, 24 h; (ii) R,RNH (10 equiv),
AlMe3, (5 equiv), toluene, 50 °C, 16 h or NaOMe (2.5 equiv), THF/
MeOH (4:1), 50 °C, 1 h.
a Purity assessed by HPLC. b Yield of pure product after isola-
tion by TLC.
SCHEME 4a
reaction is well documented;9 however, our poor yield of
indole 6 was attributed to its decomposition during silica
gel chromatography. Finally, it is noted that when the
reaction was performed with sulfone 1o, the correspond-
ing N-H insertion product was not observed in the
reaction products (entry 15).
In our original report of the N-H insertion reactions
of primary ureas, a series of polymer-bound R-diazo-â-
ketoesters were utilized to prepare diverse solid-phase
libraries of imidazolones. To expand this methodology,
the utility of the imidazolone scaffold for further diver-
sification was investigated.10 The first procedure was the
alkylation of the N-H of the imidazolone 4, Scheme 3.
When reactions were performed in solution, a combina-
tion of potassium carbonate and either methyl iodide or
benzyl bromide in DMF provided the desired N-alkylimi-
dazolones 7 in nearly quantitative yield. Since we had a
number of JandaJel11 polymer-polymer-bound imidazo-
lones 8 on hand, whose syntheses were described in our
original report,7 we also investigated their application in
this N-alkylation reaction. However, when the above
conditions were applied to 8, very poor yields of N-
alkylated products 9 were observed after cleavage from
the resin. After extensive optimization experiments, the
selection of base proved to be crucial to the success of
the reaction. Lithium tert-butoxide base gave the best
results when used in 5-fold excess over the polymer-
bound substrate. A mixed solvent system of DMF and
tetrahydrofuran (THF) gave the best results and the
addition of tetrabutylammonium iodide proved essential
when alkyl bromide alkylating reagents were employed.
a Reagents and conditions: (a) POBr3, benzene, reflux 6 h. (b)
ArB(OH)2 (3 equiv), Pd(dppf)Cl2‚CH2Cl2 (3 mol %), Cs2CO3 (3
equiv), toluene 110 °C, 2 h.
After alkylation, the N-alkylimidazolones were cleaved
from the resin by using either a transesterification or
diversity building amide formation reaction.12 The results
from this study are presented in Table 2.
The second aspect of our study for the further deriva-
tization of the imidazolones centered upon their conver-
sion into imidazoles. Treatment of imidazolones 4e, 4n,
and 4p with phosphorus oxybromide (POBr3) in benzene
or toluene under reflux conditions gave the corresponding
2-bromoimidazoles 10e, 10n, and 10p respectively in
excellent yields, Scheme 4. After brief experimentation
we discovered that the 2-bromoimidazole 10p served as
an excellent substrate in the Suzuki coupling reaction13
with phenylboronic acid (Scheme 4 and Table 3, entries
1-4). Additionally, treatment of 10e, 10n, and 10p with
an array of aryl boronic acids in toluene in the presence
of Pd(dppf)Cl2 catalyst and cesium carbonate base at 110
°C gave the corresponding 2-arylimidazoles 11a-i in
excellent yields, Table 3. Since there is little methodology
available for the regioselective functionalization of imi-
dazoles at the C2 position,14 we feel this method for the
(9) Etkin, N.; Babu, S. D.; Fooks, C. J.; Durst, T. J. Org. Chem. 1990,
55, 1093.
(10) (a) Ostresh, J. M.; Husar, G. M.; Blondelle, S. E.; Do¨rner, B.;
Weber, P. A.; Houghten, R. A. Proc. Natl. Acad. Sci. U.S.A. 1994, 91,
11138. (b) Houghten, R. A.; Blondelle, S. E.; Dooley, C. T.; Do¨rner, B.;
Eichler, J.; Ostresh, J. M. Mol. Diversity 1996, 2, 41. (c) Nicolaou, K.
C.; Pfefferkorn, J. A.; Barluenga, S.; Mitchell, H. J.; Roecker, A. J.;
Cao, G. Q. J. Am. Chem. Soc. 2000, 122, 9968.
(11) JandaJel resins are available from Aldrich Chemical Co. (a)
Toy, P. H.; Reger, T. S.; Garibay, P.; Garno, J. C.; Malikayil, J. A.;
Liu, G.; Janda, K. D. J. Comb. Chem. 2001, 3, 117. For recent
applications, see: (b) Brummer, O.; Clapham, B.; Janda, K. D.
Tetrahedron Lett. 2001, 42, 2257. (c) Clapham, B.; Cho, C.-W.; Janda,
K. D. J. Org. Chem. 2001, 66, 868.
(12) (a) Barn, D. R.; Morphy, J. R.; Rees, D. C. Tetrahedron Lett.
1996, 37, 3213. (b) Ley, S. V.; Mynett, D. M.; Koot, W.-J. Synlett 1995,
1017. For the application of this chemistry in the preparation of
benzimidazoles, benzothiazoles, and ureas see: (c) Matsushita, H.; Lee,
S.-H.; Joung, M.; Clapham, B.; Janda, K. D. Tetrahedron Lett. 2004,
45, 313. (d) Lee, S.-H.; Matsushita, H.; Clapham, B.; Janda, K. D.
Tetrahedron 2004, 60, 3439. (e) Lee, S.-H.; Matsushita, H.; Koch, G.;
Zimmermann, J.; Clapham, B.; Janda, K. D. J. Comb. Chem. 2004, 6,
822.
(13) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(14) Evans, D. A.; Bach, T. Angew. Chem., Int. Ed. Engl. 1993, 32,
1326.
J. Org. Chem, Vol. 69, No. 25, 2004 8831

Lee et al.
TABLE 3. Suzuki Coupling Reactions of
2-Bromoimidazoles 10
(4 mL) was added over 10 min. After addition of the catalyst,
the mixture was stirred for an additional 30 min. For entries
1-3, 7, 9, 11, and 14, the solvent was removed under reduced
pressure and the residue was purified by flash chromatography
and/or recrystallization to give the corresponding insertion
products 3.
entry SM
R1
R2 R3
Ar
11 yield/%
1
2
10p CO2Et Ph Me Ph
10p CO2Et Ph Me Ph
10p CO2Et Ph Me Ph
10p CO2Et Ph Me Ph
10p CO2Et Ph Me 4-CF3C6H4
10p CO2Et Ph Me 4-Ph-C6H4
10p CO2Et Ph Me 1-naphthyl
10p CO2Et Ph Me styryl
a
a
a
a
b
c
d
e
f
43a,b
83b
87b
99
3
2-(3-Phenylureido)malonic Acid Diethyl Ester (3a).
Purified by column chromatography (CHCl3-CH3CN, 15:1)
and recrystallization (EtOAc-hexanes); white solid; mp 116-
117 °C; 1H NMR (500 MHz, CDCl3) δ 1.30 (t, J ) 7.0 Hz, 6H),
4.27 (m, 4H), 5.21 (s, 1H), 6.18 (br s, 1H), 7.00-7.10 (m, 1H),
7.11 (br s, 1H), 7.22-7.38 (m, 4H); 13C NMR (125 MHz, CDCl3)
δ 14.0, 57.2, 62.7, 120.8, 124.0, 129.2, 138.0, 154.5, 167.3;
HRMS m/z 295.1282 [M + H]+, calcd for C14H19N2O5 295.1288.
(3-Phenyluriedo)acetic Acid Ethyl Ester (3b). Purified
by column chromatography (CHCl3-CH3CN, 10:1) and recrys-
tallization (EtOAc-hexanes); colorless needles; mp 107-108
4
5
99
6
97
7
97
8
95
9
10e CO2Et Me Ph 4-CH3OC6H4
10e CO2Et Me Ph 4-(CO2Et)C6H4
10e CO2Et Me Ph 4-TBDMSOC6H4
90
10
11
12
g
h
i
97
93
10n
H
Ph Ph Ph
41
a Pd(Ph3P)4 catalyst used. b 1.5 equiv of ArB(OH)2 and Cs2CO3
used.
1
°C; H NMR (600 MHz, DMSO-d6) δ 1.20 (t, J ) 7.1 Hz, 3H),
3.85 (d, J ) 6.1 Hz, 2H), 4.11 (q, J ) 7.1 Hz, 2H), 6.43 (t, J )
6.1 Hz, 1H), 6.90 (t, J ) 7.7 Hz, 1H), 7.22 (t, J ) 8.0 Hz, 2H),
7.38 (d, J ) 8.3 Hz, 2H), 8.78 (br s, 1H); 13C NMR (150 MHz,
CDCl3) δ 14.1, 42.1, 61.5, 121.0, 123.8, 129.2, 138.3, 156.0,
171.3; HRMS m/z 223.1076 [M + H]+, calcd for C11H15N2O3
223.1077.
regioselective synthesis of 2-functionalized imidazoles
may find application in the synthesis of imidazole-
containing natural products. Unfortunately, we were not
able to successfully transfer these protocols to a solid-
phase format for the synthesis of an imidazole library.
Although the acid-stable hydroxyalkyl linker was em-
ployed, several unidentifiable cleavage products were
observed by TLC analysis when polymer-bound imida-
zolones 8 were treated with POBr3 in benzene or toluene
at reflux.
(Diethoxyphosphoryl)-(3-phenylureido)acetic Acid Eth-
yl Ester (3c). Purified by column chromatography (CHCl3-
acetone, 9:1) and recrystallization (EtOAc-hexanes); white
1
solid; mp 93-94 °C; H NMR (500 MHz, DMSO-d6) δ 1.19-
1.29 (m, 9H), 4.05-4.25 (m, 6H), 4.84 (dd, J ) 8.8, 22.7 Hz,
1H), 6.86 (dd, J ) 4.3, 8.8 Hz, 1H), 6.94 (t, J ) 7.3 Hz, 1H),
7.25 (t, J ) 7.9 Hz, 2H), 7.37 (dd, J ) 1.1, 8.5 Hz, 2H), 8.89 (s,
1H); 13C NMR (125 MHz, DMSO-d6) δ 13.9, 16.1 (d, J ) 5.7
Hz), 16.2 (d, J ) 5.7 Hz), 51.0 (d, J ) 150.0 Hz), 61.6, 63.1 (d,
J ) 6.7 Hz), 63.2 (d, J ) 5.7 Hz), 117.6, 121.7, 128.8, 139.6,
154.2 (d, J ) 9.5 Hz), 167.5 (d, J ) 2.9 Hz); HRMS m/z
359.1371 [M + H]+, calcd for C15H24N2O6P1 359.1366.
Conclusion
In summary, we have demonstrated the application of
primary ureas as substrates in rhodium-catalyzed N-H
insertion reactions with a series of R-diazocarbonyls
including diazoketones, diazodiketones, diazoketoesters,
diazoketoamides, and diazoketophosphonates. The N-H
insertion reaction works with great efficiency and the
corresponding insertion products are easily converted into
the corresponding imidazolones that can be further
derivatized by N-alkylation with alkyl halides. Finally,
the imidazolone products are easily converted into the
corresponding 2-bromoimidazoles that serve as precur-
sors for the synthesis of 2-arylimidazoles by using a
Suzuki coupling reaction.
6. Purified by column chromatography (EtOAc-hexanes,
1
1:4); H NMR (600 MHz, CDCl3) δ 2.42 (s, 3H), 3.31 (s, 3H),
6.92 (d, J ) 7.3 Hz, 1H), 7.05-7.14 (m, 1H), 7.17-7.25 (m,
1H), 7.33 (d, J ) 7.3 Hz, 1H), 13.65 (br s, 1H); 13C NMR (150
MHz, CDCl3) δ 20.2, 25.5, 101.6, 108.3, 119.6, 122.0, 122.1,
125.1, 138.8, 170.9, 172.8; HRMS m/z 190.0864 [M + H]+, calcd
for C11H12N1O2 190.0863.
[2-Oxo-2-phenyl-1-(3-phenylureido)ethyl]phosphon-
ic Acid Diethyl Ester (3i). Reaction time 1.5 h; purified by
column chromatography (CHCl3-CH3CN, 5:1); colorless oil; 1H
NMR (500 MHz, CDCl3) δ 1.08 (t, J ) 7.4 Hz, 3H), 1.35 (t, J
) 7.4 Hz, 3H), 3.94-4.14 (m, 2H), 4.28-4.46 (m, 2H), 6.29 (dd,
J ) 9.2, 22.0 Hz, 1H), 6.95-7.02 (m, 1H), 7.12 (br d, J ) 8.5
Hz, 1H), 7.20-7.65 (m, 7H), 7.98-8.07 (m, 2H), 8.29 (br s, 1H);
13C NMR (125 MHz, CDCl3) δ 15.9 (d, J ) 6.7 Hz), 16.5 (d, J
) 5.7 Hz), 53.5 (d, J ) 147.9 Hz), 63.3 (d, J ) 7.6 Hz), 65.0 (d,
J ) 7.6 Hz), 118.8, 122.4, 128.5, 128.8, 129.3, 133.9, 135.4 (d,
J ) 1.9 Hz), 139.5, 154.7 (d, J ) 6.7 Hz), 194.0 (d, J ) 3.8
Hz); HRMS m/z 391.1433 [M + H]+, calcd for C19H24N2O4P1
391.1417.
1-(1-Benzoyl-2-oxo-2-phenylethyl)-3-phenylurea (3k).
Purified by column chromatography (CHCl3-CH3CN, 125:1);
white solid; mp 195-196 °C; 1H NMR (500 MHz, CDCl3) δ 5.74
(s, 1H), 7.05-7.13 (m, 1H), 7.24-7.31 (m, 2H), 7.32-7.48 (m,
9H), 7.52-7.60 (m, 1H), 7.92-8.02 (m, 2H), 9.69 (br s, 1H),
10.38 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 60.9, 120.3,
124.4, 128.7, 128.92, 128.97, 129.03, 129.7, 132.5, 134.1, 135.3,
136.9, 150.7, 170.2, 194.5; HRMS m/z 359.1390 [M + H]+, calcd
for C22H19N2O3 359.1390.
Experimental Section
General Methods. General methods have been reported
elsewhere.15 Ethyl diazoacetate 1b was obtained from Aldrich
Chemical Co. All R-diazo carbonyl compounds 1 were prepared
according to literature precedent,16 except for 1c,17 1f,9 1i,j,18
1n,19 and 1o.20
Rhodium-Catalyzed N-H Insertion Reaction (1 f 3).
A vigorously stirred suspension of R-diazo compound 1 (2
mmol) and finely powdered phenyl urea 2 (408 mg, 3 mmol)
in toluene-1,2-dichloroethane (1:1, 20 mL) was heated to 80
°C and a suspension of Rh2Oct4 (31 mg, 0.04 mmol) in toluene
(15) Clapham, B.; Cho, C.-W.; Janda, K. D. J. Org. Chem. 2001, 66,
868.
(16) (a) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D.
Synth. Commun. 1987, 17, 1709. (b) Bagley, M. C.; Buck, R. T.; Hind,
S. L.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1 1998, 591.
(17) Moody, C. J.; Sie, E. R. H. B.; Kulagowski, J. J. Tetrahedron
1992, 48, 3991.
1-(2-Oxo-2-phenylethyl)-3-phenylurea (3n). Purified by
column chromatography (CHCl3-acetone, 10:1); white solid;
mp 146-147 °C; 1H NMR (600 MHz, DMSO-d6) δ 4.69 (d, J )
5.5 Hz, 2H), 6.52 (d, J ) 5.5 Hz, 1H), 6.90 (t, J ) 7.7 Hz, 1H),
7.23 (t, J ) 7.7 Hz, 2H), 7.42 (d, J ) 7.7 Hz, 2H), 7.56 (t, J )
7.7 Hz, 2H), 7.67 (t, J ) 7.7 Hz, 1H), 8.01 (d, J ) 7.1 Hz, 2H),
8.91 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ 46.8, 117.6,
(18) Callant, P.; D’Haenens, L.; Vandewalle, M. Synth. Commun.
1984, 14, 155.
(19) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J.
Org. Chem. 1990, 55, 1959.
(20) Monteiro, H. J. Synth. Commun. 1987, 17, 983.
8832 J. Org. Chem., Vol. 69, No. 25, 2004

Synthesis of Imidazolones and Imidazoles
121.2, 127.8, 128.7, 128.9, 133.6, 134.9, 140.4, 155.2, 196.2;
HRMS m/z 255.1134 [M + H]+, calcd for C15H15N2O2 255.1128.
TFA-Promoted Cyclization Reaction (3 f 4). For en-
tries 4-6, 8, 10, 12, and 13, to the cooled insertion reaction
mixture was added TFA (1 mL), and the resulting solution
was stirred for 1 h at room temperature. For entry 10, insertion
mixture was evaporated, and then treated with neat TFA (10
mL) for 3 h at 50 °C. After removal of solvent under reduced
pressure, the residue was purified by flash chromatography
to give corresponding 2-imidazolone 4. For entries 9, 11, and
14, the insertion product 2 (1 mmol) was treated with neat
TFA (10 mL) (entries 9, 11) or 10% TFA in 1,2-dichloroethane
(10 mL) (entry 14), and the resulting solution was stirred for
several hours (see below). After removal of solvent under
reduced pressure, the residue was purified by flash chroma-
tography and/or recrystallization to give corresponding 2-imi-
dazolone 4.
Oxo-1,5-diphenyl-2,3-dihydro-1H-imidazole-4-carboxy-
lic Acid Ethyl Ester (4d). Purified by column chromatogra-
phy (CHCl3-CH3CN, 5:1). An analytical sample was obtained
by recrystallization (EtOAc); white solid; mp 237-238 °C; 1H
NMR (500 MHz, CDCl3) δ 1.16 (t, J ) 7.4 Hz, 3H), 4.19 (q, J
) 7.4 Hz, 2H), 7.08-7.16 (m, 2H), 7.18-7.34 (m, 8H), 9.83 (br
s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.9, 60.9, 110.6, 127.4,
127.5, 127.7, 127.8, 128.8, 129.1, 130.6, 132.4, 134.0, 152.0,
159.3; HRMS m/z 309.1235 [M + H]+, calcd for C18H17N2O3
309.1234.
5-Methyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-
carboxylic Acid Ethyl Ester (4e). Purified by column
chromatography (CHCl3-CH3CN, 5:1). An analytical sample
was obtained by recrystallization (EtOAc-hexanes); white
solid; mp 182-183 °C; 1H NMR (500 MHz, CDCl3) δ 1.34 (t, J
) 7.4 Hz, 3H), 2.26 (s, 1H), 4.32 (q, J ) 7.4 Hz, 2H), 7.27-
7.33 (m, 2H), 7.39-7.54 (m, 3H), 8.29 (br s, 1H); 13C NMR (125
MHz, CDCl3) δ 11.0, 14.3, 60.7, 109.8, 127.7, 128.7, 129.5,
130.7, 133.6, 151.9, 160.0; HRMS m/z 247.1077 [M + H]+, calcd
for C13H15N2O3 247.1077.
2-Oxo-1,5-diphenyl-2,3-dihydro-1H-imidazole-4-carbox-
ylic Acid Methylphenylamide (4f). Purified by column
chromatography (CHCl3-CH3CN, 4:1) and recrystallization
(CHCl3-hexanes); white solid; mp 275-278 °C; 1H NMR (500
MHz, DMSO-d6) δ 7.01-7.08 (m, 1H), 7.09-7.15 (m, 2H),
7.20-7.40 (m, 10H), 7.42-7.52 (m, 2H), 9.28 (s, 1H), 11.07 (s,
1H); 13C NMR (125 MHz, DMSO-d6) δ 114.1, 119.5, 123.6,
127.5, 127.8, 127.9, 128.11, 128.14, 128.5, 128.70, 128.73,
130.5, 134.6, 138.5, 151.6, 157.1; HRMS m/z 356.1385 [M +
H]+, calcd for C22H18N3O2 356.1393.
1.9 Hz, 3H), 3.80-4.20 (m, 4H), 7.30-7.60 (m, 5H), 10.54 (br
s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 10.5, 16.1 (d, J ) 6.7
Hz), 61.8 (d, J ) 4.8 Hz), 103.9 (d, J ) 233.7 Hz), 127.9, 128.1,
129.1, 131.9 (d, J ) 23.9 Hz), 134.3, 153.0 (d, J ) 12.4 Hz);
HRMS m/z 311.1161 [M + H]+, calcd for C14H20N2O4P1
311.1155.
4-Benzoyl-1,5-diphenyl-1,3-dihydroimidazol-2-one (4k).
Reaction conditions, neat TFA, 70 °C, 18 h; purified by column
chromatography (CHCl3-CH3CN, 9:2); white solid; mp >300
°C; 1H NMR (500 MHz, CDCl3) δ 6.82-6.87 (m, 2H), 6.92-
7.25 (m, 13H), 8.75 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ
115.6, 127.2, 127.6, 127.7, 128.4, 128.5, 128.8, 129.4, 129.8,
131.1, 132.2, 132.3, 136.8, 150.6, 153.1, 162.5; HRMS m/z
341.1277 [M + H]+, calcd for C22H17N2O2 341.1284.
4-Acetyl-5-methyl-1-phenyl-1,3-dihydroimidazol-2-
one (4l). Purified by column chromatography (CHCl3-CH3-
CN, 2:1) and recrystallization (EtOAc-hexanes); white solid;
mp 250-251 °C; 1H NMR (500 MHz, DMSO-d6) δ 2.20 (s, 3H),
2.33 (s, 3H), 7.35 (d, J ) 7.8 Hz, 2H), 7.46 (t, J ) 7.8 Hz, 1H),
7.53 (t, J ) 7.8 Hz, 2H), 10.73 (br s, 1H); 13C NMR (125 MHz,
DMSO-d6) δ 11.5, 28.2, 119.0, 128.0, 128.4, 129.2, 130.1, 133.7,
151.6, 186.7; HRMS m/z 217.0970 [M + H]+, calcd for
C12H13N2O2 217.0971.
4-Benzoyl-5-methyl-1-phenyl-1,3-dihydroimidazol-2-
one (4m). Purified by column chromatography (CHCl3-CH3-
CN, 4:1); white solid; mp 235-237 °C; 1H NMR (500 MHz,
CDCl3) δ 1.94 (s, 3H), 7.30-7.35 (m, 2H), 7.42-7.60 (m, 6H),
7.65-7.75 (m, 2H), 8.09 (br s, 1H); 13C NMR (125 MHz, CDCl3)
δ 12.6, 118.9, 127.8, 128.2, 128.6, 129.0, 129.6, 132.0, 132.1,
133.3, 138.5, 151.9, 184.7; HRMS m/z 279.1132 [M + H]+, calcd
for C17H15N2O2 279.1128.
1,5-Diphenyl-1,3-dihydroimidazol-2-one (4n). Reaction
conditions, 10% TFA in ClHC2CH2Cl, room temperature, 1 h;
purified by recrystallization (CHCl3-hexanes); white solid; mp
228-230 °C; 1H NMR (500 MHz, DMSO-d6) δ 6.85 (d, J ) 2.2
Hz, 1H), 6.96-7.07 (m, 2H), 7.08-7.25 (m, 5H), 7.29 (t, J )
7.4 Hz, 1H), 7.37 (t, J ) 7.7 Hz, 2H), 10.55 (br s, 1H); 13C NMR
(125 MHz, DMSO-d6) δ 108.1, 123.5, 126.3, 126.80, 126.82,
127.3, 128.3, 128.7, 129.8, 135.8, 153.6; HRMS m/z 237.1018
[M + H]+, calcd for C15H13N2O1 237.1022.
4-(Hydroxyphenylmethyl)-5-methyl-1-phenyl-1,3-dihy-
droimidazol-2-one (5). To a stirred solution of imidazolone
4m (20 mg, 0.072 mmol) in MeOH (2 mL) was added NaBH4
(2.7 mg, 0.285 mmol) at room temperature, and the mixture
was stirred for an additional 30 min. After removal of solvent
under reduced pressure, the residue was purified by prepara-
tive TLC (CHCl3-MeOH, 7:3) to afford alcohol 5 (19 mg, 0.068
5-Methyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-
carboxylic Acid Dimethylamide (4h). Purified by column
chromatography (acetone-hexanes, 1:1). An analytical sample
was obtained by recrystallization (CHCl3-hexanes); yellow
1
mmol, 94%) as a white solid; mp 185-186 °C; H NMR (500
MHz, DMSO-d6) δ 1.91 (s, 3H), 5.64 (d, J ) 3.7 Hz, 1H), 5.77
(d, J ) 3.7 Hz, 1H), 7.21-7.30 (m, 3H), 7.31-7.38 (m, 3H),
7.41-7.51 (m, 4H), 10.03 (s, 1H); 13C NMR (125 MHz, DMSO-
d6) δ 9.4, 65.8, 113.8, 120.0, 126.1, 126.9, 127.0, 127.5, 128.0,
128.9, 135.2, 143.4, 152.7; HRMS m/z 281.1280 [M + H]+, calcd
for C17H17N2O2 281.1284.
1
solid; mp 220-222 °C; H NMR (500 MHz, CDCl3) δ 2.04 (s,
3H), 3.05 (s, 6H), 7.26-7.32 (m, 2H), 7.36-7.43 (m, 1H), 7.44-
7.51 (m, 2H), 10.31 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ
11.1, 37.2, 113.0, 124.3, 127.7, 128.4, 129.4, 133.9, 152.9, 162.5;
HRMS m/z 246.1235 [M + H]+, calcd for C13H16N3O2 246.1237.
(2-Oxo-1,5-diphenyl-2,3-dihydro-1H-imadazol-4-yl)phos-
phonic Acid Diethyl Ester (4i). Reaction conditions, neat
TFA, 40 °C, 3 h; purified by column chromatography (EtOAc-
hexanes, 4:5); white solid; mp 203-205 °C; 1H NMR (500 MHz,
CDCl3) δ 1.13 (t, J ) 7.0 Hz, 6H), 3.90-4.10 (m, 4H), 7.09-
7.15 (m, 2H), 7.19-7.31 (m, 8H), 9.53 (br s, 1H); 13C NMR (125
MHz, CDCl3) δ 15.9 (d, J ) 6.7 Hz), 62.8 (d, J ) 5.7 Hz), 107.1
(d, J ) 235.6 Hz), 127.4, 127.5, 127.8, 128.0, 128.8, 129.0,
129.9, 133.3 (d, J ) 20.0 Hz), 134.4, 153.2 (d, J ) 12.4 Hz);
HRMS m/z 373.1296 [M + H]+, calcd for C19H22N2O4P1
373.1312.
General Solution-Phase Procedure for the Alkylation
at the N-3 Position of 2-Imidazolones (4 f 7). To a
vigorously stirred mixture of 2-imidazlone 4 (1 mmol) and K2-
CO3 (346 mg, 2.5 mmol) in DMF (5 mL) was added alkyating
agent (5 mmol) at room temperature under argon, and the
resulting suspension was stirred for 3 h. After removal of
solvent under reduced pressure, the residue was suspended
in EtOAc-CHCl3 (1:1, 20 mL) and then passed through a short
silica gel plug (∼5 cm3) and further eluted with EtOAc-CHCl3
(1:1, 30 mL). The combined filtrate was concentrated under
reduced pressure to afford analytically pure, imidazolone 7 in
nearly quantitative yield.
3-Methyl-2-oxo-1,5-diphenyl-2,3-dihydro-1H-imidazole-
4-carboxylic Acid Ethyl Ester (7d). Colorless oil; 1H NMR
(500 MHz, CDCl3) δ 1.02 (t, J ) 7.0 Hz, 3H), 3.64 (s, 3H), 4.10
(q, J ) 7.0 Hz, 2H), 7.03-7.12 (m, 2H), 7.14-7.32 (m, 8H);
13C NMR (125 MHz, CDCl3) δ 13.7, 30.2, 60.4, 112.4, 127.6,
(5-Methyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazol-4-
yl)phosphonic Acid Diethyl Ester (4j). Reaction conditions,
neat TFA, 40 °C, 3 h; purified by column chromatography
(EtOAc-acetone, 11:4); yellow solid; mp 123-125 °C; 1H NMR
(500 MHz, DMSO-d6) δ 1.27 (t, J ) 7.2 Hz, 6H), 2.09 (d, J )
J. Org. Chem, Vol. 69, No. 25, 2004 8833

Lee et al.
127.7, 128.5, 128.8, 130.7, 132.4, 134.2, 152.5, 160.1; HRMS
m/z 323.1380 [M + H]+, calcd for C19H19N2O3 323.1390.
3,5-Dimethyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-
4-carboxylic Acid Ethyl Ester (7e). Colorless needles; mp
114-115 °C; 1H NMR (500 MHz, CDCl3) δ 1.37 (t, J ) 7.0 Hz,
3H), 2.25 (s, 3H), 3.54 (s, 3H), 4.33 (q, J ) 7.0 Hz, 2H), 7.21-
7.32 (m, 2H), 7.38-7.55 (m, 3H); 13C NMR (125 MHz, CDCl3)
δ 11.7, 14.4, 30.2, 60.4, 111.6, 127.9, 128.7, 129.4, 130.7, 133.9,
152.6, 160.7; HRMS m/z 261.1235 [M + H]+, calcd for
C14H17N2O3 261.1234.
2-Oxo-3-(2-oxo-2-phenylethyl)-1-phenyl-5-(4-(trifluro-
methyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxylic
Acid Methyl Ester (9f). Yellow solid; mp 163-165 °C; 1H
NMR (500 MHz, CDCl3) δ 3.51 (s, 3H), 5.64 (s, 2H), 7.08-
7.15 (m, 2H), 7.24-7.32 (m, 3H), 7.34-7.41 (m, 2H), 7.48-
7.58 (m, 4H), 7.59-7.68 (m, 1H), 7.98-8.08 (m, 2H); HRMS
m/z 481.1358 [M + H]+, calcd for C26H20F3N2O4 481.1370.
2-Oxo-1-phenyl-3-(3-phenylpropyl)-5-(4-(trifluoro-
methyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxylic
Acid Methyl Ester (9g). White solid; mp 100-102 °C; 1H
NMR (500 MHz, CDCl3) δ 2.15 (quint, J ) 7.6 Hz, 2H), 2.77
(t, J ) 7.8 Hz, 2H), 3.59 (s, 3H), 4.21 (t, J ) 7.5 Hz, 2H), 7.01-
7.06 (m, 2H), 7.16-7.21 (m, 1H), 7.22-7.32 (m, 9H), 7.49 (d,
J ) 8.0 Hz, 2H); HRMS m/z 481.1722 [M + H]+, calcd for
C27H24F3N2O3 481.1733.
3-Cyclopropylmethyl-2-oxo-1-phenyl-5-(4-(trifluoro-
methyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxylic
Acid Methyl Ester (9h). Colorless oil; 1H NMR (500
MHz, CDCl3) δ 0.45-0.58 (m, 4H), 1.28-1.38 (m, 1H), 3.65 (s,
3H), 4.02 (d, J ) 7.0 Hz, 2H), 7.04-7.10 (m, 2H), 7.21-7.30
(m, 3H), 7.33 (d, J ) 8.0 Hz, 2H), 7.51 (d, J ) 8.5 Hz, 2H);
HRMS m/z 417.1420 [M + H]+, calcd for C22H20F3N2O3
417.1420.
(3-Benzyl-2-oxo-1,5-diphenyl2,3-dihydro-1H-imidazol-
4-yl)phosphonic Acid Diethyl Ester (7i). White solid; mp
1
92-93 °C; H NMR (500 MHz, CDCl3) δ 1.04 (t, J ) 7.2 Hz,
6H), 3.63-3.75 (m, 2H), 3.88-4.01 (m, 2H), 5.41 (s, 2H), 7.15-
7.21 (m, 2H), 7.23-7.37 (m, 9H), 7.38-7.45 (m, 2H), 7.53-
7.60 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 15.7 (d, J ) 7.6
Hz), 46.3, 62.2 (d, J ) 5.7 Hz), 108.4 (d, J ) 233.7 Hz), 127.3,
127.50, 127.53, 127.7, 128.18, 128.26, 128.28, 128.7, 128.9,
130.7, 134.0 (d, J ) 21.0 Hz), 134.5, 137.8, 153.4 (d, J ) 12.4
Hz); HRMS m/z 463.1768 [M + H]+, calcd for C26H28N2O4P1
463.1781.
General Solid-Phase Procedure for the Alkylation at
the N-3 Position of Polymer-Bound 2-Imidazolones (8 f
9), Scheme 3. LiOtBu (1 M in THF, 0.75 mL, 0.75 mmol) was
added to a stirred suspension of polymer-bound 2-imidazolone
8 (200 mg, ∼ 0.15 mmol) and DMF-THF (2 mL:1.25 mL) in a
6-mL vial at 0 °C under argon, and then the resulting mixture
was stirred for 1 h at room temperature. The alkylating agent
(1.5 mmol) was added, and the mixture was stirred for 24 h
at room temperature, after which time, acetic acid (1 mL) was
added to quench the reaction. In the cases of using alkyl
bromide as alkylating agents (entries 7 and 8), anhydrous
tetrabutylammonium iodide (276 mg, 0.747 mmol) was added
to the reaction mixture after the addition of alkylating agent,
and the reaction was carried out at 45 °C. The resin was
collected in a plastic syringe equipped with a polyethylene frit
and washed several times with DMF, DMF-water (1:1), THF,
methanol, ether, CHCl3, and hexanes, then dried in vacuo to
give N-3 alkylated 2-imidazolone resin as a brown powder.
1-Benzyl-3-methyl-2-oxo-5-(4-trifluoromethylphenyl)-
2,3-dihydro-1H-imidazole-4-carboxylic Acid Methyl Es-
1-Methyl-3-phenyl-5-(piperidine-1-carbonyl)-4-(4-(tri-
fluoromethyl)phenyl)-1,3-dihydroimidazol-2-one (9i).
1
Brown solid; mp 117-119 °C; H NMR (600 MHz, CDCl3) δ
0.50-0.85 (br s, 1H), 1.12-1.34 (br s, 1H), 1.35-1.70 (m, 4H),
2.72-3.02 (br s, 1H), 3.07-3.30 (br s, 1H), 3.36 (s, 3H), 3.42-
3.78 (m, 2H), 7.09-7.19 (m, 4H), 7.24-7.35 (m, 3H), 7.46 (d,
J ) 8.8 Hz, 2H); HRMS m/z 430.1739 [M + H]+, calcd for
C23H23F3N3O2 430.1737.
1-Methyl-5-(morpholine-4-carbonyl)-3-phenyl-4-(4-(tri-
fluoromethyl)phenyl)-1,3-dihydroimidazol-2-one (9j).
1
Brown solid; mp 178-180 °C; H NMR (600 MHz, CDCl3) δ
2.60-3.90 (m, 8H), 3.39 (s, 3H), 7.07-7.12 (m, 2H), 7.16 (d, J
) 8.8 Hz, 2H), 7.26-7.36 (m, 3H), 7.50 (d, J ) 8.8 Hz, 2H);
HRMS m/z 432.1532 [M + H]+, calcd for C22H21F3N3O3
432.1529.
3-Benzyl-2-oxo-1-phenyl-5-(4-(trifluoromethyl)phenyl)-
2,3-dihydro-1H-imidazole-4-carboxylic Acid Phenyla-
mide (9k). Brown solid; mp 151-154 °C; 1H NMR (600 MHz,
CDCl3) δ 5.35 (s, 2H), 6.83 (br s, 1H), 6.94-7.13 (m, 5H), 7.18-
7.39 (m, 10H), 7.48-7.62 (m, 4H); HRMS m/z 514.1737 [M +
H]+, calcd for C30H23F3N3O2 514.1737.
1
ter (9a). Colorless oil; H NMR (600 MHz, CDCl3) δ 3.56 (s,
3H), 3.63 (s, 3H), 4.73 (s, 2H), 6.87-6.94 (m, 2H), 7.15-7.28
(m, 5H), 7.60 (d, J ) 8.3 Hz, 2H); HRMS m/z 391.1267 [M +
H]+, calcd for C20H18F3N2O3 391.1264.
3-Benzyl-2-oxo-1-phenyl-5-(4-(trifluoromethyl)phenyl)-
3-Benzyl-1-methyl-2-oxo-5-(4-(trifluoromethyl)phenyl)-
2,3-dihydro-1H-imidazolecarboxylic Acid (3-Phenyl-
1
2,3-dihydro-1H-imidazole-4-carboxylic Acid Methyl Es-
propyl)amide (9l). Yellow solid; mp 141-143 °C; H NMR
1
ter (9b). Colorless oil; H NMR (500 MHz, CDCl3) δ 3.13 (s,
(600 MHz, CDCl3) δ 2.55 (t, J ) 6.5 Hz, 2H), 3.41 (dt, J ) 6.2,
6.5 Hz, 2H), 5.16 (br t, J ) 5.5 Hz, 1H), 5.28 (s, 2H), 6.77-
6.87 (m, 2H), 7.04 (d, J ) 7.4 Hz, 2H), 7.12-7.20 (m, 5H),
7.23-7.31 (m, 4H), 7.34 (t, J ) 7.5 Hz, 2H), 7.43 (d, J ) 8.3
Hz, 2H), 7.48 (d, J ) 7.0 Hz, 2H); HRMS m/z 542.2043 [M +
H]+, calcd for C32H27F3N3O2 542.2050.
3H), 3.51 (s, 3H), 5.31 (s, 2H), 7.23-7.29 (m, 1H), 7.30-7.35
(m, 2H), 7.37-7.42 (m, 2H), 7.46 (d, J ) 8.1 Hz, 2H), 7.72 (d,
J ) 8.1 Hz, 2H); HRMS m/z 391.1264 [M + H]+, calcd for
C20H18F3N2O3 391.1264.
3-Methyl-2-oxo-1-phenyl-5-(4-(trifluoromethyl)phenyl)-
2,3-dihydro-1H-imidazole-4-carboxylic Acid Methyl Es-
ter (9c). Brown solid; mp 137-139 °C; 1H NMR (500 MHz,
CDCl3) δ 3.64 (s, 3H), 3.66 (s, 3H), 7.01-7.08 (m, 2H), 7.20-
7.33 (m, 5H), 7.50 (d, J ) 8.8 Hz, 2H); HRMS m/z 377.1109
[M + H]+, calcd for C19H16F3N2O3 377.1107.
2-Bromo-1-methyl-5-phenyl-1H-imidazole-4-carboxy-
lic Acid Ethyl Ester (10p). A round-bottomed flask fitted
with a reflux condenser was charged with imidazolone 4p (R1
) CO2Et, R2 ) Ph, R3 ) Me; 3.20 g, 13.0 mmol) and toluene
(70 mL). After complete dissolution of 4p, phosphorus oxybro-
mide (4.48 g, 15.6 mmol) was added, the apparatus was purged
with argon, and the mixture was heated to reflux for 6 h. After
cooling, the mixture was slowly added to a separating funnel
that contained saturated sodium hydrogen carbonate (100 mL).
The mixture was extracted three times with ethyl acetate, and
the extracts were combined, dried over magnesium sulfate, and
concentrated under reduced pressure to give the crude product.
Column chromatography (40-60% ethyl acetate in hexanes)
gave 2-bromoimidazole 10p (3.51 g, 87%) as a white solid; mp
3-Benzyl-2-oxo-1-phenyl-5-(4-(trifluoromethyl)phenyl)-
2,3-dihydro-1H-imidazole-4-carboxylic Acid Methyl Es-
1
ter (9d). Colorless oil; H NMR (500 MHz, CDCl3) δ 3.58 (s,
3H), 5.38 (s, 2H), 7.04-7.11 (m, 2H), 7.23-7.32 (m, 6H), 7.33-
7.39 (m, 2H), 7.44-7.53 (m, 4H); HRMS m/z 453.1411 [M +
H]+, calcd for C25H20F3N2O3 453.1420.
3-Allyl-2-oxo-1-phenyl-5-(4-(trifluoromethyl)phenyl)-
2,3-dihydro-1H-imidazole-4-carboxylic Acid Methyl Es-
1
ter (9e). Colorless oil; H NMR (500 MHz, CDCl3) δ 3.64 (s,
1
3H), 4.78 (dddt, J ) 1.1, 1.5, 5.5 Hz, 2H), 5.23 (ddt, J ) 10.3,
1.1, 1.5 Hz, 1H), 5.27 (ddt, J ) 16.9, 1.1, 1.5 Hz, 1H), 6.01
(ddt, J ) 16.9, 10.3, 5.5 Hz, 1H), 7.02-7.10 (m, 2H), 7.21-
7.35 (m, 5H), 7.50 (d, J ) 8.1 Hz, 2H); HRMS m/z 403.1263
[M + H]+, calcd for C21H18F3N2O3 403.1264.
93-94 °C; H NMR (600 MHz, CDCl3) δ 1.22 (t, J ) 8.0 Hz,
2H), 3.44 (s, 3H), 4.23 (q, J ) 7, 14 Hz, 2H), 7.35-7.36 (m,
2H), 7.48 (m, 3H); 13C (125 MHz) 14.1, 33.2, 60.4, 121.6, 128.3,
128.6, 129.5, 130.2, 130.3, 140.8, 161.8; HRMS m/z 309.0231
[M + H]+, calcd for C13H13BrN2O2 309.0233.
8834 J. Org. Chem., Vol. 69, No. 25, 2004

Synthesis of Imidazolones and Imidazoles
2-Bromo-5-methyl-1-phenyl-1H-imidazole-4-carboxy-
lic Acid Ethyl Ester (10e). White solid; mp 119-120 °C; 1H
NMR (600 MHz) δ 1.41 (t, J ) 7 Hz, 3H), 2.37 (s, 3H), 4.41 (q,
J ) 7, 14, 2H), 7.23 (m, 2H), 7.56-7.57 (m, 3H); 13C NMR (125
MHz) 11.2, 14.3, 60.4, 120.0, 127.7, 129.6, 129.9, 134.8, 139.2,
162.6; HRMS m/z 299.0186 [M + H]+, calcd for C15H11BrN2
299.0178.
2-Bromo-1,5-diphenyl-1H-imidazole (10n). White solid;
mp 121-123 °C; 1H NMR (500 MHz) δ 7.05-7.07 (m, 2H),
7.19-7.22 (m, 5H), 7.25 (s, 3H), 7.42-7.44 (m, 2H); 13C (125
MHz) δ 121.7, 127.7, 127.8, 128.3, 128.4, 129.1, 129.3, 129.4,
136.3, 136.6; HRMS m/z 309.0232 [M + H]+, calcd for C13H13-
BrN2O2 309.0233.
129.2, 129.4, 129.5, 130.2, 130.5, 132.4, 133.5, 139.5, 147.2,
163.2; HRMS m/z 357.1589 [M + H]+, calcd for C23H20N2O2
357.1597.
1-Methyl-5-phenyl-2-styryl-1H-imidazole-4-carboxyl-
ic Acid Ethyl Ester (11e). Yellow solid; mp 101-102 °C; 1H
NMR (600 MHz, CDCl3) δ 1.22 (t, J ) 7.0 Hz, 3H), 3.51 (s,
3H), 4.26 (q, J ) 7.0 Hz, 2H), 6.94 (d, J ) 16.2 Hz, 1H), 7.31
(t, J ) 7.4 Hz, 1H), 7.35-7.40 (m, 4H), 7.45-7.50 (m, 3H),
7.56 (d, J ) 7.6 Hz, 2H), 7.84 (d, J ) 15.8 Hz, 1H); 13C NMR
(150 MHz, CDCl3) δ 14.2, 31.3, 60.4, 112.7, 127.0, 128.3, 128.7,
128.8, 129.1, 129.3, 129.7, 130.5, 135.2, 136.2, 139.5, 147.0,
163.1; mp 94-96 °C; HRMS m/z 333.1587 [M + H]+, calcd for
C21H20N2O2 333.1597.
General Procedure for the Suzuki Coupling of 2-bro-
moimidazole 10 with Aryl Boronic Acids. Anhydrous
toluene (0.5 mL) was added to a flask charged with 2-bro-
moimidazole 10 (0.1 mmol), aryl boronic acid (0.3 mmol), [Pd-
(dppf)Cl2]‚CH2Cl2 (2.4 mg, 3 mol %), and Cs2CO3 (98 mg, 0.3
mmol) and flushed with argon. The flask was immersed in a
oil bath maintained at 110 °C and stirred for 2 h. After cooling
to room temperature, saturated NaHCO3 (1 mL) was added
to the suspension and extracted with EtOAc (5 mL × 3). The
combined extract was dried over MgSO4, filtered, and concen-
trated in vacuo, and then the residue was purified by prepara-
tive TLC (EtOAc-hexanes) to give the corresponding aryl-
imidazole 11.
1-Methyl-2,5-diphenyl-1H-imidazole-4-carboxylic Acid
Ethyl Ester (11a). White solid; mp 117-118 °C; 1H NMR (600
MHz, CDCl3) δ 1.22 (t, J ) 7.0 Hz, 3H), 3.48 (s, 3H), 4.26 (q,
J ) 7.0 Hz, 2H), 7.42-7.53 (m, 8H), 7.70 (d, J ) 6.5 Hz, 2H);
13C NMR (150 MHz, CDCl3) δ 14.2, 33.4, 60.3, 128.3, 128.5,
129.1, 129.29, 129.33, 129.46, 129.48, 130.0, 130.4, 140.1,
148.4, 163.1; mp 113-115 °C; HRMS m/z 307.1430 [M + H]+,
calcd for C19H18N2O2 307.1441.
1-Methyl-5-phenyl-2-(4-(trifluoromethyl)phenyl)-1H-
imidazole-4-carboxylic Acid Ethyl Ester (11b). White
solid; mp 128-129 °C; 1H NMR (600 MHz, CDCl3) δ 1.21 (t, J
) 7.0 Hz, 3H), 3.51 (s, 3H), 4.26 (q, J ) 7.0 Hz, 2H), 7.42-
7.45 (m, 2H), 7.48-7.54 (m, 3H), 7.75 (apparent d of a AA′BB
system, Jab + Jab′ ) 7.9 Hz, 2H), 7.86 (apparent d of a AA′BB
system, Jab + Jab′ ) 7.9 Hz, 2H); 13C NMR (150 MHz, CDCl3)
δ 14.2, 33.6, 60.4, 123.0, 124.8, 125.50, 125.53, 125.55, 125.57,
128.4, 129.1, 129.4, 129.6, 129.9, 130.4, 131.1, 131.3, 133.4,
140.6, 146.8, 162.9; mp 124-126 °C; HRMS m/z 375.1312 [M
+ H]+, calcd for C20H17F3N2O2 375.1315.
2-Biphenyl-4-yl-1-methyl-5-phenyl-1H-imidazole-4-car-
boxylic Acid Ethyl Ester (11c). White solid; 146-147 °C;
1H NMR (600 MHz, CDCl3) δ 1.23 (t, J ) 7.0 Hz, 3H), 3.52 (s,
3H), 4.27 (q, J ) 7.0 Hz, 2H), 7.38 (t, J ) 7.4 Hz, 1H), 7.44-
7.54 (m, 7H), 7.64 (d, J ) 7.4 Hz, 2H), 7.71 (apparent d of a
AA′BB system, Jab + Jab′ ) 8.3 Hz, 2H), 7.79 (apparent d of a
AA′BB system, Jab + Jab′ ) 8.3 Hz, 2H); 13C NMR (150 MHz,
CDCl3) δ 14.2, 33.6, 60.3, 127.1, 127.2, 127.8, 128.3, 128.8,
128.9, 129.1, 129.5, 129.6, 129.7, 130.5, 140.2, 140.3, 142.0,
148.1, 163.1; mp 122-124 °C; HRMS m/z 383.1743 [M + H]+,
calcd for C25H22N2O2 383.1754.
2-(4-Methoxyphenyl)-5-methyl-1-phenyl-1H-imidazole-
4-carboxylic Acid Ethyl Ester (11f). Brown solid; mp 127-
129 °C; 1H NMR (600 MHz, CDCl3) δ 1.43 (t, J ) 7.0 Hz, 3H),
2.39 (s, 3H), 3.75 (s, 3H), 4.44 (q, J ) 7.0 Hz, 2H), 6.71
(apparent d of a AA′BB system, Jab + Jab′ ) 8.8 Hz, 2H), 7.15-
7.18 (m, 2H), 7.27-7.30 (m, 2H), 7.46-7.49 (m, 3H); 13C NMR
(150 MHz, CDCl3) δ 11.1, 14.6, 55.2, 60.4, 113.4, 122.3, 128.0,
128.8, 129.2, 129.8, 130.2, 136.6, 137.9, 146.8, 159.8, 164.2;
HRMS m/z 333.1541 [M + H]+, calcd for C20H20N2O3 337.1547.
2-(4-(Ethoxycarbonyl)phenyl)-5-methyl-1-phenyl-1-
phenyl-1H-imidazole-4-carboxylic Acid Ethyl Ester (11g).
White solid; mp 93-94 °C; 1H NMR (600 MHz, CDCl3) δ 1.36
(t, J ) 7.0 Hz, 3H), 1.44 (t, J ) 7.0 Hz, 3H), 2.42 (s, 3H), 4.33
(q, J ) 7.0 Hz, 2H), 4.45 (q, J ) 7.0 Hz, 2H), 7.17-7.20 (m,
2H), 7.44 (d, J ) 8.3 Hz, 2H), 7.48-7.52 (m, 3H), 7.87 (d, J )
8.3 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 11.1, 14.3, 14.5,
60.5, 61.1, 127.8, 128.5, 129.2, 129.5, 129.6, 130.0, 130.2, 133.7,
136.2, 138.8, 145.7, 163.8, 166.1; mp 78-81 °C; HRMS m/z
379.1643 [M + H]+, calcd for C22H22N2O4 379.1652.
2-[4-(tert-Butyldimethylsilanoxy)phenyl]-5-methyl-1-
phenyl-1H-imidazole-4-carboxylic Acid Ethyl Ester (11h).
Brown solid; mp 58-63 °C; 1H NMR (600 MHz, CDCl3) δ 0.13
(s, 6H), 0.93 (s, 9H), 1.43 (t, J ) 7.0 Hz, 3H), 2.40 (s, 3H), 4.43
(q, J ) 7.0 Hz, 2H), 6.65 (apparent d of a AA′BB system, Jab
+ Jab′ ) 8.8 Hz, 2H), 7.15-7.18 (m, 2H), 7.22 (apparent d of a
AA′BB system, Jab + Jab′ ) 8.8 Hz, 2H), 7.44-7.47 (m, 3H);
13C NMR (150 MHz, CDCl3) δ -4.5, 11.1, 14.6, 18.2, 25.61,
60.4, 119.8, 123.0, 127.9, 128.8, 129.2, 129.7, 130.2, 136.5,
137.8, 146.9, 156.1, 164.2; mp 88-90 °C; HRMS m/z 437.2248
[M + H]+, calcd for C25H32N2O3Si1 437.2255.
1,2,5-Triphenyl-1H-imidazole (11i). White solid; mp 247-
248 °C; 1H NMR (600 MHz, CDCl3) δ 7.06-7.12 (m, 4H), 7.18-
7.28 (m, 6H), 7.32-7.40 (m, 6H); 13C NMR (150 MHz, CDCl3)
δ 127.4, 128.1, 128.21, 128.27, 128.29, 128.30, 128.5, 128.6,
128.8, 129.4, 129.8, 130.6, 135.1, 137.2, 148.0; mp 237-239
°C; HRMS m/z 297.1379 [M + H]+, calcd for C21H16N2 297.1386.
Acknowledgment. We gratefully acknowledge fi-
nancial support from The Scripps Research Institute,
The Skaggs Institute for Chemical Biology, and Novartis
Pharma AG. We also thank Drs. Carsten Spanka and
Ju¨rgen Hinrichs (Novartis Pharma AG) for helpful
discussions.
1-Methyl-2-naphthalen-1-yl-5-phenyl-1H-imidazole-4-
carboxylic Acid Ethyl Ester (11d). Brown oil; 1H NMR (600
MHz, CDCl3) δ 1.25 (t, J ) 7.0 Hz, 3H), 3.23 (s, 3H), 4.29
(q, J ) 7.0 Hz, 2H), 7.46-7.55 (m, 7H), 7.57 (t, J ) 7.9
Hz, 1H), 7.65-7.70 (m, 2H), 7.90-7.94 (m, 1H), 7.98 (d, J )
8.3 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 14.3, 32.6,
60.3, 125.1, 125.2, 126.3, 127.1, 127.6, 128.3, 128.5, 129.1,
Supporting Information Available: 1H NMR spectra for
all novel compounds 3-11. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO048353U
J. Org. Chem, Vol. 69, No. 25, 2004 8835